Mechanisms of Disease
Terms
undefined, object
copy deck
- Six causes of acute inflammation
- Microorganisms Foreign Particles Necrotic Tissue Physical agents Chemicals Hypersensitivity
- Three Changes of acute inflammatory response
- Haemodynamic changes - Peripheral hyperaemia Alterations of vessel permeability - direct injury & inflamm. mediators Recruitment and migration of neutrophils - Accumulation of PMNs
- Cellular Response in Acute inflammation
- Margination Adhesion (Selectins, Integrins, Ig Gene Superfamily) Emigration Chemotaxis
- What do PMNs recognise?
- Dead tissue Foreign material Opsonins Ig/complement (Fc & C3b receptors)
- Phagocytic Killing mechanisms
- Oxygen Dependent Oxygen independent
- Inflammatory mediators
- Complement Kinins Arachidonic Acid (PG & Leukotrienes) PAFs Cytokines Acute Phase Proteins
- Systemic effects of acute inflammation
- Pyrexia Malaise Weight loss Reactive Lymphoid Lymph-hyperplasia Acute Phase Response
- Benefits of inflammation
- Dilution of toxins entry of Ab Fibrin network formation Nutrients & Oxygen Delivery of neutrophils Immunse response stimulated Entry of drugs
- Problems caused by inflammation
- Destruction of tissue Swelling Blockage of tissues Fluid loss Pain Inappropriate inflammation
- Outcomes of acute inflammation
- Resolution Suppuration (pus) Organisation Calcification Chronic Inflammation Septicaemia Death
- Examples of Pro-inflammatory cytokines
- IL1 IL6 IL8 TNF Alpha
- Definition of Chronic Inflammation
- Long standing inflammation Characterised by mononuclear/chronic inflamm. cells Results in destruction, fibrosis or repair Granulomatous inflammation specific pattern
- Causes of Chronic inflammation
- Primary (infection/irritation/autoimmune) Progression of acute Recurrent acute
- Patterns of chronic inflammation
- Lymphatic Granulomatous Mixed acute/chronic
- Cells involved in chronic inflammation
- Macrophages Lymphocytes Plasma cells Eosinophils
- Macrophage Functions
- Phagocytosis Cytokine production Tissue destruction & repair APC
- Three stages of wound healing
- Inflammation Tissue formation Tissue remodelling
- Three processes of Wound healing
- Cellular migration ECM reorganisation & remodelling Cell proliferation
- Three types of cell
- Labile (skin) Stable (Liver) Permanent (Cardiac)
- Important Collagen types & location
- Type 1 - Bone, tendon, scars Type 2 - Cartilage Type 4 - Basement membrane
- Three parts of ECM reorganisation & remodelling
- Remodelling (Macrophages) Angiogenesis (IL8) Granulation Tissue (perfused, fibrous connective tissue)
- From Wound to Scar Development
- Incision Blood clot Acute inflammation Granulation tissue forms Epithelium proliferation Myofibroblasts invade Collagen & Glycoproteins produced Cell population falls & vessels reduced Collagen matures & contracts
- Healing by primary intention
- Edges of wound opposed & fixed Epidermis regenerates
- Healing by Secondary intention
- Wound not closed Initial contraction Epidermis regenerates at base Granulation tissue bed Longer process, more scarring, more contraction
- What cells cause scar contraction in remodelling, and over what time?
- Myofibroblast Over many months (Poorly understood)
- Local factors affecting wound healing
- Site Size Tissue Type Apposition Infection Blood supply Foreign material Radiation damage
- General factors affecting wound healing
- Age Chronic Diseases Drugs CVA status Dietary insufficiency
- Complications of tissue repair
- Scarring cosmetics Contracture Loss of architecture & function Dihescence
- What do Cadherins do?
- Cell-Cell Adhesion
- What do Intergrins do?
- Cell-Stroma adhesion
- What are the stages of malignant spread
- Invade BM Passage through ECM Intravasation Immune interaction Platelet adhesion Adhesion to endothelium/BM Extravasation Angiogenesis
- Routes of metastatic Spread
- Lymphatics Vascular Trans-Coelomic Spread
- Common Sites of vascular metastatic spread
- Lung Liver Bone Brain
- Local Benign Effects of Neoplasms
- Compression Obstruction Ulceration Space occupying lesion
- Local malignant effects of neoplasms
- Destruction of local tissue Obstruction or constriction Ulceration Infiltration SOL
- Systemic effects of neoplasms
- Haematological (anaemia, low WBC & Thrombosis) Endocrine (excessive / ectopic) Skin (pigmentation, pruritis) Neuromuscular (Balance, sensory) Cachexia Malaise Pyrexia
- Why do neoplasms kill?
- Local effects (Brain perforation, haemorrhage) replacement of essential body organs
- By what mechanism do cells invade & spread
- Altered cell adhesion (Cadherins) Altered cell stromal interactions (integrins) Secretion of proteins (MMPs etc)
- Common secondaries in brain
- Breast Bronchus Testicular Malignant Melanoma
- Common secondaries in Bone
- 5B\'s Bronchial Breast Byroid Brostate Bidney
- Common secondaries in Lung
- Osteosarcoma Breast Stomach Large intestine Kidney cannonball Testes
- Common secondaries in Liver
- GI Breast Bronchial
- Tumour Suppressor Genes
- APC NF1 RB1 BRCA1 p53
- Oncogenes
- c-myc src ras c-erb her-2
- Essential Alterations for malignancy (Mag 7)
- Self-sufficiency in growth signals Insensitivity to negative growth signals Defects in DNA repair Evasion of apoptosis Limitless replicative potential Sustained angiogenesis Ability to invade & metastasise
- Definition of Dysplasia
- Premalignant condition (still confined by BM) Atypia (alteration to cell size, shape etc) Alt. Differentiation (CIN)
- Cytological features of malignant cells
- Poor differentiation Many mitotic figures Increased chromatin Cell & nuclear pleomorphism
- Extrinsic Carcinogens
- Radiation Chemical Virus
- Three Chemical Carcinogens
- Polycyclic Hydrocarbons (tobacco smoke) Aromatic amines Nitrosamines
- Two Radiation carcinogens
- Ionising (Xrays etc) Non-Ionising (UV)
- Inherited Susceptibility to Neoplasms
- Xeroderma Pigmentosum (Bad skin) Ataxia Telangiectasia (Bad skin) Down\'s syndrome (increased risk of ALL)
- Inherited Tumours
- Retinoblastoma Familial Polyposis Coli Breast Cancer Neurofibromatosis
- Stages of Carcinogenesis
- Initiation (Stimulus / unstable genome) Promotion (hormones etc) Progression (6+ gene alterations)
- What is the Ann Arbour Staging System
- I - One group of nodes involved II - two seperate groups, same side of diaphragm III - Nodes on both sides of diaphragm + spleen IV - Bone Marrow, Lungs, other sites A - No symptoms B - Itching & Fever
- Dukes Staging for Colorectal cancer
- A) Not through muscularis propria B) Extended through MP C) Lymph node involvement
- TNM Staging
- T1 < 2cm, T2 2-5cm, T3 Skin/chest wall involvement N0 - no axillary nodes N1 - nodes M0 - No mets M1 - (demonstrable) mets
- Tumour marker for Ovarian cancer
- Ca-125
- Tumour marker for testicular cancer
- Beta-hCG Alpha-fetoprotein
- Tumour marker for Prostate
- PSA Acid Phosphatase
- Tumour marker for GI
- Carcinoembryonic Antigen
- Factors in Radiotherapy
- Type of radiation Rate of delivery Cumulative dose Target tissues Phase of cell cycle Repair mechanisms Oxygenation
- Successful Haemostasis Depends on
- Vessel Wall Endothelial Cells Platelets Coagulation Cascade Fibrinogenesis / Fibrinolysis
- Coagulation is controlled by
- Site restriction & dilation Antithrombin III / Thrombomodulin Negative Feedback by thrombin Release of t-PA Metabolism of active coagulation factors in the liver
- Causes of excessive Bleeding
- Congenital Liver Disease Vitamin K Deficiency DIC
- Congenital clotting factor deficiencies
- Von-Willebrands Disease (Autosomal Dominant - low factor VIII) Haemophilia A (X-linked recessive, low factor VII) Haemophilia B (Factor IX deficient)
- Causes of excessive clotting
- Thrombocytosis Sticky platelets Cancer SLE Acquired (Protein S&C deficiency)
- Constituents of a thrombus
- Platelets Fibrin Trapped cells
- Definition of thrombus
- Solid mass of blood constituents formed in circulation in life
- Predisposing factors to thrombosis
- Vessel wall abnormalities Changes in blood constituents Changes in blood flow
- Clinical effects of arterial thrombosis
- Cuts off blood supply to part of an organ causing ischaemic necrosis (infarction) Source of emboli MI / Stroke
- Fates of thrombus
- Propogation in direction of blood flow Fibrinolysis & removal Organisation into scar tissue Recanalisation
- What is an embolism?
- A mass which travels through vascular tree & becomes lodged so as to obstruct blood flow
- Types of Embolism
- Air Amniotic Fluid Atheroma Fat Foreign Material Nitrogen Tumour Cells
- DVT Prophylaxis
- Heparin & Leg compression
- DVT Treatment
- Heparin & Warfarin
- Arterial Thrombosis Prophylaxis
- Aspirin
- Arterial Thrombosis Treatment
- Streptokinase t-PA
- What regulates cell growth?
- Rate of population growth Signal molecules Cell-Cell interactions Cell-Matrix interactions General factors (Nutrition, blood supply etc)
- Phases of cell cycle
- G0 G1 S G2 M
- Different Cellular Responses in Growth & Differentiation
- Hyperplasia (more cells) Hypertrophy (big cells) Atrophy (Shrinking cells) Metaplasia (Reversibly changing mature cells) Hypoplasia (incomplete development of an organ)
- Causes of Atrophy
- Reduced workload Loss of nerve supply Reduced blood supply Inadequate nutrition Loss of endocrine stimulation Ageing
- What is atherosclerosis
- Chronic arterial disease characterized by intimal accumulation, resulting in narrowing of arterial lumen, weakening of wall, sudden local thrombus formation
- What accumulates in atherosclerosis
- Lipid Inflammatory cells Vascular smooth muscle cells ECM
- Three types of atheroma
- Fatty Streaks Simple (Fibrous) Plaque Complicated plaque
- Describe a simple plaque
- Peripheral proliferating vessels Raised Irregular outline Central Necrosis Enlarged & coalesced
- Four complications of a plaque
- ARSE Aneurysm Rupture Stenosis Embolism
- Effects of Atheroma
- IHD Cerebral Ischaemia (Cerebral Infarct, TIA or Multi Infarct dementia) Mesenteric Ischaemia Aortic aneurysm & rupture (& Peripheral Vascular disease - intermittient claudication)
- Non Modifiable risk factors for atheroma
- Age Family Hx Male
- Modifiable risk factors for Atheroma (The \'Deadly Quartet\')
- Hyperlipidaemia Hypertension Cigarette Smoking Diabetes
- Pathogenesis of Atheroma
- Lipid & Lipoproteins - Oxidisation leads to... Endothelial dysfunction & Altered Cell Adhesion - Vasoconstriction & cell adhesion / chemoattractants Macrophages & other Inflam cells - Inflammatory response Inflammation & Cytokines - More recruitment ECM - Proliferation & migration of vascular smooth muscle
- What causes silent lesion to rupture
- Degradation of cap by proteases from macrophages etc
- 5 Causes of cell injury
- Hypoxia Chemical Physical Immune Nutrition
- Pathogenesis of reversible cell injury
- Loss of ATP - failure of Na/K ATPase Increased glycolysis Increased lactic acid Detachment of ribosomes etc
- Microscopic features of reversible cell injury
- Cellular swelling Loss of microvilli Blebbing ER swelling Myelin figures Clumping of chromatin Mitochondrial swelling
- Pathogenesis of Irreversible Cell Injury
- Massive Ca accumulation Enzyme activation
- Microscopic features of irreversible cell injury
- Rupture of lysosomes & autolysis Mitochondrial swelling Lysis of ER Defects in cell membrane Nuclear Pyknosis, Karyolysis, Karyorhexis
- Free radicals generated by
- Irradiation Normal metabolism Transition Metals Nitric Oxide Toxins
- Free radicals removed by
- Spontaneous decay Antioxidants Storage proteins Enzymes
- Free radical Injury
- Membrane lipid peroxidation DNA damage Interaction with proteins
- Three Patterns of Necrosis
- Coagulative (Ischaemia) Liquefactive (Brain) Caseous (TB) (Fat)
- Triggers for Apoptosis
- Withdrawal of growth stimuli Death signals DNA damage
- Ann Arbour is used for...?
- Lymphoma
- MOD
- MOD