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Pathology - Cell Injury


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Basic cell & tissue reactions that underlie disease
Special or systemic PATHOLOGY
Specific responses of specialized organs to stimuli that result in disease
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
decrease in size & function
increase in size
increase in number of cells
change from one cell type to another(altered differentiation)
abnormal changes in cellular components, usually a cancer precursor
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)
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
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
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 ________
persistant irritation of metaplastic cells can result in ________
cancer transformation
Metaplasia requires Reprogramming of _________, involving (3)__________
stem (reserve) cells/ Cytokines, growth factors, & extracellular factors
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
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
1)biochemical (functional) changes occur first
2)morphologic (structural) alterations next
2)morphologic (structural) alterations in order of severity include
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
plasma membrane alterations

mitochondrial alterations

endoplasmic reticulum alterations

lysosomal alterations
cell swelling
cytoplasmic blebs
blunting of microvilli
myelin forms
loosening of intercellular attachments
membrane breaks
mitochondrial swelling
matrix condensation
bizarre forms
amorphous densities
calcium deposits
membrane rupture
Endoplasmic Reticulum changes result in decreased ____________
Protein synthesis
Reversible ER changes
ribosomes detach
polysomes dissociate
irreversible ER changes
progressive fragmentation
Lysis of ER
-may be swollen
-no leakage of enzymes
-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
Cellular swelling
-Cytoplasmic eosinophilia
-Homogeneous (glycogen loss)
-Eosinophilic globules(swollen mitochondria)
-Cellular calcification
increase granularity
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
(compression of capillaries)
Increase weight
(due to cellular swelling)
Increase turgor
(due to increase in size)
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
Morphologic changes
Clinical significance
-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)
-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?
-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)
Define the following terms:

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?
⬢ 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?
-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
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,­enzyme 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?
-- 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)
What happens with persitent hypoxia?
Irreversible injury – ischemia
-- severe swelling (vacuolization)
-- large flocculent amorphous densities

plasma membrane
--extensive damage
--leakage of enzymes, coenzymes, proteins

--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?

• Hypoxia leads to ¯ mitochondrial oxidative respiration
• Changes in plasma membrane (ATP-dependent)
• Altered energy metabolism
– Glycolysis,­enzyme 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?
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?
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
o is the accumulation of carbon particles (exogenous)
What are the two principal patterns of cell death, resulting from cell injury & their definitions
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•

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
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
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

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
 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)

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