Pathology - Cell Injury
Terms
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- General PATHOLOGY
- Basic cell & tissue reactions that underlie disease
- Special or systemic PATHOLOGY
- Specific responses of specialized organs to stimuli that result in disease
- PATHOGY
-
Study of disease (suffering)
-Cause (etiology)
-Mechanism of development (pathogenesis)
-Structural alteration in cells and organs (morphologic changes)
-Functional consequences (clinical significance - cell’s ability to handle normal physiologic demands (normal homeostasis) depends on:
- Its genetic program of metabolism, differentiation, specialization, constraints of neighboring cells, availability of metabolic substrates
- when physiologic demands are excessive
- cellular adaptation may result
- atrophy
- decrease in size & function
- hypertrophy
- increase in size
- hyperplasia
- increase in number of cells
- metaplasia
- change from one cell type to another(altered differentiation)
- dysplasia
- abnormal changes in cellular components, usually a cancer precursor
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Atrophy (shrinkage in size)
Pathologic Causes: -
-atrophy of disuse
-loss of innervation
-diminished blood supply
-inadequate nutrition
-loss of endocrine stimulation
(thyroid & corticosteroids)
-aging (senile atrophy)
-pressure (masses) - Features of Atrophy
-
-Diminished size & function (not dead)
-Similarities to apoptosis (programmed cell death)
-Biochemical mechanisms involve an imbalance in the regulation of:
-Protein synthesis
-Protein degradation (key role)
-Atrophy is usually associated with
-Autophagic vacuoles
-Residual bodies: lipofuscin granules (brown discoloration) -
MECHANISMS OF ATROPHY
Increased Protein Degradation -
-Lysosomes: acid hydrolases (e.g.,cathepsins) degrade proteins
-Ubiquitin-proteasome pathway of protein degradation (catabolic cancer cachexia)
-Hormones: glucocorticoids and thyroid stimulate:
-Proteasome-mediated protein degradation (opposed by insulin)
-Cytokines: TNF-a and IL-1B accelerate muscle proteolysis
-May progress to cell death - Lipofuscin
- residual bodies that resist digestion
- Types of Hypertrophy
-
1) Physiologic
– e.g.: uterus & breast in pregnancy --Stimulated by hormones: e.g., estrogen & prolactin
2)Pathologic – e.g., heart muscle adaptation due to increased workload (associated with changes in gene expression: e.g., atrial/brain natriuretic factors, a-myosin replaced by B-myosin heavy chain, TGF-B, etc.) - types of hyperplasia w/ examples
-
1)Physiologic:
Hormonal: female breast at puberty & during pregnancy
Compensatory: liver after partial hepatectomy
2) Pathologic (may be precancerous):
Excessive hormonal stimulation: endometrium
Effects of growth factors on target cells:
Repair: fibrovascular proliferation
Viruses (HPV)
Epithelial/epidermal proliferative lesions - METAPLASIA results in the loss of important _______at expense of ________
- function/durability
- persistant irritation of metaplastic cells can result in ________
- cancer transformation
- Metaplasia requires Reprogramming of _________, involving (3)__________
- stem (reserve) cells/ Cytokines, growth factors, & extracellular factors
-
CELL INJURY-CELL DEATH
etiologic agents -
HYPOXIA & ISCHEMIA: anemia, CO poisoning, occlusive atherosclerosis
physical agents: burns, cold, radiation, electric shock⬦.
chemicals and drugs: glucose, salt, oxygen, arsenic⬦
microbiologic agents: bacteria, viruses⬦.
immunologic derangements: drug rx --- autoimmunity
genetic derangements:
congenital malformation --- single amino acid substitution
nutritional imbalances: anorexia --- obesity - bichemical mechanisms of cell injury may be well defined or not well understood. Well defined mechanisms involve can involve interference with with endogenous or enzymes or pathways like glycolosis, TCA cycle, or oxidative phosphorylation. The result of
- low ATP
-
CELL INJURY & NECROSIS
common pathways to cell injury -
1) oxidative stress
2) ATP depletion
3) defects in selective membrane permeability
4) increase in intracellular Ca & loss of Ca homeostasis leads to activation of intracellular enzymes
5) irreversible mitochondrial damage - oxidative stress is damage sustained from
- oxygen-derived free radicals
- ATP depletion results from ________
- ischemic and toxic injury
- irreversible mitochondrial damage results from _______ which can result in _______ which can trigger _________
-
mitochondrial permeability/
leakage of cytochrome c /apoptosis - SEQUENCE OF EVENTS IN CELL INJURY
-
1)biochemical (functional) changes occur first
2)morphologic (structural) alterations next - 2)morphologic (structural) alterations in order of severity include
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ultrastructural
light microscopic
macroscopic (gross) - the extent of morphologic (structural) alterations can define:
-
reversible cell injury
or irreversible cell injury (cell death) - MORPHOLOGIC CHANGES--ultrastructural findings
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plasma membrane alterations
mitochondrial alterations
endoplasmic reticulum alterations
lysosomal alterations - Reversible CELL MEMBRANE CHANGES
-
cell swelling
cytoplasmic blebs
blunting of microvilli
myelin forms
loosening of intercellular attachments - Irreversible CELL MEMBRANE CHANGES
- membrane breaks
- Reversible MITOCHONDRIAL CHANGES
-
mitochondrial swelling
matrix condensation - Irreversible MITOCHONDRIAL CHANGES
-
vacuoles
bizarre forms
amorphous densities
calcium deposits
membrane rupture - Endoplasmic Reticulum changes result in decreased ____________
- Protein synthesis
- Reversible ER changes
-
dilatation
ribosomes detach
polysomes dissociate - irreversible ER changes
-
progressive fragmentation
Lysis of ER - Reversible LYSOSOMAL CHANGES
-
-may be swollen
-no leakage of enzymes - Irreversible LYSOSOMAL CHANGES
-
-clear and markedly swollen
-rupture and disappearance
-leakage of enzymes - describe normal cell
- orderly and intact subcellular structures
- Reversable cell changes
-
-cell/ER swelling/blebs
-loosen attachments
-mitochondrial swelling
-detachment of ribosomes - Irreversible cell changes
-
-membranes break
-large bizarre mitochondria
-calcium deposits
-rupture/disappearance of lysosomes - MORPHOLOGIC CHANGES visable by light microscopy
-
cytoplasmic changes
nuclear changes
nucleolar changes - Reversible CYTOPLASMIC CHANGES
- Cellular swelling
- Irreversible CYTOPLASMIC CHANGES
-
-Cytoplasmic eosinophilia
-Homogeneous (glycogen loss)
-Eosinophilic globules(swollen mitochondria)
-Cellular calcification - Reversible NUCLEOLAR CHANGES
- increase granularity
- irreversible NUCLEOLAR CHANGES
- nucleolar loss
- Cell response to injury depends on __________
- Type of injury, duration, and its severity
- The consequences of injury depend on __________
- The type, state, and adaptability of injured cell
- Cellular sites particularly vulnerable to injury________
- Cell mem, aerobic resp, protein syn, genetic apparatus
- Morphologic change becomes apparent only after _________
- derangement of some critical biochemical system
- REVERSIBLE CELL INJURY--effect on tissues or organs
-
Pallor
(compression of capillaries)
Increase weight
(due to cellular swelling)
Increase turgor
(due to increase in size) - COMMON FORMS OF CELL INJURY
-
Ischemic and hypoxic injury
Injury induced by free radicals including activated oxygen species
Toxic injury - Ischemic/Hypoxic Injury--sequence of widespread effects
-
2) Hypoxia leads to decreased mitochondrial oxidative respiration which results in low ATP
2) ATP Changes in plasma membrane occur
3) Altered energy metabolism results
- there is increased enzyme activity, glycolysis speeds up, glycogen is degraded, pH is lowered making cell more acidic
3) Structural disruption of protein synthesis in the ER occurs -
In heart ischemic/hypoxic injury consequences in 60sec are __________ but ________
After this ________ occurs - functional/reversable/ irreversible injury
- What is the definition of pathology?
-
Literally: it is the study (logos) of suffering (pathos) or disease
Specifically: Discipline devoted to the study of structural and functional changes in cells, tissues, and organs that underlie disease? - Name the 4 aspects of a disease process that form the core of pathology
-
Etiology
Pathogenesis
Morphologic changes
Clinical significance - Etiology
-
-Definition: primary cause of a disease
- 2 major classes of etiologic factors: intrinsic or genetic, and acquired (see Chart 1 for examples of acquired factors) - Pathogenesis:
-
-Definition: Mechanisms of development
-Specifically refer to the sequence of events in the response of the cells or tissues to the etiologic agent, from the initial stimulus, to the ultimate expression of the disease - Morphologic changes
-
Definition: Structural alterations induced in the cells and organs of the body
-Are either characteristic of the disease or diagnostic of the etiologic agent - What is cellular adaptation and what are some forms of it?
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-Cellular adaptation: new but altered steady states of a cell are achieved, preserving the viability of the cell
-Forms: atrophy, hypertrophy, hyperplasia, metaplasia - What is the sequence of events leading to cell injury?
-
-First: biochemical (functional) changes
-Second: morphologic (structural) changes (from microscopic changes gross (macroscopic) changes) - What does the homeostasis of a cell depend on?
-
-Genetic program
-Constraints of neighboring cells
-Availability of metabolic substrates - Clinical significance
- Definition: Functional consequences of the morphologic changes (symptoms and signs that determine the prognosis of the disease)
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Define the following terms:
Metaplasia
Hypertrophy
Atrophy
Hyperplasia
Dysplasia -
a)Change from one cell type to another
b)Increase in size
c)Decrease in size and function
d)Increase in the number of cells
e)Abnormal changes in cellular components - What is the difference between the mechanisms of hypertrophy and hyperplasia?
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⬢ The mechanism of hypertrophy does NOT involve cells that undergo division whereas that of hyperplasia does
⬢ Hypertrophy:--Mostly due to increased functional demand of cell which leads to an increase in protein production
⬢ Hyperplasia: -Restricted to cells that have the ability to synthesize DNA (ie liable cells) - What is dysplasia? How is it categorized?
-
An abnormal organization of cells; loss of polarity is involved w/nuclei at different sites
- 4 categories: very mild, mild, moderate, and severe
-Cells go from normal to dysplasia to carcinoma - What are the states of progressive encroachment to the cell if the physiologic demands on it’s normal structure and function are too excessive
- Adaptation to reversible injury to irreversible injury to cell death
- What are the three most common forms of cell injury?
-
-Ischemic and hypoxic injury
-Injury induced by free radicals
-Toxic injury - What ultrastructural cell components are altered in cell injury/death? Which cell components seen with light microscopy are altered?
-
Ultrastructural
-plasma membrane -mitochondria
-ER -lysosome
Light Microscope:
-Cytoplasm -Nucleus -Nucleolus - What does high cytosolic calcium concentration levels tell about the state of the cell?
- Indicates a pathologic response, such as ischemia
- What are the most common pathways to cell injury and cell death?
-
-ATP depletion
-↑ in oxygen-derived free radicals
-↑ in intracellular Ca and loss of Ca homeostasis - 4 intracellular systems are particularly vulnerable in most forms of cell injury?
-
a)Maintenance of the integrity of the cell membrane (especially ionic & osmotic homeostasis)
b)Aerobic respiration (involves oxidative phosphorylation and ATP production)
c)Protein synthesis
d)Preservation of the integrity of genetic apparatus of the cell - ⬢ Which cellular sites particularly vulnerable to injury?
- – Cell mem, aerobic resp, protein syn, genetic apparatus
- Hypoxia
- Inadequate oxygenation of the blood due to problems concerning aerobic oxidative respiration, but NOT affecting glycolytic energy production!
-
What happens in an ischemia injury?
(in words) -
• Hypoxia leads to decreased mitochondrial oxidative respiration
• Changes in plasma membrane (ATP-dependent)
• Altered energy metabolism
– Glycolysis,Âenzyme activity,¯glycogen, ¯pH
• Structural disruption of protein synthesis (ER)
• Functional, but reversible, consequences in 60sec in the heart
• Persistent hypoxia ® irreversible injury - What is the “Irreversible Ctiical Events†of ischemia?
-
ATP depletion leads to
**Profound dist in membrane function leads to Inability to reverse mito dysfunction with reperfusion, leading back to ATP depletion
Irreversible a early as 30-40 min in heart – before that, injury is reversible - What effects does reversible cell injury have on tissues or organs?
-
-Pallor (from compression of capillaries)
-Increase weight (due to cellular swelling)
-Increase turgor (due to increase in cell size) - What are the other forms of cell injury besides ischemia/hypoxia?
-
-Free radical injury
-Chemical injury - Outcome of Ischemia?
-
MEMBRANE DAMAGE
-- damage to cytoskeleton (due to swelling)
--free radical injury/lipid breakdown/glycine loss
--entry of extracellular Ca & water
--leakage of enzymes/proteins (clinical utitility)
-- lysosomal rupture (enzymatic digestion of cell)
COAGULATIVE NECROSIS - What happens with persitent hypoxia?
-
Irreversible injury – ischemia
mitochondria
-- severe swelling (vacuolization)
-- large flocculent amorphous densities
plasma membrane
--extensive damage
--leakage of enzymes, coenzymes, proteins
lysosomes
--swelling and activation of enzymes leading to digestion - What is the effect of reversible cell injury on tissues or organs?
-
• Pallor
– compression of capillaries
• Increase weight
– due to cellular swelling
• Increase turgor
– due to increase in size -
What happens in an ischemia injury?
(diagram) -
• Hypoxia leads to ¯ mitochondrial oxidative respiration
• Changes in plasma membrane (ATP-dependent)
• Altered energy metabolism
– Glycolysis,Âenzyme activity,¯glycogen, ¯pH
• Structural disruption of protein synthesis (ER)
• Functional, but reversible, consequences in 60sec in the heart
• Persistent hypoxia leads to irreversible injury - What is the mechanism of Iscemic injury – steps?
-
1)Damage to cytoskeleton (due to swelling)
2)Free radical injury/lipid breakdown/glycine loss
3)Entry of extracellular Ca and water
4)Leakage of enzymes/proteins (clinical utility!)
5)Lysosomal rupture leads to Coagulative necrosis - What are free radicals? Name some characteristics of them
-
-Extremely unstable and reactive chemical species with single unpaired electron in the outer orbit
-React with key molecules in membrane and nucleus (organic and inorganic chemicals)
-Capable of autocatalytic rxn (to increase # of radicals) - What are the 2 mechanisms for chemical injury? Give at least 2 examples for each mechanism listed
-
1st one: Direct combination with cell components
a)Mercuric chloride poisoning (binds to sulfhydral groups of cell membranes and other proteins
b)Cyanide: directly poisons mitochondrial enzymes
2nd one: Free radical formation (by P-450 mixed function oxidase in ER)
a)CCl4 leads to free lipid radicals which leads to an inability to form lipoproteins leading to cell membrane damage and fatty liver or cell death
b)Acetaminophen (Tylenol): ↑↑ Tylenol leads to ↑ toxic metabolites (oxidative) leads to massive liver cell necrosis (antioxidants helpful as tx) - Whar are some of the actions of free radicals?
-
--Lipid peroxidation of membranes- lipid-radical interactions yield peroxides, which are unstable and reactive= propogation and maybe termination by Vit E, etc
--Protein damage- oxidation of protein backbone results in protein fragmentation and degradation of enzymes by proteasome complex
--DNA damage- rxns w/ thymine in nuclear and mitochondrial DNA produce single-stranded breaks in DNA - What are the causes of Atrophy?
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o Loss of innervation: normal functioning of skeletal muscle is dependent on its nerve supply; damage to the nerves leads to rapid atrophy of the muscle fibers supplied by those nerves
o Loss of endocrine stimulation: the loss of estrogen stimulation after menopause results in physiological atrophy of the endometrium, vaginal epithelium and breast
o Pressure atrophy- as an organ gets enlarged, the surrounding tissue gets crowded and cells atrophy; a tumor can cause same effects - How is atrophy different than apoptosis?
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In apoptosis, the cell initially enlarges and then dies
In atrophy, the cell simply diminishes in size Main point fo Atrophy: protein degradation with accumulation of metabolic by-products - Anthracosis
- o is the accumulation of carbon particles (exogenous)
- What are the two principal patterns of cell death, resulting from cell injury & their definitions
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Necrosis -Spectrum of morphologic changes that follow cell death in living tissue
-results from:
1)enzymatic digestion of the cell
2)denaturation of proteins
apoptosis-Programmed cell death during embryogenesis
-Shares some common mechanisms with necrotic cell death
-Much more rapidly progressing process - Describe the steps taken in the prevention of free radicals by the body
-
1st, here’s the mechanism: O2 (spontaneous rnx)leads to O2- (spontaneous rxn or SOD)leads to H2O2 leads to (Fenton rxn) OH•
Prevention:
a)catalase in peroxisomes decomposes H2O2
b)Glutathione peroxidase: converts OH• to H2O
c)Antioxidants: E, A, ascorbic acid (C) - What Is happening in Iscemia?
-
-Inadequate oxygenation from loss of blood supply due to impeded arterial flow or reduced venous drainage in a tissue
-As oxygen within the cell ↓, there is a loss of oxidative phosphorylation and ↓ generation of ATP***(All ischemic disease can ultimately be traced back to cellular depletion of ATP!)
-↓ availability of metabolic substrates, including glucose, which are supplied by flowing blood - What are Lipofusin granules
-
common in elderly
Residual cellular components destined for degradation in the lysosomes - What are the mechanisms of physiological hyperplasia in hepatocytes?
-
 Initial priming signal by remnant hepatic cells
 Growth factors: both TGF-alpha and EGF are mitogenic for hepatocytes in culture. EGF plays a role in early stages after partial hepatectomy, while TGF-alpha acts at a later time - What’s happening during an irreversible change?
-
cell membrane disruption + eosinophilic cytoplasm + pyknosis (small nucleuses). Sometimes even karyignosis (no nucleus)
--Large, flocculent densities develop in mitochondrial matrix
--Injury to lysosomes and release of damaging enzymes
Membrane disruption is a central factor in pathogenesis of irreversible cell injury
Loss of intracellular AA’s, principally glycine, disables ATP-depleted cells from resisting lethal effects of high Ca and thus remain viable - What is happening in a reperfusion Injury
-
New damage by increased generation of oxygen-free radicals
Free radicals promote mitochondrial permeability transition
Cytokines (inflammatory molecules) and adhesion molecules in ischemia recruit PMN’s w/ reperfusion - Describe Coagulative necrosis
-
protein denaturation
*most common necrosis manifestation
-characterized by denaturation of cytoplasmic AND enzymatic proteins, breakdown of cell organelles and cell swelling
-implies preservation of the basic outline of the coagulated cell for a span of at least some days, which is characteristic of hypoxic death of cells in all tissues except the brain
-affected tissue exhibits a firm texture
Example MI (myocardial infaction) - Describe Caseous necrosis
-
-distinctive form of coagulative necrosis
-encountered most often in TB infections
-characterized by a white cheesy appearance of the area of necrosis
There are no cell outlines
Very amorphous material
Example TB granulomas - Describe Liquifactive necrosis
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enzymatic digestion
-Characteristic of bacterial or fungal infections
-Completely digests the dead cells
-End result is a transformation of the tissue into a liquid viscous mass
-Material is frequently creamy yellow b/c of the presence of dead white cells (pus)
Example: Abcess, hetolysis -
Infarctions are the result of what kind of cellular injury?
What is the most common type of this kind of injury? -
Infarctions result from necrosis
The most common type of necrosis, with the exception of the brain, is coagulative necrosis - What is happening during a reversible change?
-
cell swelling + accumulation of fluid
-- ATP depletion causes inactivity of ATPase pump, causing sodium to accumulate intracellularly w/ diffusion of potassium out of the cell
* this causes a net gain of water intracellularly and cell swelling
*ATP depletion also causes a depletion in glycogen stores and an increased rate of anaerobic glycolysis
--Detachment of ribosomes from ER and disassociation of polysomes into monosomes, w/ a reduction in protein synthesis
If oxygen is restored, all of these disturbances are reversible - Ubiquitin-proteasome pathway is responsible for what?
- for the degradation of cytosolic and nuclear proteins
- Describe Enzymatic Fat necrosis
-
-Descriptive of focal areas of fat destruction
-Result of release of activated pancreatic lipases into the pancreas, causing acute pancreatitis
-Look like white blobs (soap bubbles)
Example: Acute pancreatitis - Describe Fibrinoid necrosis
-
 occurs b/c of immune complexes that have accumulated in vascular wall, leading to a lack of blood supply to area
 Fibrinoid necrosis is seen w/ immune diseases - What are some disorders of Apoptosis?
-
Inhibition of apoptosis & increased cell survival
Cancers (e.g., p53 mutations)
Autoimmune disorders (autoreactive lymphocytes)
Increased apoptosis and excessive cell death
Neurodegenerative diseases
Contributes to ischemic injury
Virus-induced lymphocyte depletion - Suponification
- bubbles of fat in tissue due to combining of fat w/ Ca
- Calcified deposits in the bone are a good sign of?
-
cell injury-
the increase in cytoplasmic Ca concentrations that occurs b/c of cell membrane degradation is responsible for these deposits - Cytochrome C acts as what kind of signal?
-
apoptotic signal
when it gets released by mitochondria during mitochondrial membrane degradation, it causes the cell to die
Damage to mitochondria causes formation of a channel on inner mitochondrial membrane called mitochondrial permeability transition (MPT)
This MPT, if injury persists, leads to leaking out of H+ (loss of proton-motive force) and leakage of
cytochrome c - What is Oxidative stress?
- results from an imbalance between free radical-generating and radical-scavenging systems (wins out over former)
- What are the four steps in Apoptosis?
-
Signaling pathway-
Needs to be there to initiate apoptosis – pos or neg stimuli
Control/Integration stage:
It can either promote progression of apoptosis or stop it
Execution phase:
Stage in which apoptosis is made certain - caspases disrupt the cytoskeleton
Removal:
Cell is removed via macrophages - What organelles are effected during subcellular response to injury?
-
-Lysosome: Catabolism, storage diseases
-Smooth ER: induction tolerance or adaptation
-Mitochondria: hypertrophy, atrophy, myopathies, oncocytomas
-Cytoskeleton: Chediak-Higashi, Mallory bodies (intermediate filaments), neurofibrillary tangle - Describe Gangrenous Necrosis
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 Not a distinctive pattern of cell death that has lost its blood supply and has undergone coagulation necrosis Gangrenous necrosis usually occurs in the lower extremities in patients w/ diabetes, etc.
 Dry Gangrene: occurs b/c of coagulative necrosis
 Wet Gangrene: occurs b/c of liquifactive necrosis
Ex. : atherosclerotic ischemia (wet)