Cell Injury and Inflammation

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True or false: all anthracyclines cause tissue necrosis if extravastated: true
Name the top 3 cancers in women by incidence. Name by death rates.: By incidence 1. breast 2. lung 3. colorectal Name by death rates 1. lung 2. prostate 3. colorectal
Prostate cancer likes to metastasize to the ____.: -bone -not well understood
Name 2 cancers that like to invade veins during hematogenous metastasis.: 1. renal cell carcinoma -invades renal vein 2. hepatocellular carcinoma
What 2 organs are the frequent sites of hematogenous metastasis?: 1. liver 2. lung
Name the top 3 cancers in men by incidence. Name by death rates.: By incidence 1. prostate 2. lung 3. colorectal by death rates 1. lung 2. prostate 3. colorectal
Name four cellular adaptations to stress: 1. Hypertrophy 2. Hyperplasia 3. Atrophy 4. Metaplasia
What is the progression of irreverisble cell injury as duration of injury increases?: 1. cell death 2. ultrastructural changes (minutes) 3. light microscopy changes (hours) 4. gross morphologic changes (days)
When does cellular injury occur?: 1. When adaptive capability of cell to respond to stress is exceeded 2. external stress is inherently harmful
Define hypertrophy: hypertrophy =increase in cell size -can be physiologic or pathologic
Define Hyperplasia: =increase in cell number -can also be physiologic or pathologic -occurs in cells capable of replication
Define atrophy: =shrinkage in size of cell by loss of cell substance -cells may have diminished fxn but are NOT dead
What are the causes of atrophy?: 1. Decreased workload 2. loss of innervation 3. loss of endocrine stimulation 4. aging
Define Metaplasia: =reversible change in which one adult cell type is replaced by another adult cell type
What are some examples of hyperplasia?: 1. Gingival hyperplasia 2. Breast hyperplasia during pregnancy
What are some examples of hypertrophy?: 1. Cardiac muscle hypertrophy due to hypertension 2.Myostatin -block this growth factor that limits muscle growth --> increased muscle mass 3. Fat cell hypertrophy -from excess calories 4. Endometrial hypertrophy -changes in SM cells in pregnant uterus
What are the cellular characteristics of an atrophied cell?: 1. decreased cell size 2. decreased cellularity 3. decreased interstitial substance
What are some causes of metaplasia?: 1. Cigarette smoking 2. Vit. A deficiency 3. Chronic gastric reflux 4. Injury => results in genetic "reprogramming" of stem cells -if causes of metaplasia persist, may predispose to malignant transformation of the epithelium
What are the 2 types of cell death?: 1. Necrosis 2. Apoptosis
Define necrosis: =series of changes that accompany cell death, resulting from degradative action of enzymes on injured cells -always due to pathologic cell injury =gross irreversible cell injury due to disease process -DNA looks smudged -accompanied by inflammatory rxn -passive cell death not requiring gene expression or new protein synthesis
What are the features of necrosis?: 1. enlarged cell (swelling) 2. Nuclear changes (pyknosis -> karyorrhexis -> karyolysis) 3. Disrupted plasma membrane 4. Enzymatic digestion of cellular contents (may leak out of cell) 5. frequently associated with inflammation 6. always pathologic
Define apoptosis: =active, energy-dependent, tightly regulated type of cell death -involves gene expression and new protein synthesis -can be physiologic (development) or pathologic -protects against neoplastic transformation -DNA frgamentation looks "laddered" -no inflammatory rxn -cytoplasm shrinks, chromatin condenses and neatly chopped up -cell fragmented into apoptotic bodies
What are some of features of apoptosis?: 1. Reduced cell size 2. Chopping up of DNA in nucleus 3. Intact plasma membrane 4. Intact cellular contents 5. No adjacent information 6. can be physiologic or pathologic
Define dysplasia: =change to an abnormally differentiated form
Define anaplasia: =loss of differentiation
What are some causes of cell injury?: 1. oxygen deprivation (hypoxia, ischemia) 2. chemical agents 3. infectious agents 4. immunologic rxns 5. genetic defects 6. nutritional imbalances 7. physical agents 8. aging
What is the difference between hypoxia and ischemia?: hypoxia= O2 deficiency -can have a variety of causes including ischemia -common cause of cell death ischemia=O2 def. caused by loss of blood supply to a tissue b/c of -impeded arterial flow -reduced venous drainage
What are 2 morphological changes that can be associated with reversible cell injury?: 1. cellular swelling -failure of energy-dependent ion pumps in membrane -> not able to maintain ionic,fluid balance -usu. 1st morphologic change seen with injury 2. fatty change -seen in cells involved in fat metabolism (hepatocytes, myocardial cells)
What are some morphologic features of necrosis?: 1. increased eosinophilia 2. myelin figures -whorled phospholipid masses that can replace dead cells 3. calcification
Define pyknosis: =condensation of DNA in a nucleus -change in cells undergoing necrosis
Define karyorrhexis: = fragmentation of the condensed DNA in the nucleus of a cell undergoing necrosis -subsequently nucleus of cell disappears
What are some of the morphologic patterns of necrosis?: 1. Coagulative necrosis 2. Liquefactive necrosis 3. Gangrenous necrosis 4. Caseous necrosis 5. Fat necrosis 6. Fibrinoid necrosis
Define coagulative necrosis: =cell components are dead but cell outline survives -results in eosinophilic, anucleate cells -eventually cleared by phagocytes -results from ischemia to organ esp. heart, kidney -also see nuclear changes (irreversible cell injury)
Coagulative necrosis is characteristic of infarcts in all organs except the...: brain
Define liquefactive necrosis: =rapid dissolution of necrosed cells ->soup of liquefied tissue -seen in: 1. Brain (infarcts) 2. Pancreas (b/c lots of digestive enzymes) -secondary to ischemia or purulent (pus-forming) infections
Define caseous necrosis: =discrete necrotic foci full of fragmented or lysed cells -cheese-like -cell outlines do NOT survive -ex. granuloma -often seen with TB infection -shows combined features of coagulative and liquefactive necrosis but not liquefied
Define fat necrosis: =focal areas of fat destruction (leaving chalky white deposits) -seen with acute pancreatitis -digestive enzymes leaked out of pancreas and chew up fat of peritoneum
Define fibrinoid necrosis: =special form of necrosis seen with immune rxns involving blood vessels (vasculitis) -deposits of Ag-Ab complexes on walls of arteries -complexes stain along with leaked fibrin to give pink, amorphous appearance
What are some mechanisms of intracellular accumulations and examples of each?: 1. Abnormal metabolism -fatty liver 2. Defect in protein folding, transport -Wilson's disease (can't pump out copper) 3. Lack of an enzyme -Tay Sachs 4. Ingestion of indigestible materials -iron overload
What are some organs in which cellular hypertrophy is a common adaptive process?: 1. Skeletal muscle 2. Adipose tissue
What is the difference between necrosis and apoptosis?: -apoptosis is due to a programmatic change (normal or pathologic) -necrosis is due to a disease process -differences on a number of morphological changes (cell size, plasma membrane changes, nuclear changes)
How does alcohol cause fat accumulation in liver cells?: -alcohol alters mitochondrial and SER fxn and inhibit fatty acid oxidation -metabolic rate is inadequate to remove fats -excess accumulatio of TGs in liver cells
Define ischemia-reperfusion injury: =when restoration of blood flow to a normally viable tissue affected by ischemia results in exacerbated injury
What are the mechanisms of ischemia-reperfusion injury?: 1. increased generation of ROS during reoxygenation 2. inflammation b/c of increased influx WBCs and plasma proteins
What are some intracellular changes associated with cell injury?: 1. ATP depletion 2. Mitochondrial damage 3. Influx of calcium 4. Accumulation of ROS 5. Increased permeability of cellular membranes 6. accumulation of damaged DNA and misfolded proteins
What is lipofuscin?: =an endogenous pigment of insoluble brownish-yellow granular intracellular material -accumulates in variety of tissues with age/atrophy -doesn't injure the cell but is a marker of past free radical injury
Define hemosiderin: =hemoglobin-derived pigment (yellow-brown) -accumulates in tissues where there is iron overload -cells not irreversibly injured
What are some causes of hemosiderosis?: =deposit of hemosiderin in tissues due to iron overload 1. hemachromatosis (genetic defect) 2. multiple blood transfusions
Define pathologic calcification: =abnormal deposition of calcium salts and other minerals -occurs in many disease states -2 types of calification (dystrophic and metastatic)
What are the 2 types of pathologic calcification?: 1. dystrophic -deposition at sites of cell injury and necrosis 2. metastatic -deposition into normal tissues (usu. caused by hypercalcemia)
What are some of the cellular consequences of ischemia?: 1. Reduced generation of ATP (aerobic and anaerobic pathways knocked out) -results in: 1. failure ion pumps --> swelling 2. depletion glycogen, accumulate lactic acid -> lower
Define acute inflammation: =rapid response to injury or other microbes or foreign material that is designed to deliver leukocytes and plasma proteins to site of injury -involves both: 1. vascular changes 2. cellular events
What are the symptoms of acute inflammation?: 1. Heat 2. Swelling 3. Redness 4. Pain
What are the stimuli for acute inflammation?: 1. infections 2. trauma, physical, and chemical agents 3. tissue necrosis 4. foreign bodies 5. immune reactions
Described the vascular changes in acute inflammation: 1. vasodilation Transient vasoconstriction -> arterial vasodilation -> capillaries engorged ->redness and warmth 2. increased vascular permeability -RBCs accumulate -> stastis -> neutrophils accumulate on walls (margination)
Compare transudate vs exudate: transudate = released ultrafiltrate of blood plasma -comes out of capillaries 1st at site of acute inflammation exudate= contains proteins and cells -comes out after increased vascular permeability -comes out 2nd -results in edema
What are the mechanisms of increased vascular permeability in acute inflammation?: 1. endothelial cell contraction 2. endothelial injury 3. leukocyte-mediated endothelial injury 4. increased transcytosis 5. leakage from new blood vessels
Describe the response of lymphatics to acute inflammation.: 1. increase lymph flow 2. Removal of fluids, cell, debris 3. lymphangitis 4. lymphadenitis 5. lymph vessels undergo hyperplastic expansion
Compare lymphangitis vs lymphadenitis: lymphagitis= secondary inflammation of lymph vessels lymphadenitis= secondary inflammation of lymph nodes
Name the stages of leukocyte recruitment.: 1. Capture of leukocyte on endothelium -mediated by selectins 2. rolling -mediated by selectins and integrins 3. slow rolling 4. firm adhesion 5. transmigration
Name 3 types of selectins and what kinds of cells they are found on: 1. P selectins -activated platelets -endothelial cells 2. L-selectins -leukocytes 3. E. selectin -on activated endothelial cells -impt for mediating capture, rolling of leukocytes in their recruitment to sites of acute inflammation -induced by IL-1 and TNF
Define VLA-4: =integrin impt for leukocyte recruitment -found on leukocytes -binds to VCAM1 on endothelial cells -contains binding sites for Mg and Ca (needed for adhesive fxn)
What types of leukocytes arrive first on site of acute inflammation?: 1. neutrophils -later, macrophages/monocytes
What kinds of stimuli cause leukocyte activation?: 1. LPS/bacterial/viral peptides --> bind TLR 2. bacterial peptides/chemokines -> GPCRs 3. also signals to cytokine Rs, phagocytic Rs
What are the steps involved in phagocytosis?: 1. Attachment and binding of particle to receptors on leukocyte surface 2. engulfment and fusion of phagocytic vacuole with granules 3. Destruction and ingested particles by iNOS, ROS
When does leukocyte-induced tissue damage occur?: 1. difficult to erradicate microbes 2. normal attempt to clear damaged tissue 3. inflammmatory repsondse directed against host tissue -once activated, leukocytes can't distinguish pathogen and host -release of lysosomal enzymes, ROS cause host tissue damage
Name some acute inflammatory disorders.: 1. Acute respiratory distress syndrome 2. Acute transplant rejection 3. Asthma 4. Glomerulonephritis 5. Septic shock 6. Vasculitis
What are some causes of defects in WBC fxns?: 1. Acquired -> Suppression of BM -chemo/radiation -metabolic disease (diabetes) 2.Genetic LAD-1, LAD-2, chronic granulomatous disease, MPO deficiency, Chedik-Higashi syndrome
What are some of the outcomes of acute inflammation?: 1. Resolution 2. Tissue destruction and persistent acute inflammation -abscesses, ulcer, fistula, scar 3. Conversion to chronic inflammatin
What are the key events in resolution of acute inflamamation?: 1. Phagocytes clear necrotic tissue and microbes 2. Fluids and proteins are removed by lymphatic drainage 3. Growth factor stimulate new vessel formation and fibroblasts repair ECM
Name some morphologic patterns in acute inflammmation.: 1. serous inflammation 2. fibrinous inflammation 3. suppurative (purulent) inflammation 4. ulceration
Define serous inflammation: =characterized by outpouring of a protein-poor fluid derived from serum or secretions of mesothelial cells lining body cavities. -effusion=fluid in a serous cavity
Define fibrinous inflammation.: Results from more serious injury that allows large molecules (ex. fibrinogen) to pass through endothelium
Fibrinous exudate characteristic for:: =inflammation in lining of body cavities -meninges -pericardium -pleura
Define suppurative (purulent) inflammation: =full of pus pus= neutrophils, necrotic cells, edema fluid
Define ulcer: =local surface defect on organ or tissue -produced by 1. necrosis of cells 2. sloughing off of inflammatory necrotic tissue
Cell-derived mediators of inflammation include:: 1. Vasoactive amines 2. arachadonic acid metabolites 3. platelet activating factor 4. cytokines 5. ROS 6. Nitric oxide 7. lysosomal enzymes of leukocytes 8. neuropeptides
Name 2 vasoactive amines: 1. histamines 2. serotonin
What are stimuli for histamine release?: -released from mast cells 1. physical injury 2. immune reactions 3. C3a and C5b 4. leukocyte-derived histamine releasing proteins 5. substance P 6. certain cytokines
In what inflammatory cell type is serotonin found?: 1. platelets -serotonin gets released during platelet activation
What is the role of arachadonic acid metabolites in acute inflammation?: -derived from dietary linoleic acid -2 metabolic pathways 1. Cyclooxygenase (PGs, TXA2) -cause pain, vascular changes 2. Lipoxygenase (leukotrienes) -cause vasodilation, chemotaxis, leukocyte adhesion
What is the role of PAF in acute inflammation?: =platelet activating factor 1. stimulate platelet aggregation 2. very potent vasodilator 3. has broad spectrum of inflammatory effects
Define Hageman factor: =coagulation factor XII; plasma protein-derived -activation of 4 systems 1. clotting cascade 2. kinin cascade -proinflammatory properties 3. fibrinolytic system -limits clotting 4. complement cascade -impt for host defense -also pro-inflammatory -able to cause serious tissue damage
Define chronic inflammation: =inflammation of prolonged during (weeks-years) in which active inflammation, tissue injury, and healing proceed simultaneously
Chronic inflammation is characterized by:: 1. Infiltration with mononuclear cells (macrophages, lymphocytes, plasma cells) 2. Tissue destruction -caused by products of inflammatory cells 3. Repair, angiogenesis, fibrosis
When do you get chronic inflammation?: -when acute inflammation is not resolved. Could be due to: 1. persistence of injurious agens 2. something interfering with normal healing process
Which of these does NOT involve chronic inflammation? 1. peristent infections 2. athlerosclerosis 3. autoimmune diseases 4. prolonged exposure to toxic agent (ex. silica) 5. They all are associate with chronic inflammation: They are all associated with chronic inflammation
True or false: macrophages are the dominant cell type in chronic inflammation: true
What changes happen when a macrophage gets activated?: 1. increased cell size 2. increased lysosomal enzymes 3. more active metabolism 4. greater ability to kill phagocytosed organisms
What are some activation signals to macrophages?: 1. bacterial endotoxin (LPS) 2. other microbial products 3. IFNgamma, other cytokines from sensitized T cells 4. chemical mediators of acute inflammation
What are some of the products secreted by activated macrophages?: 1. ROS and NO 2. acid and neutral proteases 3. arachadonic acid metabolits (eicosanoids) 4. cytokines (IL-1, TNF) 5. Growth factors -stimulate fibrosis, angiogenesis -if macrophages allowed to continuously secrete they can cause tissue injury and inflammation through many of the secretory products
True or false: plasma cells are involved in chronic inflammation: true
Describe how T cells and macrophages have a bidirectional relationship in chronic inflammation: Macrophage: -display antigen to T cells -express cotsim. molecules -produce IL-12 T cells: -produce cytokines (IFN gamma) that promote macrophage activation -this bidirectional activation prolongs chronic inflammation
True or false: Neutrophils are not found in chronic inflammation: False. can still be found in infiltrates even though neutrophils hallmark for acute inflammation
Define granulomas: =discrete mass containing aggregates of: 1. activated macrophages 2. ring of lymphocytes 3. +/- giant cells (multiple fused macrophages) 4.central zone of necrosis -granuloma walls off infectious agent or foreign body
What are some diseases that can have granulomatous inflammation?: 1. TB 2. leprosy 3. syphilis 4. cat-scrath disease -gram neg. bacillus 5. sarcoidosis -unknown etiology 6. Crohn disease
What are the inflammatory chemical mediators of vasodilation?: 1. NO 2. prostaglandins
What are the inflammatory chemical mediators of increased vascular permeability?: 1. vasoactive amines 2. C3a and C5a -induce release vasoactive amines 3. Bradykinin 4. LTC4, LTD4, LTE4 5. Platelet activating factor
What are the inflammatory mediators of chemotaxis and leukocyte activation?: 1. C5a 2. LTB4 3. Bacterial products 4. chemokines (IL-8)
What are the inflammatory mediators that cause fever?: 1. Il-1, Il-6, TNF 2. prostaglandins
What are the chemical inflammatory mediators that cause pain?: 1. Prostaglandin 2. bradykinin
What are the chemical inflammatory mediators that can result in tissue injury?: 1. Neutrophil and macrophage lysosomal enzymes 2. Oxygen metabolites 3. NO
Define granulation tissue: =proliferation of: 1. capillaries 2. fibroblasts 3. inflammatory cells -this is the start of repair by connective tissue and eventually gets replaced by fibrous tissue -appears by 3-5 days -pink (b/c of new vessels), loose ECM -progressively accumulates connective tissue
True or false: an abscess is a form of chronic inflammation: true -main component in abscess is neutrophils
Name 2 ways tissues can be healed:: 1. regeneration -with complete restoration of function and form 2. replacement with connective tissue, scar formation
Name 4 major components of connective tissue repair: 1. angiogenesis 2. migration & proliferation of fibroblasts 3. collagen synthesis 4. connective tissue remodeling
Describe angiogensis in tissue repair.: -capillary sprouting from pre-existing vessels -can involve endothelial precursor cells from BM -VEGF very impt -> increased permeability -vasodilation by NO -newly formed vessels are leaky -as scar matures, there is vascular regression
Describe the process of scar formation.: -starts w/granulation tissue 1. migration and proliferation of fibroblasts to site of injury 2. Deposition of ECM by these cells -as scar matures, progressive vascular regression -accumulation of collagen contributes strength to healing wound
Name some critical factors in wound healing: 1.Vit C 2. adequate blood supply 3. lack of infection 4. profound anemia inhibits wound healing 5. severe protein deficiency inhibits 6. Lack of amino acids w/sulfur inhibits 7. Extreme old age inhibits 8. Chronic autoimmune disease inhibits 9. Diabetes mellitus inhibits 10. Zinc, glucocorticoids, ACTH, T3, T4, and growth hormone all necessary
Why is Vitamin C an important factor for wound healing?: -b/c it aids in cross-linking of collagen -scurvy-> get poor wound healing
Describe collagen synthesis in wound healing: -Fibroblasts make stimulated by FGF make and secrete tropocollagen -tropocollagen polymerizes in ECM -collagen polymers are dissolved by enzymes from macrophages -repetition of process causes fibers to build up along lines of stress -new collagen has 80% of original strength, not as flexible
What 2 factors affect collagen synthesis: 1. Vitamin C -needed for cross-linking -reduces strength of scar 2. Protein deficiency -delays rate of collagen synthesis
Name the important steps in angiogenesis: 1. Proteolysis of ECM 2. Endothelial migration and chemotaxis 3. Endothelial proliferation 4. lumen formation, maturation, inhibition of growth -includes recruiting pericytes and SM cells 5. increased permeability through gaps and transcytosis -deposition of plasma proteins (fibrinogen) -transcytosis of fibroblasts
Describe re-epithelialization: -new epithelium grows over healing wound -stimulated by PDGF from platelets and macrophages -not all tissues require new epithelium
Compare healing potential of liver and heart: Live -able to regenerate by production of new, functional cells Heart -cannot regenerate damaged tissue -heal by making fibrotic scar
Does cortisone have an effect on wound healing: Yes -decreased protein synthesis -decreased capillary budding -decreased fibroblast growth -wound healing delayed but not stopped
Does aspirin have an effect on wound healing?: No significant effects
Does cytotoxic chemotherapy have an effect on wound healing?: less than we would expect for the doses we use -however, it must have some effect since chemotherapy usu. postponed until 6 weeks postsurgery
Describe the biochemical process of healing a bleeding wound: 1. bleeding and clotting produces fibrin matrix 2. clot is cross-linked by factor XIII; fibronectin linked to fibrin 3. PDGF stimulates fibroblasts 4. More fibronectin made by macrophages 5. As fibronectin cross-linked to fibrin, makes chemotactic pathway for fibroblasts-> fibroblasts crawl along and drag wound edges -> wound contraction 6. Fibroblasts synthesize type III collagen onto fibronectin
What are some changes to the skin with the formation of cutaneous scars?: 1. lose papillal-dermal ridges 2. lose sweat glands
Why does Diabetes mellitus result in poor wound healing: -b/c of problems with blood vessels and lack of perfusion of tissue -this reduces ability to deliver inflammatory cells to site of injury
Define TGF-beta: =growth factor involved in ECM deposition and scar formation -binds to cell surface R with serine/threonine kinase activity ->phosphorylation of transcription factors -involved also in fibrosis formation in chronic inflammation
Describe some of the actions of TGF-beta: 1. stimulates production of collagen, fibronetin, proteoglycans -inhibits collagen degredation -inhibits lymphocyte proliferation -anti-inflammatory
Define PDGF: =platelet-derived growth factor =growth factor involved in ECM deposition and scar formation -sources 1. activated platelets 2. endothelial cells 3. activated macrophages 4. SM cells 5. tumor cells -chemotactic for migration of fibroblasts and SM cells and promotes their prolif. -also chemotactic for monocytes
Name some functions of PDGF: 1. Monocyte chemotaxis 2. fibroblast migration 3. fibroblast proliferation 4. Collagen synthesis 5. Collagenase secretion
Name some functions of TGF beta: 1. monocyte chemotaxis 2. fibroblast migration 3. collagen synthesis 4. inhibit collagenase secretion
Describe tissue remodeling in wound healing: -scar ECM continues to be remodeled after deposition through both ECM synthesis and degredation -degredation by matrix metalloproeinases (zinc dependent)
Compare wound healing by first intention vs second intention: first intention -healing of clean surgical incision; involves sutures second intention -no suturing; wound heal by contraction, granulation tissue, and new epithelium
What are the key features of wound healing by second intention: 1. more intense inflammatory rxn 2. lots of granulation tissue formed 3. myofibroblasts contract the wound -then you get accumulation of ECM and BIG scar (vs little scar with 1st intention)
How does infection influence wound repair?: 1. prolong inflammation phase (1st phase in wound healing) 2. potential to increase local tissue injury
Define a keloid: =raised scar caused by excess collagen deposition in the skin -genetic predisposition common in African Americans
Name 3 chronic inflammatory diseases that have associated fibrosis: 1. rheumatoid arthritis 2. chirrosis 3. pulmonary fibrosis -chronic inflammation causes persistent stimulation of collagen synthesis -> results in fibrosis
What are the 2 complement pathways?: 1. Classical -complement activated by antibodies 2. Alternate -complement activated by spontaneous hydrolysis of C3 and C3B subsequently stabilized by foreign cells -C3 provides linkage point between classical and alternate pathways
Which antibodies can fix complement?: 1. IgM (only need 1) 2. IgG (IgG-1, IgG-3) -need 2 adjacent molecules
What are the major actions of C3b?: 1. opsonin -marks stuff for phagocytosis 2. If binds near C42, can create a new complex that digests C5
What are the major actions of C5a?: 1. major chemotactic factor for leukocytes 2. increased vascular permeability 3. increase inflammation
Name 3 molecules that can down-regulate the complement cascade: 1. C1 inhibitor (C1INH) -prevents C1r and s from activating themselves spontaneously 2. C4 binding protein (C4bp) -competes with C2a for binding to C4b 3. I -digests C4b into inactive components -people with no I-> C3 deficient -> recurrent infections
How does lack of DAF and MCP-CD59 cause paroxysmal nocturnal hemoglobinuria?: sleep->slow breathing ->slightly acidic -> favors formation of C3b on cells on RBCs -> potential for lysis -DAF and MCP-CD59 normally prevent by interacting with C4b and C3b to prevent activation of rest of pathways and lysis -lack of these, RBCs can lyse in sleep
Which bacteria are resistant to the alternate pathway?: -resistant to alternate pathway b/c express sialic acid -more pathogenic in newborns 1. group B strep type III 2. Group B and C Neisseria meningitidis 3. E. Coli K1
Name the inhibitory activities of C1INH: =C1 Inhibitor 1. Inhibits blood clotting factor XII 2. Inhibits plasmin 3. Inhibits kalikrein 4. Inhibits C1 activities
Describe the pathophysiology of hereditary angioneurotic edema (HANE): -lack C1INH ->C1 can be spontaneously activated -chronic spontaneous activation of complement C2a, C4a -C2a cleaved by plasmin-> product increases vascular permeability and swelling
Do you get itching in HANE?: No-b/c no mast cells involved -only get swelling b/c of complement activation
True or false: active C3b or C4b can lyse host cell if accidentally becomes bound to its surface instead of pathogen: true -this is limited by rapid hydrolysis of C3b and C4b
Define hereditary angioneurotic edema: 1. due to genetic deficiency of C1INH 2. Presentation: 1. recurrent episodes of swelling of skin, intestines, airway
What are some of the triggers of episodes of HANE: 1. trauma 2. menstrual periods 3. excessive exercise 4. exposure to extremem temp 5. mental stress
Describe pathophysiology of HANE: -triggers associated with activation of serine proteases normally inhibited by C1INH -kallikrein forms bradykinin -plasmin -> C1-> C2-> C2a kinin -BK and C2a kinin increase postcapillary venules by contraction of endothelial cells -> edema
What are the 3 major characteristics of the adaptive immune system?: 1. High antigen specificity -from unique recombination and expression of B and T celll receptors 2. Tolerance 3. Memory
How does the adaptive immune system achieve tolerance?: =via specific processes to remove or kill self-reactive cells during T and B cell development 1. central tolerance -in primary lymphoid organs 2. peripheral tolerance -in secondary lymphoid tissues
CD4+ T cells are: TH (helper T cells) fxn=mediate responses via secreted cytokines or surface costim proteins
CD8+ T cells are: cytotoxic T cells -fxn=kill cells by secreted perforins/granzymes
Contrast microbes and parasites: microbes=small enough to be phagocytosed (bacteria, viruses, single-cell protozoa) parasites-some are too large to be eaten by phagocytes
Can B cells act as APCs?: yes. =when Ag bound to BCRs is presented on MHC for a few hours
Define leukocytes: =immune cells, WBCs -lymphocytes (B and T cells, NK cells) + myeloid cells (eosinophil, neutrophil, macrogphage, DC, mast cell)
Primary lymphoid organs include: 1. bone marrow 2. thymus
Secondary lymphoid organs include: 1. lymph nodes 2. spleen white pulp 3. MALT
True or false: 2/3 of circulating leukocytes are neutrophils: -true -neutrophils are: 1. first to extravasate to inflamed tissue 2. live 1-3 days in tissue
What immune cell type is most important for defense against extracellular bacteria?: =phagocytes (neutrophils, macrophages)
What immune cells are important against virally-infected cells: 1. NK cells -innate lymphocyte cells
What immune cells are important for defense against parasites?: 1. eosinophils
Where do naive, mature B and T cells get activated?: =secondary lymphoid tissues (lymph nodes, white pulp of spleen, MALT) -Activation results in: 1. clonal expansion (days) 2. generate effector cells (deal with pathogen) and memory cells (for better response next time)
How long does it take antigen-specific adaptive effector cells to differentiate?: -about a week
What are the sources of antigen to activate naive, mature T cells? B cells?: T cells -DC migrate to lymph node, present Ag on MHC and costim proteins B cells -pathogen fragments wash into B cell follicles in lymph nodes
Where are the antigen binding sites on BCRs and TCRs?: 1. antigen binding sites are created by 2 N terminal variable domains
Describe BCRs: =transmembrane antibodies -made up of 2 heavy chains and 2 light chains -stick in membrane by C terminal domain -both heavy and light chains have variable domains on N terminus
Contrast the BCRs on naive B cells vs memory cells: BCRs=transmembrane antibodies Naive B cells -IgM and IgD Memory cells -IgG, IgA, IgE
Define isotype switching: -antibodies are named by the heavy chain constant domain =DNA recombination between HC constant domain in clonally-expanding B cells w/in germinal center -result: swithcing to a different isotype changes the effector fxns of secreted antibodies
What do TCRs recognize?: ONLY processed peptides displayed in MHC proteins on a cell surface -vs B cells can recognize portions of the surface on an antigen
What do BCRs recognize?: =portions of surface of an antigen 1. cluster of AAs 2. sugars 3. nucleic acids 4. organic molecules -ex penicillin
Define MHC: =major histocompatibility complex =proteins specialized to display processed peptides to TCRs on T cells -2 classes: MHC I and MHC II
Describe MHC I: -found on ALL nucleated cells -3 MHC I isotypes in humans impt for Tc reponses=HLA-A, HLA-B, HLA-C -fxn: display intracellular peptides to CD8+ Tc cells
Describe MHC II: =found on DC, macrophages, B cells, thymic epithelial cells -3 isotypes: HLA-DP, HLA-DQ, HLA-DR -fxn: display endocytosed peptides to CD4+ helper T cells
True or false: immature DC anergize naive T effector cells ONLY to provide peripheral tolerance: False -they also anergize naive helper T cells
True or false: only TH2 helper cells help activate B cells: False -TH1 cells can also activate B cells, TH2 just better at it -TH1 cells also help activate CD8+ Tc cells -in peripheral tissues, effector TH1 can hyperactivate macrophages
What is the general path of recirculation of naive B and T cells: -in the blood -enter secondary lymphoid organs (lymph nodes,white pulp of spleen, tonsils and MALT) -exit blood and enter secondary lymphoid tissue -usually return to blood via efferent lymphatic (nodes) or vein (spleen)
Name some types of receptors found on macrophages: 1. pathogen receptors (ex TLRs) 2. phagocytic receptors 3. MHC I and MHC II 4. cytokine Rs
True or false: TLRs are found on neutrophils: -false -TLRs are found on macrophages, but no neutrophils
What are some examples of bacterial or viral cellular components that TLRs recognize?: 1. dsRNA (viral) 2. LPS 3. flagellin 3. DNA rich in unmethylated CpG dinucleotides
Name 3 general effects of inflammatory cytokines: 1. cause symptoms of inflammation 2. recruit circulating reserves to site of inflammation 3. initiate antigen delivery
Name the most important chemokine/chemotaxin for neutrophils: =CXCL8 -secreted by macrophages -expressed by neutrophils
Which chemokines vasodilate arterioles, open endothelial tight jxns, and vasoconstrict venules: =TNF, HM, PG, LT -increase blood flow and make easier for immune cells and plasma proteins to get to site of infection -result in inflammatory symptoms
How do immature DC cells get activated?: =constantly phagocytosing stuff around them -displaying self peptides at low levels -pathogen fragments released by neutrophils, mac bind DC R--> activate -activate DC upregulate B7, upregulate MHC I and II (display Ag), migrate to lymph nodes to present Ag to naive T cells
How does naive T cell get activated?: By mature DC in lymph node -need protein interactions and IL-2
What are the protein interactions in activation of naive T cell by DC?: 1.TCR binds peptide in MHC II 2. T cell CD4 binds to MHC II 3. T cell CD28 binds B7 (costim on DC)
What stimulates clonal expansion of naive T cell? (3 signals): 1. Antigen specific recognition -TCR 2. costim protein (B7 on DC binds CD28 on T cell) 3. IL-2
Where does the IL-2 in T naive T cell activation/clonal expansion come from: from the activated T cell itself (acts in autocrine fashion--secrete IL-2 that binds to its own IL-2 Rs)
What causes TH1 vs TH2 to be produced during clonal expansion of activated T cell?: Biases to produce TH1 cells 1.high freq. Ag presentation 2. IL-12 -promotes TH1 diff. 3. IFN gamma -inhibits TH2 prolif.
What does IL-10 do?: -secreted by TH2 cells -fxn: inhibit TH1 differentiation
Both TH1 and TH2 cells do all of the folowing EXCEPT: 1. express CD40 ligand 2. secrete IL-3 3. secrete IL-10 4. secrete GM-CSF: -secrete IL-10 -secreted by TH2 effectors to inhibit TH1 differentiation
What is the effect of TH1 and TH2 cells secreting IL-3 and GM-CSF?: -stimulate more leukocyte development in BM
True or false: CD8+ T cell response to pathogen depends on mature DC presentation of pathogen peptides on MHC I proteins.: true -pathogens can be expressed on MHC I if 1. DC is infected 2. viral infection stimulated cross-presentation in uninfected DC
What happens in a germinal center?: =area of proliferating B cells in a B cell follicle (follicle=cluster of B cells) 1. Antibody class switching -vis DNA recombination 2. Somatic mutation -via DNA repair mechanisms-> diversity in variable regions of antibody HC and LC 3. clonal selection -pick higher affinity B cells
True or false: humoral (antibody) responses are important for viral infections.: -true -think vaccines -Ab can neutralize and help opsonize viruses
Name the functions of effector CD4+ TH1 cells.: 1. cause inflammation by TNF 2. help activate CD8+ Tc by IL-2 or stimulate DC to upregulate B7 3. Hyperactivate macrophage by CD40L and IFN gamma--> more effective pathogen killing 4. Help clonally expand B cells
Name the functions of effector CD4+ TH2 cells.: 1. help clonally expand B cells (better than TH1 at this) 2. help attract and activate eosinophils via IL-5 and eotaxin 3. help activate mast cells via IL-4
Name the antibody effector fxns.: Major: 1. neutralize 2. activate complement cascade 3. opsonize Other 1. stimulate NK killing 2. eosinophil exocytosis 3. sensitization of mast cells
What do complement C3a and C5a do?: -both are soluble complement factors that float off to: 1. degranulate mast cells -results in inflammation
What does C5a do?: =soluble complement factor 1. chemotactic and activator of neutrophils 2. increases capillary permeability 3. degranulate mast cels
What does C3b do?: -complement factor that binds membranes 1. act as an opsonin 2. form more C3bBb (C3 convertase) 3. bind with C3bBb --> make C3bBbC3b (a C5 convertase)
What happens during positive selection of T cells?: -part of T cell education in thymus -testing to see whether baby T cells bind to MHC I or MHC II on thymic epithelial cells or not at all -determines CD4+ or CD8+ 1.no binding to MHC ->die 2. bind MHC I -> + signal -> CD8+ thymocyte 3. bind MHC II ->+ signal -> CD4+ thymocyte
What happens during negative selection of T cells?: -part of T cell education in thymus -checking to see if reacts with self peptides on MHC I -reacts -> die
Actions of IL-1 include:: -secreted by macs 1. stimulate T cells, B cells, neutrophils, fibroblasts to grow, differentiate or syntheize specific products 2. endogenous pyrogen (cause fever)
Actions of IL-2 include:: -secreted by TH cells 1. stimulates growth of helper and cytotoxic T cells (clonal expansion and differentiation)
Actions of IL-3 include:: -secreted by activated T cells 1.stimulates bone marrow to make more leukocytes -acts like GM-CSF
Actions of IL-4 include:: -secreted by TH2 1. promotes growth of B cells 2. enhances class switching of IgE and IgG -promotes IgE production
Actions of IL-5 include: -secretion by TH2 cells 1. promotes differentiation of B cells 2. enhance class switching to IgA 3. Stimulates production and activation of eosinophils
Actions of IL-6 include:: -Secreted by TH cells and macrophages 1. stimulates production of acute-phase reactants and immunoglobulins
Actions of IL-8 include:: 1. Major chemotactic factor for neutrophils
Actions of IL-10 include:: -secreted by TH2 cells 1. inhibits TH1 differentiation and stimulates TH2
Actions of IL-12 include:: -secreted by B cells and macrophages 1. Activates TH1 cells 2. Activates NK cells
Actions of IFN gamma include:: -secreted by TH1 cells 1. stimulates macrophages
Actions of TNF alpha include:: -secreted by macrophages 1. increased IL-2 R synthesis by TH cells 2. Increased B cell proliferation 3. Attracts and activates neutrophils 4. Stimulates DC migration to lymph nodes
Cell surface proteins found on helper T cells include:: 1. CD4 2. TCR 3. CD 3 4. CD28 5. CD40L
Cell surface proteins found on cytotoxic T cells include:: 1. CD8 2. TCR 3. CD3
Cell surface proteins found on B cells include:: 1. IgM 2. B7 3. CD 19 4. CD20 5. CD40 6. MHC II
Cell surface proteins found on macrophages include: 1. MHC II 2. CD14 3. Fc receptor 4. C3b receptor 5. TLRs
Cell surface proteins found on NK cells include:: 1. Receptors for MHCI 2. Receptors for CD16 3. Receptors for CD56
Define neoplasm: ="new growth" -abnormal mass of tissue where growth exceeds and is uncoordinated with that of normal tissues -genetic changes allow for the excessive and unregulated proliferation -continues to grow independent of stimuli -neoplasm=tumor -can be benign or malignant
Define transformed: -neoplastic cells said to be transformed because of ability to replicate independent of normal regulatory mechanisms that control cell growth
Define tumor: =neoplasm that forms a mass -can be 1. benign 2. malignant (cancer)
Describe benign tumors: =neoplasm that in terms in clinical behavior is innocent (does not cause cancer) -remains localized -will not spread to other sites -can be removed with surgery -patient generally survives -can cause problems (ex mass effect) but not cancerous
Describe malignant tumors: =neoplasms that invade and destroy adjacent structures -metastasize -may lead to death
Name the 2 basic components that make up ALL tumors: -includes benign and malignant 1. Parenchyma -neoplastic cells 2. Stroma -non-neoplastic supporting tissue derived from host -connective tissue, blood vessels
How are benign tumors named?: 1. tissue of origin + "-oma" 2. microscopic pattern + "-oma" -some epithelial tumors
How are malignant tumors named?: 1. If tumor arises in mesenchymal tissue or derivative -tissue of origin + "sarcoma" 2. If tumor arises in epithelial tissue -tissue of origin + "carcinoma"
Compare adenoma and adenocarcinoma: Adenoma= benign epithelial neoplasm producing gland patterns Adenocarcinoma= malignant neoplasm of epithelial tissue that grow in a glandular pattern
Define mixed tumor: =neoplasm contains pleomorphic (diff cell types) -neoplasm still has monoclonal origin but cells underwent divergent differentiation -NOT the same thing as a teratoma -ex. fibroadenoma -benign breast neoplams with fibrous and ductal elements
Define teratoma: -neoplasm derived from stem cells -can resemble any tissue in the body -usually benign but in rare cases malignant
Name some exceptions to the naming rules for tumors.: Names that would be classified as benign but are actually malignant 1. lymphoma 2. mesothelioma 3. melanoma 4. seminoma
Define hamartoma: =beningn neoplasm of focal, disorganized overgrowth of normal tissue -mass of tissue native to where it's located but disorganized =coin lesions
How do we distinguish between benign and malignant tumors?: -Benign and malignant tumors are different in 4 main features: 1. Differentiation and anaplasia 2. rate of growth 3. Local invasion 4. metastasis
Differentiation and anaplasia of benign vs malignant tumors refers to...: -the extent to which they resemble their normal forebears: 1. morphologically 2. functionally -applies to parenchymal cells ONLY (not stroma)
Which tumors are more differentiated, benign or malignant?: -benign -closely resemble normal counterparts malignant -range of differentiation (can look well differentiated to not at all)
How does extent of differentiation of a tumor relate to functionality?: -usually well-differentiated tumors (ex. benign) tend to retain functionality -some tumors can gain new functionality 1. Lung tumors and PTHrp
What does the grade of a tumor mean?: =how differentiated is the tumor 1. low grade tumor =well-differentiated -more likely to retain funtionality 2. high grade tumor =poorly differentiated
In general, what is the difference in rate of growth of beningn vs malignant tumors?: Benign tumors = slow-growing -exception: uterine fibroids malignant tumors= fast growing -rate of growth correlates with differentiation (more rapidly growing less differentiated)
What is the role of cancer stem cells in a neoplasm?: =a small population (less than 2%) of cells in a neoplasm that initiate and sustain the tumor -implications for tx b/c if don't eliminate cancer stem cells, tumor will keep growing back
How do benign vs malignant tumors differ by local invasion?: Benign tumors -remain localize -no capacity to invade -many are encapsulated Malignant -invade and destroy adjacent tissue -good marker for malignancy
How do benign vs malignant tumors differ by metastasis?: -tells you the tumor is malignant -but not all malignant tumors metastasize 1. basal cell carcinoma -metastases= development of tumors at sites distant from primary tumor
Name 3 mechanisms for how malignant neoplasms metastasize.: 1. Seeding within body cavities -neoplasm invades a natural body cavity 2. lymphatic spread 3. hematogenous spread -by the blood
Lymphatic spread of metastases is favored by____ while hematogenous spread is favored by ______.: 1. carcinomas 2. sarcomas
How does lymph node involvement work in cancer metastasis?: -lymphatic spread favors carcinomas -pattern of lymph node involvement depends on 1. where the neoplasm is located in body 2. what is the natural pathways of lymphatics draining that site
True or false: cancer mortality is highest between ages 55-75 and after 75 it goes down: true
What is the major difference between the 3 major classes of hereditary cancers?: 1. Inherited cancer syndrome -single mutant gene that increases risk of developing tumor 2.familial cancers -not associated with specific marker phenotype -may be early onset, bilateral tumors, ets 3. autosomal recessive syndromes of defective DNA repair -dna instability -ex xeroderma pigmentosum
Define acquired preneoplastic disorders.: =clinical conditions that are well-recognized predispositions to development of malignant neoplasms
Name some examples of acquired preneoplastic disorders.: 1. Cirrhosis -> hepatocellular carcinoma 2. dysplastic changes in smoker's lung -> lung cancer 3. chronic atrophic gastritis -> gastric carcinoma
True or false: autosomal dominant hereditary cancers tend to be associated with germ-line mutation of tumor suppressor genes: true
True or false: cancers are most common at the 2 extremes of age: true
Define carcinogenesis.: -the molecular basis of cancer -nonlethal genetic damage (mutation) is crucial -genetic mutations can be hereditary or acquired -tumor mass results from clonal expansion of single progenitor cell with genetic damage
Name 4 classes of normal regulatory genes, which if mutated may lead to cancer: 1. proto-oncogenes -promote growth 2. tumor suppressor genes -inhibit growth 3. apoptosis -genes that regulate apoptosis 4. genes involved in DNA repair
Define oncogenes: =mutant alleles of proto-oncogenes -promote cell growth -considered dominant b/c mutation of single allele can lead to cellular transformation
Define tumor suppresor genes.: =genes that normally inhibit cell proliferation -recessive b/c both allele must be mutated for transformation to occur -can be classified as: 1.promoters/gatekeepers 2. caretakers based on action of the gene
Contrast gatekeeper and caretaker genes: gatekeeper genes -mutation leads to transformation of cell by releasing breaks on cellular proliferation -ex. RB, p53 Caretaker genes -DNA repair, etc -do not directly affect proliferation or apoptosis -affect ability of cell to repair DNA damage to other genes
What are the major features of carcinogenesis?: 1. tumors have monoclonal origin 2. subsequent mutations in subsets of clones and selection produces tumor cell heterogeneity 3. Growth starts from single cell with DNA damage 4. DNA damage in one of 4 classes of regulatory genes 5. Multi-step process
Name the steps involved in carcinogenesis.: -genomic instability resulting from defects in DNA repair 1. Self-sufficiency of growth signals 2. Insensitivity to growth inhibitory signals 3. Evasion of apoptosis 4. Limitless replicative potential -overcome cellular senescence 5. Development of sustained angiogenesis 6. Ability to invade and metastasize
Define oncoproteins: =translated protein products of oncogenes -resemble the normal proto-oncoproteins EXCEPT: 1. devoid of regulatory elements 2. production of oncoprotein in transformed cell does NOT depend on growth signals/factors
How do cancer cells acquire growth self-sufficiency?: -most gain growth self-sufficiency by acquiring the ability to synthesize the same growth factors to which they are responsive to if paracrine stimulation
Name some mechanisms by which oncogenes can promote uncontrolled cell proliferation.: 1. stimulus-independent expression of growth factor and its R 2. mutations in growth factor R genes -overexpresion of R -constituitive signaling by R 3. Mutations in genes encoding signaling molecules 4. overproduction of unregulated activity of txn factors 5. mutations that activate cyclin genes or activate normal regulators of cyclins and CDKs
How do changes in growth factor receptors influence carcinogenesis?: 1. overexpression of growth factor R -> cancer cells hypersensitive to levels of GF that would not normally stimulate cell proliferation 2. Mutations in GF r -> constituitive activation ->signaling to cell even when no GF present
Define Her2/Neu: -growth factor receptor that gets upregulated in many types of cancers, esp. breast -High Her2/Neu protein levels correlates with poor prognosis for breast cancer -can use anti-Her2/neu antibodies to block extracellular domain and treat cancer (Herceptin)
Name 2 important signal transducing molecules that are involved in cancers.: 1. Ras -commonly mutated proto-oncogene 2. ABL -non-receptor associated tyrosine kinase -also proto-oncogene
How does Ras play a role in carcinogenesis?: -GTP binding protein that fxns as a signal transducer -Growth factor R stimulation -> GDP displaced on Ras for GTP -> Ras stimulates downstream regulators of proliferation (Raf, MAPK) -> txn changes -> cell proliferation -Ras inactivated by GTP hydrolysis -w/cancer, point mutations in Ras -> can't hydrolyze GTP -> Ras constituitively active
How does ABL play a role in carcinogenesis?: -non-receptor associated tyrosine kinase -fxns as a signal transduction molecule -proto-oncogene carries internal regulatory domains -CML -> translocation from chromosome 9->22 -> break in DNA -> novel fused protein that lacks reg. fxns -affects cell by: 1. being retained in nucleus and not being able to induce apoptosis as normally would 2. tyrosine kinase activity on many other pathways
Describe Myc: -proto-oncogene ubiquitously expressed -Myc induced when quiescent cell receive signal to divide -cancer: Myc gets overexpressed or expressed all the time -> sustained cell proliferation -Myc protein is txn factor that can activate or repress txn of lots of genes
How does Myc play a role in carcinogenesis?: -promotes tumor progression by: 1. increasing expression of genes that promote progression through cell cycle (CDKs) 2. repress genes that slow or prevent progression through cell cycle
Name some cancers where myc is involved: 1. Burkitt's lymphoma -translocation (8;14)-> dysregulation of myc 2. breast, colon, lung, other cancers -myc overexpressed
What is the role of cyclins and CDKs in the cell cycle?: 1. CDKs =cyclin-dependent kinases -coordinate orderly progression of cells through various phases of cell cycle 2. Cyclins -proteins that bind to CDKs and activate them
How do cyclins, CDKs, and CDK inhibitors play a role in carcinogenesis?: -mutations in these genes -> loss of activity (CDK inhibitor) or not well coordinated -> uncontrolled cell cycle progression
Name 2 important tumor suppressor genes: 1. p53 -can be mutated in a variety of cancers 2. Rb
Define Rb: -tumor suppressor gene -need mutations in both copies of the gene in a single cell for tumor to arise -familial cases increased risk of retinoblastoma b/c inherited on nonfxnal copy of Rb
Describe the fxn of the RB gene.: -tumor suppressor gene -antiproliferative effects by controlling the G1 to S transition in cell cycle -mutations -> disable the G1 checkpoint -> cancers
Describe the fxns of p53 gene: =tumor suppressor gene -p53 senses DNA damage and: 1. assist DNA repair by causing G1 arrest 2. inducing DNA repair genes -if DNA damaged beyond repair, p53 wil: 3. direct cell to apaoptosis -loss of p53 implicated in most kinds of cancer
How do you get loss of p53?: 1. Sporadic -somatic inactivating mutations in both alleles in a somatic cell 2. Inherited -Li-Fraumeni syndrome -inherit mutatnt p53 allele -predisposed to tumor formation b/c only need 1 hit to get tumor
True or false: certain DNA viruses can nullify fxn of p53: -true: HBV (hep B), HPV -can also do the same to the RB gene
Describe apoptosis.: -can be initiated through extrinsic or intrinsic pathways -both pathways activate proteolytic cascade of caspases that destroy cell -caspases cause mitochondrial permeabilization of mitochondrial outer membrane -> molecules get released that intiate apoptosis -without apoptosis, cells will accumulate more DNA damage
How do cancer cells evade apoptosis?: 1. BCL2 activation mitochondrial membrane permeabilization regulated by balance of pro-apoptotic (BAX, BAK) and anti-apoptotic (BCL2) molecules -in follicular B lymphoma, BCL2 (anti-apoptotic) gets activated by a translocation 2. p53 mutation -p53 pro-apoptotic -loss of p53, loss of induce apoptosis when too much DNA damage
Describe how telomeres act in cell senescence: -normal cells lack expression of telomerase and telomeres get shorter as cells age -shortened telomeres activate cell cycle checkpoints -> limit # of cell divisions and cell senesces
How do cancer cells achieve limitless replicative potential?: 1. disable cell cycle checkpoints (mutations in RB, p53) -> telomeres treated as ds DNA breaks and inappropriately repaired -> chromosomal instability and mitotic crisis 2. tumor cells reactivate telomerase to deal with shortened telomeres-> avoid mitotic catastrophe ->immortal
How do tumors develop sustained angiogenesis?: -vascularization needed for tumor growth -hypoxia triggers angiogenesis through actions of HIFalpha (oxygen-sensitive transcription factor) -other things can also trigger but you need production of VEGF (vascular endothelial growth factor)
Define HIFalpha.: -oxygen-sensitive txn factor -normally at low levels in cell b/c degraded by VHL -hypoxia -> HIFalpha resists degredation -> translocates to nucleus and activates genes, including VEGF
List the molecular steps in metastasis: 1. Clonal expansion and diversification produces metastatic subclone 2. M clone adheres to and invades basement membrane 3. M clone passes through ECM 4. Intravasation into blood stream 5. M clone interacts with lymphoid cells in blood stream 6. M clone gets covered with platelets and forms tumor cell embolus 7. m clone adheres to basement membrane downstream 8. extravasation 9. metastatic deposit 10. angiogenesis 11. growth
How do metastatic clones locally invade tissues?: -4 steps 1. loosening of cell-cell contacts (loss E-cadherin) 2. degredation of ECM -proteolytic enzymes like cathepsins 3. attachment to novel ECM components 4. Migration of tumor cells -metastasis is a marker of malignancy
How do we explain the patterns of metastasis?: 1. many metastatic clones extravasate at 1st capillary bed reached after entering circulation (liver, lungs) 2. Some types of cancers show preferences for various organs (tropism)
Name 3 classes of carcinogenic agents: 1. Chemicals -mutate DNA -direct acting or indirect acting 2. Radiation -lots of ways to damage DNA 3. Viruses -expression of oncoviral proteins, activation of txn factors (myc)
Contrast direct acting and indirect acting chemical agents: direct-acting =does not need to be metabolized to be carcinogenic and mutate DNA Indirect acting -need to be metabolized before acts as carcinogen
Name some types of DNA damage caused by radiation carcinogens: 1. chromosome breaks 2. translocations 3. mutations
Name some viruses associated with carcinogens and what cancers they are associated with:: 1. HPV ->cervical cancer -expression of oncoproteins 2. EBV ->Burkitt's lymphoma (Africa), B cell lymphomas in immunosuppressed -myc overexpression 3. Hep B, C -> liver cancer -increased cell turnover-> increased rate of mutations 4. H.pylori -> MALT lympoma -from inflammation -also causes stomach cancer b/c increased cell turnover
Define staging of cancers.: -describes how far cancer has already spread -use TNM criteria T= size N= # of lymph nodes involved M= + of metastasis -stage highly predictive of clinical outcome (vs grading of tumors)
Name 5 malignancies that can be potentially cured by chemotherapy: 1. Acute leukemias 2. Hodgkin's disease and aggressive NHL 3. testicular cancer 4. small cell lung carcinoma (limited stage) 5. childhood solid tumors
Name 4 cancers where chemotherapy is used as a post-surgical adjuvant.: -prevent relapse and increase survival 1. breast cancer 2. colorectal cancer 3. lung cancer (non small cell) 4. ? bladder cancer
Name 5 cancers where chemotherapy is a helpful neo-adjuvant: -given before surgery to down-stage tumor so surgery is curative 1. breast cancer 2. rectal cancer 3. squamous cell carcinoma of head and neck 4. esophageal cancer 5. bladder cancer
Name some non-malignant diseases where chemotherapy is used as treatment: -used for immunosuppressive effects 1. Rheumatoid arthritis 2. SLE 3. Sickle cell 4. Organ transplants 5. Psoriasis 6. MS 7. Autoimmune hemolysis and ITP
Problems with efficacy of chemotherapy drugs include:: 1. low therapeutic index 2. emergence of resistant clones 3. limited effect on slow growing cancer stem cells 4. many cancers involve mutations in multiple pathways so agents targeting a single pathways are insufficient
Which chemotherapy agents act during S phase of cell cycle: -S phase is when DNA is made =inhibitors of DNA synthesis 1. antimetabolites 2. hydroxyurea
Which chemotherapy agents act during M phase of cell cycle: M=mitosis -inhibitors of microtubules -> prevent formation of mitotic spindle 1. vinca alkaloids 2. taxenes
Name some drugs that do are not cell phase specific in their action.: -effective against non-dividing cells (Go/G1) 1. alkylating drugs 2.platinum drugs 3. Anthracyclines 4. bleomycin
How do cytotoxic agents induce apoptosis?: 1. indirectly through p53 -cytotoxic drugs cause DNA damage-> p53 senses damage -> p53 induces apoptosis -requires fxnal p53 2. cytotoxic drugs directly activate caspases
Name some mechanisms of resistance to chemotherapy.: -could be specific to one chemotherapeutic agent or broad resistance to many drugs 1. impaired transport 2. loss of necessary activating enzymes 3. over-expression of metabolic enzymes 4. mutation of cellular target protein 5. Over-expression of drug efflux pump MDR 6. Enhanced DNA repair 7. Defects in apoptotic signaling -ex loss p53
Name some approaches to overcome resistance to chemotherapy.: 1. combination of agents with different mechanisms of action and toxicities 2. sequential or alternating therapy w/ different agents 3. dose-intense chemo 4. High dose chemo with BM rescue 5. MDR modulating drugs 6. Addition of targeted agents to sensitize cells to chemo
Define MDR: = Multiple drug resistance =membrane bound, energy-dependent pump capable of getting rid of unrelated chemo drugs and xenobiotics -P glycoproteinn confers drug resistance to malignant cells
Name 3 types of chemo drugs affected by MDR: 1. vinca alkaloids 2. taxanes 3. topoisomerase inhibitors
Name the 3 general toxicities of chemotherapy.: 1. myelosupression -leads to neutropenia, thrombocytopenia, immunosuppression 2. alopecia (hair loss) 3. GI toxicity -nausea/vomitting, mucositis, diarrhea -nausea/vomitting also do to CNS toxicity
Which chemotherapeutic drugs can cause nephrotoxicity?: 1. platinum agents 2. taxanes 3. vinca alkaloids
Which chemotherapeutic drugs can cause neurotoxicity?: Peripheral neuropathy 1. platinum agents 2. taxanes 3. vinca alkaloids CNS toxicity 1. high dose methotrexate 2. Ara C
Which chemotherapeutic drugs cause cardiotoxicity?: 1. Anthracyclins 2. Herceptin
Which chemotherapeutic drugs cause pulmonary toxicity?: 1. bleomycin 2. alkylating agents 3. methotrexate
Which chemotherapeutic drugs cause gametotoxicity?: -ex sterility 1. alkylating agents
Which chemotherapeutic are most likely to cause induction of secondary malignancies: 1. alkylating agents
Which chemotherapeutic drugs cause skin toxicity?: 1. 5' FU 2. Doxil 3. EGFR inhibitors
How do you determine the dosing of chemotherapeutic agents?: -dosing based on many factors: 1. Body surface area or weight 2. BM reserve 3. Renal and hepatic fxn 4. General performance status -best predictor of how chemo will be tolerated 6. Age of patient 7. Concurrent medical problems and medications 8. Goals -curative vs palliative
How can the toxicities of chemotherapeutics be minimized?: 1. adjusting dose to pt's physiology 2. careful monitoring of -clinical toxicities -lab values -specific organ fxns 3. hydration 4. Use hematopoetic growth factors and antibiotics 5. effective anti-emetics 6. specific drugs for toxicities 7. measure drug levels
Why do we use combination chemotherapy?: 1. reduce development of resistance 2. maximize antitumor activity by using compounds with diff. mechanisms of action 3. some agents act synergistically 4. minimize toxicities if use drugs with compatible toxicties
True or false: combination of chemotherapy with radiation may increase radiation sensitivity: true
Name some tumor markers that can predict response to chemotherapy.: 1. Estrogen/progesterone R -predict response of breast cancer to hormonal therapy 2. Her2/neu -overexpressed in breast cancer predicts response to Herceptin 3. Activating mutations in EGF R in lung cancer predict response to getifinib 4. gene expression profiles -predict risk of relapse and response to therapy for breast, lung cancers
Name the 4 groups of classic chemotherapeutic agents: 1. DNA damaging agents 2. Antimetabolites 3. Microtubule inhibitors 4. Topoisomerase inhibitors
Name the 2 major types of DNA damaging chemotherapeutic agents: 1. Alkylating Agents -cyclophosphamide, Melphalan 2. Platinum agents -cisplatin, carboplatin, oxaliplatin
Describe cyclophosphamide: =alkylating (DNA damaging) chemotherapeutic agent -cell cycle independent Uses: 1. breast cancer 2. lymphoma 3. auto-immune diseases
Describe melphalan: =alyklating (DNA damaging) chemotherapuetic agent -cell cycle independent -Uses 1.myeloma
How do alkylating agents work?: -drug forms adducts with DNA through covalent bonds -> destabilization of DNA structure -> when adducts recognized by repair enzymes, they create double stranded breaks in the DNA -> induces apoptosis through p53 -cell cycle independent -high mutagenic/carcinogenic potential
Name some mechanisms of drug resistance associated with alkylating agents: 1. increased intracellular thiols can conjugate and detoxify 2. increase activity of DNA repair pathways 3. mutation of p53 -resistance can be overcome by higher doses
Name some toxicities associated with alkylating agents: 1. mylosuppression 2. mucosal toxicity -esp HEMORRHAGIC CYSTITIS 3. Nausea/vomitting 4. alopecia 5. infertility 6. induction secondary malignancies
What is hemorrhagic cystitis and how can it be prevented?: =toxicity associated with alkylating agents -mucosal inflammation and pee blood -prevention 1. hydration 2. frequent voiding 3. Mesna (drug)
Cisplatin is used to treat which cancers: 1. Lung 2. testicular 3. others
Carboplatin is used to treat which cancers: -platinum DNA damaging agent 1. lung 2. ovarian 3. others
Oxaliplatin is used to treat which cancers?: =DNA damaging platinum agent 1. Colorectal cancer
How do platinum chemotherapeutic drugs work?: =DNA damaging agents -cell cycle independent -form adducts with DNA-> form inter and intra strand cross-links that disrupt structure -> DNA synthesis inhibited and get DNA breaks and miscoding -show synergy with 5'FU and taxanes
Which platinum chemotherapeutic agent has significant nephroxicity and how is it prevented?: -cisplatin 1. hydration with saline before and after giving cisplatin 2. specific drug (amiphostine) -cisplatin also causes sign nausea/vomitting and neurotoxicity
Which platinum chemotherapy drug is used for palliative chemo and why?: =carboplatin -because causes less of the toxicities and side effects -does show more myelosuppression than cisplatin or oxaliplatin
Define antimetabolites: =classic chemotherapy agents -S phase specific -inhibit precursors of DNA synthesis -many also used as immunosuppressants -includes 1. Folic acid analogs 2. Pyrimidine analogs 3. Purine analogs
Describe methotrexate: =Folic acid analog, antimetabolite chemotherapeutic agent -can be given po, iv, or intra-thecally -Uses: 1. acute leukemias 2. lympomas -S phase specific (inhibits DNA synthesis) -acts as a folic acid anatagonist
How do folic acid analogs work: =classical chemotherapy drugs (methotrexate) that work during S phase of cell cycle -folic acid antagonists -> inhibit dihydrofolate reductase -> depletion of THF cofactors needed to make thymidylate and purines -> DNA synthesis affected
True or false: effects of folic acid antagonists (methotrexate) can be reversed by giving leukovarin.: -true -leukovarin is a THF -so give the substrate the folic acid antagonist depleted the production of --> able to make DNA and RNA
Name one important mechanism of resistance for methotrexate: =folic acid analog -amplification or mutation in DHFR (the enzyme that methotrexate is inhibiting)
Name some toxicities associated with methotrexate and folic acid analogs.: 1. general toxicities 2. pulmonary toxicity (pulmonitis, reversible) 3. hepatic toxicity 4. very toxic to developing embryos (used to induce abortion) 5. immunosuppression
Describe Ara-C: =pyrimidine analog, antimetabolite chemotherapeutic agent -acts during S phase of cell cycle -Uses 1. Leukemias 2. Lymphomas -Toxicity 1. Liver 2. CNS
How does Ara-C work?: -gets phosphorylated to Ara-CTP and incorporated into DNA -> blocks elongation of DNA
Describe 5'FU: =pyrimidine analog antimetabolite chemotherapeutic agent -acts during S phase of cell cycle -Uses: 1. colorectal cancer 2. GI cancers -Toxicity 1. Diarrhea 2. skin toxicity (hand-foot syndrome)
How does 5'FU work?: -pyrimidine analog antimetabolite -phosphorylated -> blocks thymidylate synthase in presence of THF -gets incorporated into DNA and RNA -leukovorin enhances its anti-tumor activity
Name 2 chemotherapy drugs leukovorin is given with and what are its effects?: Leukovorin=THF 1. Methotrexate -rescues from disruption of DNA synthesis after high dose of methotrexate -provides product of enzyme that methotrexate inhibits 2. 5'FU -enhances cytotoxicity -5'FU works best in presence of THF
Name 2 types of microtubule inhibitors: =classic chemotherapeutic drugs that act during M phase of cell cycle 1. vinca alkaloids 2. taxanes -both have neurotoxicity
Describe Vincristine.: =vinca alkyloid chemotherapeutic agent -microtubule inhibitor, acts during M phase cell cycle -Uses: 1. Leukemias 2. Lymphomas -Severe neurotoxicity
How do vinca alkaloids work?: -microtubule inhibitor chemotherapy drugs -binds to beta tubulin and block ability to polymerize -act during M phase
Name some mechanisms of resistance associated with microtubule inhibitors: -includes vinca alkaloids and taxanes 1. MDR overexpression 2. tubulin mutations
Describe taxanes: =microtubule inhibitor chemotherapy drugs -paclitaxel,docetaxel -Uses: 1. Lung 2. Breast 3. Ovarian -Toxicity 1. severe hypersensitivty rxns 2. neurotoxicity
How do taxanes work?: -microtubule inhibitor chemotherapy agents -work during M phase of cell cycle -bind to Beta tubulin but prevent disassembly of tubules
DNA topoisomerases normally fxn to...: -relax supercoild DNA by mediating strand breakage and resealing -required for DNA replication, repair, txn
Contrast topoisomerase I and topoisomerase II: Topo I -create single strand DNA breaks -cell has to go through 1 round of replication before induction of apoptosis Topo II -creates ds DNA breaks -sufficient to induce apoptosis
Name 3 types of topoisomerase inhibitors and which enzyme (I or II) do they act on?: 1. Thecans -topo I 2. Anthracyclins -topo II 3. Epidophyllotoxins -topo II
Describe the Thecans: -topo I inhibitors -act during S phase of cell -Uses: 1. colorectal cancer (irinotecan) -Toxicity 1. Severe diarrhea (irinotecan)
Name 2 Anthracyclins: =Topoisomerase II inhibitors -chemotherapy drugs 1. Doxorubicin 2. Mitoxanthrone
Name some mechanisms of actions anthracyclins.: =topoisomerase II inhibitors, chemotherapy drugs 1. inhibition of topo II 2. intercalation with DNA 3. generation of free radicals -attack DNA directly -responsible for cardiotoxicity
Which chemotherapeutic agents are associated with cardiotoxicity and how is it prevented?: =anthracyclins (topoisomerase II inhibitors) -prevention 1. monitor cardiac ejection fraction 2. co-administer dexrazoxane
Name some clinical uses of anthracyclins: =topoisomerase II chemotherapy agents 1. lymphomas 2. breast cancer 3. acute leukemias
Describe Etoposide: =Topoisomerase II inhibitor chemotherapy drug -Uses 1. lung cancer 2. testicular 3. lymphomas -can cause secondary leukemia due to specific translocation
Name 3 classes of targeted therapy cancer drugs: 1. Protein kinase inhibitors ("ibs") 2. Monoclonal antibodies ("abs") 3. Hormones and related agents
How do protein kinase inhibitors work to treat cancer: -bind to kinase domain of enzymes and prevent binding of ATP -malignant cells gain resistance by mutations in kinase domaain that prevent drug binding
Describe Imatinib: =Gleevec -protein kinase inhibitor/targeted therapy -Inhibits c-Abl and its activated fusion proteins; inhibits c-KIT, PDGFR tyrosine kinases -Use to tx CML -toxicity: fluid retention
Describe Getifinib and Erlotinib: =protein kinase inhibitor/target chemotherapy -inhibits EGFR tyrosine kinase -Uses: 1. metastatic non-small cell lung cancer 2. colon cancer and others -Toxicity: severe acneiform rash
Describe Sorafinib and Sunitinib.: =broad spectrum kinase inhibitors -target chemotherapy drugs -inhibit multiple VEGFR and PDGFR -Uses: 1. Metastatic renal cell carcinoma 2. Hepatocellular carcincoma -b/c these are highly vascularized cancers -Toxicity 1. HTN
Describe Retuximab: =monoclonal antibody/targeted chemotherapy drug -Uses: 1. NHL B cell lymphoma 2. auto-immune -binds to CD20 on B cells -well tolerated but may have Hep B reactivation
Describe Trastuzumab: =Herceptin -monoclonal antibody/targeted chemotherapy -Uses 1. Her2/neu (GF EGF R)overexpressing breast cancer -Toxicity: 1. Cardiomyopathy
Describe Bevacizumab: =Avastin -monoclonal antibody against VEGF (ligand) -targeted chemotherapy -Uses: 1. Colorectal cancer 2. Renal cell cancer -enhances chemotherapy effects -Toxicities: 1. HTN 2. Hemorrhage
Name 2 types of hormone related treatments for breast cancer.: 1. Tamoxifen -anti-estrogen 2. Aromatase inhibitors
Describe Tamoxifen: -fake estrogen (SERM, binds to estrogen R and exerts anti-estrogen effects in breast but pro-estrogen effects in uterus, bone -Uses: 1. estrogen-receptor positive breast cancer
Name some toxicities associated with tamoxifen.: 1. hot flashes, vaginal atrophy, vaginal bleeding 2. increased risk of thromboembolic events 3. 2-3x increased risk of uterine cancer
Describe aromatase inhibitors: -aromatase is enzyme that converts testosterone to estrdiol -active in breast in post-menopausal women -Uses: 1. Breast cancers -most effective for preventing relapses in ER+ breast cancer -Toxicities: 1.Hot flashes,vaginal bleeding 2. osteoporosis and SKM pain 3.lower risk thromboembolism than tamoxifen
Name 2 types of hormone-related drugs to treat prostate cancer.: -90% of prostate cancers are hormone sensitive 1. Gonadotropin-releasing hormone agonists 2. androgen R blockers
How do Gonadotropin releasing hormone agonists work?: -tx for prostate cancer -actions: initial surge in LH and FSH followed by inhibition of LH and FSH release from pituitary -> decreased testosterone levels -Uses: 1. prostate cancer
Name some toxicities associated with GnRH agonists.: 1. Initial flare up of disease 2. hot flashes, loss of libido, potency 3. fatigue, anemia 4. osteoporosis and loss muscle mass
How do androgen receptor blockers work?: -act as competitive inhibitors to natural ligands of androgen R -used in combo with GnRH agonists -Uses: 1. prostate cancer -Toxicity: 1. Hot flashes, loss of libido, potency 2. Gynecomastia
Describe bleomycin: =classic miscellaneous chemotherapy drug -causes oxidative damage -> ds DNA breaks -Uses: 1. Testicular cancer 2. Lymphoma -Toxicity: 1. little myelosuppression 2. pulmonary toxicity 3. skin toxicity 4. hyperthermia (acute) 5. hypotension (acute)
Describe Hydroxyurea: =miscellaneous classic chemotherapy drug -inhibits ribonucleotide reductase -> depletion of deoxy-nucleotides -S phase specific -Uses: 1.Myeloprolif diseases (polycythemia vera, essential thrombocythemia) 2. sickle cell -Toxicities: 1.myelosuppression 2. mild GI upset
Name the 4 classes of immunosuppressive drugs.: 1. Glucocorticoids 2. Calcineurin inhibitors 3. Anti-proliferative/antimetabolites 4. Antibody therapy
True or false: glucocorticoids given to a patient with N stage liver disease will have a less potent immunosuppressive effect: -false! -they will have a more potent immunosuppressive effective -increased bioavailability with low serum albumin -N stage liver disease not making much albumin
Name 3 mechanisms of immunosuppression with glucocorticoids: 1. binds receptor and regulates gene txn 2. impairs expression of number of cytokines via enhanced IkB (decreased NFkB) 3. Lympholytic -redistribution into nodes; decreased activation of CTL
Glucorticoids lead to a decrease in all of the following cytokines EXCEPT: a. IFN gamma b. TNF alpha c. IL-2 d. IL-6 e. it decreases all of them: -it decreases all of them in addition to IL-1,2,3,6
Name the common side effects associated with glucocorticoids.: 1. HTN 2. glucose intolerance (DM) 3. dyslipidemia 4. osteoporosis; avascular necrosis of femoral head 5. decreased wound healing 6. cataracts 7. enhanced risk of infection; decreased signs of infection "patient smiled all the way to the morgue"
Name 2 calcineurin inhibitors: 1. cyclosporine 2. tacrolimus
Describe cyclosporine: -immunosuppressive drug -calcineurin inhibitor -lipid soluble -variable absoprtion
Describe Tacrolimus: -immunosuppressive drug -calcineurin inhibitor -macrolide -well-absorbed
How do calcineurin inhibitors produce immunosuppression?: =bind immunophilis -> decrease the phosphatase action of calcineurin -> NFAT can't translocate to nucleus and stimulate IL-2 production -also get increased TGF-beta expression (linked to side effects)
What are some side effects of calcineurin inhibitors?: 1. Nephrotoxicity -dose-dependent 2. HTN 3. Dyslipidemia 4. Glucose intolerance 5. Hirsutism/hyperplasia of gums -side effects similar to and additive with glucocorticoids -tarcolimus causes less hirsutism/gum hyperplasia
True or false: nephrotoxicity associated with calcineurin inhibitors is seen only with kidney transplants: -false -even with pts with other organ transplants, there is development of chronic renal failure w/ use calcineurin inhibitors
True or false: drug interactions are common with calineurin inhibitors.: -true -b/c metabolized by CYP3A -drugs that inhibit CYP3A augment blood concentrations of calcineurin inhbitors (watch out for grapefruit juice!) -drugs inducing CYP3A decrease blood concentrations
Name 3 antiproliferative/antimetabolites immunosuppressive drugs: 1. Azathioprine 2. Mycophenolate mofetil (MMF) 3. Sirolimus
Describe Azathioprine: =anti-prolif./antimetabolite -immunosuppressive drug -acts as mercaptopurine analog -inhibits purine synthesis ->decreases cell prolif. -no longer 1st line drug for transplants -side effect: myelosuppression
Describe mychophenolate mofetil: -immunosuppressive drug -anti-prolif/antimetabolite -gets metabolized to active drug -inhibits inosine monophosphate dehydrogenase -decreases cell prolif. -used to prevent organ transplant rejection (w/glucocorticoids, and calcineurin inhibitors)
What are the side effects of mycophenolate mofetil?: -immunosuppressive drug -antiprolif/antimetabolite 1. Diarrhea 2. myelosuppression
Describe Sirolimus: -immunosuppressive drug -antiprolif/antimetabolite -used w/ patients not tolerating calcineurin inhibitors -binds to FKBP-12, blocks m-TOR -inhibits T cell response to cytokines -Blocks G1 to S cell cycle transition -used in immunosuppression for organ transplants -side effect: BM suppression
What are immunosuppressive drugs used for?: 1. Allografts -renal, liver, lung, hear 2. Autoimmune diseases 3. Inflammatory diseases
Name 3 Antibodies that can be used in immunosuppressive therapy: 1. Antithymocyte globulin 2. Anti-CD3 3. Anti-IL-2 R antibodies
Describe Antithymocyte globulin: -immunosuppressive drug -cytotoxic antibody toward a number of CDs on lymphocytes -depletes circulating lymphocytes -used at time of induction and rejection
Describe anti-CD3: =immunosuppressive drug -antibody therapy against epsilon chain of CD3 -> R internalized -> cells die/marginalize -used for rejection -side effects: cytokine release syndrome (potentially life threatening)
How are immunosuppresive drugs used in transplants at time of transplant?: -some combo of drugs with antilymphocyte tx (monoclonal or polyclonal antibody) -then maintenace of immunosuppression -tx of rejection if needed
How are immunosuppressive drugs used to maintain immunosuppression in transplants post-allograft?: -combo of: 1.glucocorticoids 2.calcineurin inhibitor 3.antimetab -Sirolimus used to limit exposure to nephrotoxicity of calcineurin inhibitors
What is the risk-benefit ratio in immunosuppression?: -risks: 1. side effects of drugs 2. long term risks of malignancy 3. susceptibility to infection Other things 1. availability of alternate therapies (ex. dialysis for kidney)
Which immunosuppressive drugs cause direct destruction of proliferating lymphoid cells?: 1. glucocorticoids 2. antibodies
Define macule: -skin pathology -flat -different color than surrounding skin -circumscribed
Define patch: -skin pathology =big maccule
Define papule: -elevated and solid on skin -less than 5 mm
Define nodule: =big papule -bigger than 5mm
Define plaque: -skin pathology -raised and flat-topped (like a mesa) -bigger than 5 mm
Define wheal: -"to burn" =urticaria=hives -erythematous, edematous, pruritic papules to plaque -IgE mediated
Define vesicle: -skin pathology -fluid filled -less than 5 mm
Define bulla: =big vesicle -bigger than 5 mm =blister -fluid filled cavity w/in epidermis or between epidermis and dermis
Define pustule: -skin pathology -fluid filled bubble -fluid=pus
Define scale: =erythematous plaque with a scale on top -result of cornification -dry, horny, plaetlike
Define blister: =common term for vesicle or bulla
Define hyperkeratosis: =hyperplasia of the stratum corneum -often associated with qualitative abnormality of keratin
Define parakeratosis: =mode of keratinization characterized by retention of nuclei in stratum corneum -normal on mucosal membranes
Define acanthosis:: =epidermal hyperplasia preferentially involving stratum spinosum
Define dyskeratosis: =abnormal keratinization occuring prematurely within individual cels or groups of cells below the stratum granulosum
Define acantholysis: =loss of intercellular connections resulting in lack of cohesion between keratinocytes
Define papillomatosis: =hyperplasia of the papillary dermis with elongation and/or widening of dermal papillae
Define spongiosis: =intercellular edema of the epidermis
Name 8 immune mediated skin diseases and state their classification/main mechanism: 1. Urticaria -IgE mediated 2. Pemphigus vulgarius -Antibody mediated 3. Bullous pemphigoid -antibody mediated 4. dermatitis herpetiformis -antibody mediated 5. Acute Eczematous Dermatitis -Delayed CD4+ hypersensitivity 6. Erythema multiforme -direct CD8+ toxicity 7.Lichen planus -direct CD8+ cytotoxicity 8. Psoriasis -CD4+ and CD8+ T cell mediated
Name the 4 cells of the epidermis: 1.keratinocyte 2. melanocyte 3. Langerhans cell 4. Merkel cell
Name the layers of the epidermis: 1. Stratum basalis 2. Stratum spinosum 3. Stratum granulosum 4. Stratum corneum
Describe Urticaria: =hives=to burn -immediate IgE mediated hypersensitivity -triggers: food, insects, druga, pollen -1st exposure: stimulate TH2 cells -> B cells make IgE -> IgE attaches to mast cells -2nd exposure -> mast cel degranulation -> HM release -> dermal microvascular hyperpermeability -result: wheals (erythematous, edematous, pruritic plaques)
Describe acute eczematous dermatitis: =delayed type CD4+ T cell mediated (type IV hypersensitvity) -lesions are pruritic, edematous, oozing plaques, often with vesicles and bullae -persistent exposure, scratching can cause acanthosis (epidermis thickens) and progressively scaly (hyperkeratotic)
Define eczema: =bubbling over -clinical term that applies to many conditions with different underlying causes -lesions are red, papulovesicular, oozing, and crusted (early) -may later develop into scaly plaques -most types of eczema go away when offending stimulus is removed
Describe pathogenesis of acute eczematous dermatitis: -classic: poison ivy or poison oak -1st exposure: Langerhans cells process Ag-> travel to lymph nodes -> present to T cells (sensitize) -2nd exposure: CD4+ T lymphocytes migrate to affected skin sites ->release cytokines -> cell damage -edema -> separation between keratinocytes -> fluid accumulates between cells -> vesicles
Describe Erythema multiforme.: =skin hypersensitivity response to certain infections and drugs -onset in days -Direct CD8+ T cell cytotoxicity -severity of the disease varies and morphology varies -classic: looks like a bull's eye (targetoid) -more severe form=Steven-Johnson syndrome
Describe pathogenesis of Erythema multiforme.: -Cytotoxic CD8+ T cells mediated -CD8+ cells directed against drug or microbe respond to cross-reactive antigens on basal cell layer of skin -> skin cells attacked and damaged -results in: 1. necrosis of basal layer 2. fluid accumulation 3. destruction of dermal-epidermal interface
Describe Steven-Johnson syndrome: =severe form of eythema multiforme -skin sloughs off -can be life threatening b/c: 1. loss of moisture 2. loss of barrier to infections -most often seen with idiopathic rxns to drugs
Describe psoriasis: =chronic inflammatory skin disorder ="the itch" -Mediated by both CD4+ and CD8+ T cells -lesions usu. well-demarcated salmon colored plaque covered with loosely adherent white scale -can be seen on: elbows, knees, scalp, lumbosacral areas, intergluteal cleft, glans penis
Describe pathogenesis of psoriasis: -mediated by sensitized CD4+ and CD8+ T cells -lesions can be induced by local trauma -secreted cytokines and growth factors cause hyperplasia of prickle cell layer -also see: 1. parakeratosis (nuclei in top layer -> scale) 2. elongation of papillary dermis "test tube like" 3. bleed when you pick at it 4. microabscesses
Describe Lichen planus: =self-limited disorder of skin and mucosa -P's 1. pruritic 2. purple 3. polygonal 4. planar 5. papules and plaques -looks like lichen on a rock
Describe pathophysiology of Lichen planus: =CD8+ T cell mediated -T cells cross-react with Ag in basal cell layer and cause damage to the cells -infiltration of lymphocytes along dermal-epidermal jxn -> saw tooth pattern
Describe Pemphigous vulgaris: =blistering disease -IgG mediated -usu seen in middle aged people or older -superficial vesicles and bullae that rupture easily and leave erosions covered with serum crust -seen on skin and mucosa
Describe pathogenesis of pemphigous vulgaris: -make IgG antibodies to intercellular desmosomes -> cells not held together anymore -> cell layer splits -> blisters w/in epidermis -acantholysis of layer of cells immediately above basal cell layer (suprabasal)
Describe Bullous Pemphigoid: =blistering disease -often seen in elderly -can involve skin and mucosal surfaces -lesions are tense bullae, filed with clear fluid on normal or erythematous skin -can get on inner thighs, axillae, groin, lower abdomen
Describe pathogenesis of bullous pemphigoid: =blistering disease -autoimmune -make IgG antibodies against Ag (BPAG) at dermal-epidermal jxn -> IgG bind to hemidesmosomes -> activate complement -> epidermis detaches from dermis
Describe Dermatitis herpetiformis: -immune skin disorder characterized by urticaria and group vesicles -seen in males 30-40s -can be associated with celiac disease -lesions are: 1. very pruritic 2. bilateral 3. symmetric 4. involve elbows, knees, back, butt 5. looks like chicken pox rash
Describe pathogenesis of Dermatitis herpetiformis: -autoimmune -make IgA antibodies against reticulin in basement membrane of epidermis that attach to superficial dermis -> fixes complement -> subepidermal blisters
Name 3 acute inflammatory skin diseases: 1. Acute eczematous dermatitis 2. Urticaria 3. Erythema multiforme
Name 2 chronic inflammatory skin diseases: 1. Psoriasis 2. Lichen planus
Name 3 factors in a history that may suggest a genetic predisposition to cancer: 1. family clustering of specific types of cancer 2. cancer in very young patients 3. multiplicity of cancers in one individual (ex bilateral breast cancer)
Name some environmental/chemical carcinogens: 1. asbsestos 2. rubber and aniline products 3. benzene 4. vinyl chloride 5. chromates 6. nickel 7. arsenic 8. chemotherapy agents (cause secondary malignancies)
Why has obseity been linked to increased morbidity in breast cancer?: -b/c adipose tissue produces estrogen
Name 2 viruses that can cause cancer in cooperation with HIV: 1. EBV (epstein barr) -AIDs related lymphomas 2. Human herpes virus type 8 -Kaposi's sarcoma
Define chemoprevention and name 2 drugs that have been shown to be successful.: chemoprevention=use of chemical interventions to prevent development of cancer -successful drugs 1. tamoxifen -decreased incidence in women at high risk 2. NSAIDs -celecoxib decrased incidence of polyps in people with familial adenomatous polyposis
Name the 5 main causes of hypoxic cell injury: 1. ischemia 2. anemia 3. carbon monoxide poisoning 4. decreased perfusion of tissues by oxygen-carrying blood 5. poor oxygenation of blood secondary to pulmonary disease
Name some things that can generate free radicals.: 1. normal metabolism 2. oxygen toxicity 3. ionizing radiation 4. UV light 5. drugs and chemicals 6. reperfusion after ischemic injury
Decreased ATP availability due to hypoxic cell injury leads to...: 1. failure of the cell membrane pump -swelling of cell and organelles 2. Disaggregation of ribosomes -> failure protein synthesis 3. Stimulation of phosphofructokinase -increased glycolysis -> decreased intracellular pH -> reversible clumping of nuclear chromatin
What is the point of no return of cellular injury?: 1. irreversible damage to cell membranes -> massive Ca influx -> Extensive calcification of mitochondria 2. intracellular enzymes are released into environment -this is basis of many lab tests that are used as indicators of necrosis
True or false: the vulnerability of cells to hypoxic injury varies: true -hypoxic injury becomes irreversible after 1. 3-5 minutes for neurons 2. 1-2 hours for myocardial cells and hepatocytes 3. many hours for skeletal muscles
How do cells deal with free radicals?: 1. Intracellular enzymes -glutathione peroxidase, catalase, superoxide dismutase 2. Exogenous and endogenous antioxidants -vit A, Vit C, Vit E, glutathione, selenium, ceruloplasmin, transferrin 3. spontaneous decay
Name some causes of monocytosis.: =increased number of monocytes in peripheral blood 1. TB 2. brucellosis 3. typhus 4. salmonella -monocytes-macs able to proliferate in inflamed tissue
Define gangrenous necrosis: -necrosis often affecting lower limbs or bowel -usually secondary to vascular occlusion -histologic changes depend on: 1. tissue involved 2. wet vs dry gangrene
Contrast wet gangrene vs dry gangrene: Dry gangrene =coagulative necrosis w/out liquefaction Wet gangrene =w/ liquefaction
Describe fat necrosis: -can be 2 forms 1. Traumatic fat necrosis -injury to tissue with high fat content (breast) 2. Enzymatic -autodigestion of pancreas by its own enzymes -digested fatty acid form calcium salts (soap formation)
True or false: you get an inflammatory rxn with apoptosis: -false
Name some causes of basophilia: =increased number of basophils in peripheral blood 1. CML 2. other myeloproliferative diseases
Name some causes of neutrophilia: =increased neutrophils in peripheral blood 1. bacterial infections 2. acute inflammation 3. infarction
Name some causes of eosinophilia: =increased number of eosinophils in peripheral blood 1. Allergic rxns -asthma, hay fever, hives 2. parasitic infections 3. Other -polyarteritis nodosa -Hodgkin lymphoma
Name some causes of lymphocytosis: =increased number of lymphocytes in the peripheral blood 1. viral infections -influenza, mumps, rubella, infection mono 2. some bacterial infections -whooping cough, TB 3. chronic inflammation
Name 3 different ways apoptosis can be initiated.: 1. Extrinsic pathway -via cell surface R -Fas -activation of caspases 2. Instrinsic pathway -loss of GF stim or loss BCL-2 -increased mitochondrial permeability -> release cytochrome c -stim bax and bak -activate caspases 3. Cytotoxic T cell activation -direct activation of caspases by granzyme B -granzyme gets in via perforin
Name 3 important genes in apoptosis and state what their roles are:: 1. Bcl-2 -inhibits apoptosis 2. Bax -promotes apoptosis 3. p53 -promotes apoptosis when irreversible DNA damage by: 1. decreas txn bcl-2 2. increase txn bax
Name 2 diseases that cause an increased cellular accumulation of hemosiderin: -hemosiderin=iron-containing pigment 1. hemosiderosis -acumulate in macrophages -no tissue damage 2. hemochromatosis -more extensive accumulation than hemosiderosis -acumulate in parenchymal tissue -damage to organs -can be caused by genetic defect or acquired (multiple blood transfusions, cirrhosis)
How do you tell the difference between metastatic calcification and dystrophic calification?: -metastatic = caused by hypercalcemia -dystrophic= calcification of previously damaged tissue -not due to hypercalcemia (blood levels of Ca are normal)
Name 3 types of chemotactic factors for neutrophils: 1. Bacterial products (formylated proteins) 2. C5a 3. Arachadonic acid metabolits -LTB4, kallikrein 4. fibrinogen
Name the 2 most important opsonins in the immune system.: opsonins=coat stuff to be phagocytosed 1. IgG 2. C3b
Name 2 mechanisms of microbial killing of organisms engulfed by phagocytes.: 1. Oxygen-dependent killing -NADPH oxidase -> superoxide, hydrogen peroxide -myeloperoxidase-> add Cl- halide ion onto H2O2 2. Oxygen-independent -less effective -lysozymes, major basic proteins, etc
Histamine can be released from all of the following EXCEPT: a. mast cells b. activated endothelium c. basophils d. platelets: -activated endothelium (releases PGI2, PAF)
Contrast the actions of TXA2 and PGI2: TXA2 -produced by platelets from COX pathway -vasoconstricts -platelet aggregant PGI2 -produced from endothelium by COX pathway -vasodilator -inhibitor platelet aggregation
What are the actions of LTC4, LTD4, LTE4?: 1. vasoconstrictors 2. bronchoconstrictors 3. increase capillary permeability 4. slow reacting substance of anaphylaxis (delayed phase 1-2 hours after initial hypersensitivity rxn)
Name 4 hereditary disease that result in defects in neutrophils: 1. Chronic granulomatous disease -def in enzymes in NADPH oxidase 2. Myeloperoxidase def. -enzyme def. 3. Chediak-Higashi syndrome -impaired membrane fusion of lysosomes 4. Leukocyte adhesion deficiency (LAD) -type 1: def in integrins; need to bind ICAM and VCAMs -type 2: def in sialyl-Lewis X; need to bind E and P selectins
Define Fibronectin.: =ECM glycoprotein made by fibroblasts, endothelial cells, monocytes -chemotactic for fibroblasts and endothelial cells -promotes angiogenesis -links ECM proteins to cell surface integrins
True or false: PAF can cause vasoconstriction, vasodilation, and increased vascular permeability: -true
What cells synthesize tropocollagen?: -fibroblassts
What is the difference between tropocollagen and collagen?: -tropocollagen= subunit of the larger collagen molecule -collagen= 3 triple helix tropocollagens twisted around each other -larger fibrillary structure
What is the leukocyte differential in a healthy adult?: -55% neutrophils -35% lymphocytes -5% monocytes -3% eosinophils -1% basophils -1% bands
Define neutorphilia: =greater than 7,500 PMN/ uL -pathogenesis 1. increased granulopoesis 2. increased marrow release 3. decreased margination 5. decreased egress -lots of causes
List some of the main causes of neutrophilia: 1.stress 2. infection 3. inflammation 4. tumors 5. drugs (ex glucocorticoids)
Name 3 mechanisms for neutropenia.: neutropenia= less than 1500 PMN 1. Decreased granulopoesis -usu. due to drugs (chemotherapy and others) 2. Increased destruction of neutrophils 3. Increased margination -lots of causes for each mechanism -decreased neutropenia associated with increased chance of infection
What is the function of the different types of granules in neutrophils?: Types: 1. Primary granules -released first after phagocytosis -contain stuff for killing microbes -marker: MPO (myeloperoxidase) 2. Specific -contain Rs for chemotaxis/activation -marker: lactoferrin 3. Tertiary granules 4. Secretory granules
Name some causes of eosinophilia.: eosinophilia= too many eosinophils in peripheral blood -can cause tissue damage 1. Allergy -asthma, drug rxn 2. Dermatitis -atopic, pemphigous 3. Parastite 4. Malignancy -Hodgkin disease, mylelprolif syndromes (CML, etc) 5. Hypereosinophilic syndrome -have genetic translocation 5. Lots of other causes
Name 3 causes of eosinopenia: -less than 100 uL 1. Epinephrine 2. Glucocorticoids 3. Acute infection
How can eosinophils be distinguished from basophils: -both play a role in hypersensitivity 1. Morphological -eosinophils: reddish granules -basophils: blueish granules 2. Tissue phase -basophils: short -eosinophils: longer -eosinophils have major reserves outside BM (lung, skin, GI tract)
What is the main cause of basophilia?: 1. Malignancy -Myeloproliferative disorders (CML, etc) -metastasis to BM
Name some important properties of mast cells: -preformed granules (histamine, herparin, proteases--like basophils) -Long tissue phase (weeks) -Able to make other chemical mediators on activation (like basophils, eosinophils) -impt for immediate hypersensitivity
Name 5 functions of macrophages: 1. Microbial defense 2. Blood clearance -eat senescent RBCs 3. Immunity -antigen presentation -antigen processing 4. Tissue remodeling 5. Generation of soluble mediators -IL-1, TNF, IL-8, PG, LT
What are 2 causes of mastocytosis?: -increased number of mast cells in peripheral blood -mast cells also accumulate in tissues and cause symtpoms -can happen at any age 1. urticaria pigmentosa -benign, non-clonal disorder 2. SCF R mutation leads to autonomous proliferation -bad
Name 6 fxns of endothelial cells: 1. cellular interactions -w/leukocytes and plts via ICAMs, selectins, integrins -Rs upregulated when endothelium is activated 2. Neovascularization 3. Vascular permeability 4. Vascular tone 5. Metabolism -inactive kinins, serotonin, PGs, epinephrine, thrombin 6. Chemical mediator generation
Name some chemical mediators generated by endothelial cells:: 1. Anti-inflammatory molecules -PGs, 2. Mediators of inflammation -IL-1, GMCSF, PAF, PDGF, chemotaxins, IL-8
HLA-A, B, C are ______: MHC I -expressed on all nucleated cells (not RBCs)
HLA DP, DQ, DR are ____: MHC II -expressed on APCs -recognized by CD4+ helper T cells
Define haplotype: =combination of alleles -created by linkage of genes
True or false: HLA genes are the most polymorphic gene of any species: -true -HLA diversity created by: 1. Polymorphisms (more than 1 allele present at a gene locus) -polymorphisms cluster at residues on MHC that contact TCR or the peptide Ag 2. Polygeny (many genes at separate loci encode for a type of protein)
Define desmoplasia: = tumor-induced proliferation of non-neoplastic fibrous connective tissue -seen in breast, pancreas, prostate cancers
Define papilloma: =benign neoplasm that can develop from: 1. surface epipthelium (skin, larynx, tongue) 2. transitional epithelium (bladder, ureter) -tumor has finger-like epithelial processes
Define choristoma: =small, non-neoplastic area of normal tissue misplaced within another organ -benign tumor
Name some other clinical manifestations of malignancy not due to invasion and metastasis of cancer: 1. Cachexia and wasting 2. Endocrine abnormalities -abnormal secreiton from pituitary, ovaries, adrenal glands 3. Paraneoplastic syndromes -Endocrinopathies -Neurologic abnormalities -Skin lesions -Coagulation abnormalities 4. Oncofetal antigens -normally only expressed in fetal life -suggest de-differentiation by neoplasm -ex. CEA (colon cancer), AFP (hepatocellular)

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