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Flashcards in Test 2- Cell Injury Deck (106):

Reversible cell injury

– Morphologic correlates:

Reversible cell injury

– Morphologic correlates:

• Cellular swelling
• Fatty changes (lipidosis)


Irreversible cell injury and cell death

– Morphologic correlates:

– Morphologic correlates:

• Necrosis

• Apoptosis
• Other types of cell death


Acute cell swelling- other names

AKA: hydropic degeneration; hydropic change;

cytotoxic edema (CNS); ballooning degeneration (epidermis)


Highly vulnerable to hypoxia & cell swelling:

Highly vulnerable to hypoxia & cell swelling:


proximal renal tubule epithelium



CNS neurons ,oligodendrocytes, astrocytes(cytotoxic edema)


Definition of acute cell swelling

• Early,sub-lethal manifestation of cell damage, characterized by ↑ cell size & volume due to H2O overload

• Most common and fundamental expression of cell injury


Etiology of acute cell swelling

 Loss of ionic and fluid homeostasis
Failure of cell energy production
Cell membrane damage
Injury to enzymes regulating ion channels of membranes

Most frequent causes of this:

are Hypoxia, and toxic agents


Pathogenesis of acute cell swelling

less oxygen and ATP production decreases

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Gross appearance of acute cell swelling

Slightly swollen organ with rounded edges

Pallor when compared to normal

Cut surface: tissue bulges & can not be easily put in correct apposition

Slightly heavy (“wet organ”)

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Example of ballooning degeneration resulting in formation of a vesicle (bullae/blister)

Specific type of cell swelling

Cutaneous vesicles, vesicular exanthema, snout, pig.

Etiology: vesicular exanthema of swine virus, a calicivirus (vesivirus).


Histologic appearance of cellular swelling !

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H2O uptake dilutes the cytoplasm

Cells are enlarged with pale  cytoplasm

May show increased cytoplasmic eosinophilia

Nucleus in normal position, with no morphological changes


difficult morphologic change to appreciate with the light microscope!


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Epidermis - ballooning degeneration (extreme variant of hydropic degeneration)

Etiology : Swinepox virus- pox viruses in general


Ultrastructural changes of cellular swelling

1. Plasma membrane alterations, such as blebbing, blunting, and

loss of microvilli
2. Mitochondrial changes, including swelling and the appearance of small amorphous densities

3. Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figures may be present (see later)

4. Nuclear alterations, with disaggregation of granular and fibrillar elements

Kidney, epithelial cell

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Which parts of the cell are the most important for cellular swelling?

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mitchondrial swelling

ER swelling

clumping of clear chromatin

general swelling


Hydropic change, Fatty change (Cell swelling)

due to ↑uptake of H2O & then to diffuse disintegration of organelles and cytoplasmic proteins


Hypertrophy (Cell enlargement)

• the cell enlargement is caused by ↑ of normal organelles


Prognosis of cellular swelling

Depends on the number of cells affected and importance of cells

Good (if O2 is restored before the “point of no return”- changes are irreversible)

Poor (progression to irreversible cell injury)


Lipofuscin in a cell

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evidence of previous injury (e.g. neuron)

seen in cells with a longer lifespan


Definition of fatty change

• sub-lethal cell damage characterized by  intracytoplasmic fatty vacuolation
• maybe preceded or accompanied by cell swelling


All major classes of lipids can accumulate in cells:

- Triglycerides
- Cholesterol/cholesterol esters
- Phospholipids

- Abnormal complexes of lipids and carbohydrates (lysosomal storage diseases)



- accumulation of triglycerides and other lipid metabolites (neutral fats and cholesterol) within parenchymal cells heart muscle
skeletal muscle
 kidney

LIVER-clinical manifestations are most commonly detected as alterations in function (elevated liver enzymes, icterus) because the liver is the organ most central to lipid metabolism


Etiology of fatty change

Main causes: hypoxia, toxicity, metabolic disorders

Seen in abnormalities of synthesis, utilization and/or mobilization of fat


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Etiology of fatty change


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fatty change


Pathogenesis of fatty change

  1. impaired metabolism of fatty acids

  2. accumulation of triglycerides

  3. formation of intracytoplasmic fat vacuoles


Pathogenesis of fatty liver

Hepatic lipid metabolism and possible mechanisms resulting in lipid accumulation.

1, Excessive delivery of free fatty acids (FFA) from fat stores or diet.
2, Decreased oxidation or use of FFAs.
3, Impaired synthesis of apoprotein.

4, Impaired combination of protein and triglycerides to form lipoproteins.
5, Impaired release of lipoproteins from hepatocytes.

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only form in which triglycerides can be transported out of the hepatocytes



Gross appearance of fatty change

Liver: Diffuse yellow (if all cells are affected)

Enhanced reticular pattern if specific zones of hepatocytes are affected

Edges are rounded & will bulge on section

Tissue is soft, often friable, cuts easily and has a greasy texture

If condition is severe small Cat liver sections may float in
fixative or water


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fatty change


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Gross appearance of hepatic lipidosis (AKA: fatty liver, fatty change, hepatic steatosis

clinically - alterations in liver function (↑liver enzymes, icterus(yellowing))


Physiologic: in late pregnancy (pregnancy toxemia) and heavy early lactation (ketosis) in ruminants


Ketone bodies

Ketone bodies: are alternative fuel for cells

Produced in the liver by mitochondria

Convertion of acetyl CoA from fatty acid oxidation=LIPOLYSIS


Hepatic lipidosis

Nutritional disorders:


protein-calorie malnutrition (impaired apolipoprotein synthesis)

starvation (↑mobilization of triglycerides)


Hepatic lipidosis

Endocrine diseases

Endocrine diseases,

diabetes mellitus (↑mobilization of triglycerides);

feline fatty liver syndrome, fat cow syndrome (unknown cause)

Niemann Pick disease (phospholipid sphingomyelin) – a Lysosomal Storage Disease


Histologic appearance of fatty change

Well delineated, lipid-filled vacuoles in the cytoplasm

Vacuoles are single to multiple, either small or large

Vacuoles may displace the cell nucleus to the periphery

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Prognosis of fatty change

Initially reversible – can lead to hepatocyte death (irreversible)

Hepatic lipidosis: is seen in cats, ruminants, camelids, and miniature equines, but is rare in dogs and uncommon in other horses. It is seen more often in obese cats, secondary to anorexia of any cause. Mortality is high without treatment.

Identification and treatment of any predisposing diseases and aggressive nutritional support is required for therapy of hepatic lipidosis.

Oral appetite stimulants can be given but are usually inadequate alone.


Irreversible injury

 associated morphologically with:

– severe swelling of mitochondria

– extensive damage to plasma membranes(giving rise to myelin figures) – swelling ofl ysosomes

How quickly can this happen?


- 30 to 40 minutes after ischemia

Cell Death:
– mainly by necrosis
– apoptosis also contributes


Necrotic change ultrasound histologically grossly

Necrotic change:

Ultrastructurally – less than 6 hours

Histologically – 6 to 12 hours

Grossly – 24 to 48 hours


Necrosis (AKA: Oncosis, Oncotic Necrosis)

cell death after irreversible cell injury by hypoxia, ischemia, and direct cell membrane injury

morphologic aspect is due to 2 concurrent processes:

– Denaturation of proteins
– Enzymatic digestion of the cell

•by endogenous enzymes derived from the lysosomes of the dying cells=autolysis (self digestion)

• By release of lysosome’s content from infiltrating WBCs Outcome: INFLAMMATION !!! (FREQUENTLY)


Light microscopy nuclear change

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Ultrastructural changes for coagulative necrosis

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Necrosis: Gross appearance

Pale, soft, friable and

sharply demarcated

from viable tissue by a zone of inflammation


MDx: Hepatitis, multifocal to coalescing, subacute, severe, necrotizing Et: Histomonas meleagridis
Name of Disease: Blackhead


Light microscopy changes of necrotic cells in CYTOPLASM


Denatured proteins:

Loss of RNA

Loss of glycogen particles

Enzyme-digested cytoplasm organelles


↑ binding of eosin (pink)

Loosing basophilia

Glassy homogeneous

Vacuolation and moth eaten appearance

Calcification may be seen


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Patterns of tissue necrosis:

May provide clues about the underlying cause

Do not reflect underlying mechanisms but are used by

pathologists and clinicians


Coagulative (coagulation) necrosis


Coagulative (coagulation) necrosis:

architecture of dead tissues is preserved (days) ultimately the necrotic cells are removed:

• phagocytosis by WBCs
• digestion by the action of lysosomal enzymes of the WBCs

Common cause: Ischemia in all solid organs except the brain


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Infarct: localized area of coagulative necrosis


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Coagulative (coagulation) necrosis


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Coagulative (coagulation) necrosis


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Heart: Locally extensive nutritional muscular degeneration and necrosis


Cause: Vitamin E/selenium deficiency
Condition Synonyms: Nutritional myopathy, white muscle disease


affects skeletal and cardiac muscle


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Skeletal muscle:  Degeneration and necrosis


Cause: Vitamin E/selenium deficiency
Condition Synonyms: Nutritional myopathy, white muscle disease


Liquefactive necrosis

Typically in CNS  i.e. Abscess

Necrotic architecture is “liquefied” = liquid

Dead cells are “digested” into transformation of the tissue into a liquid viscous mass

Occurs in:

tissue with high Neutrophil recruitment & enzymatic release with digestion of tissue

tissues with high lipid content( i.e. brain)

focal bacterial and occasionally, fungal infections

 microbes stimulate the accumulation of WBCs & the liberation of enzymes from these cells


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Liquefactive necrosis - gross

Sheep, brain stem
MDx: Bilateral symmetrical encephalomalacia


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Pathogenesis: Ingestion of Fusarium moniliforme containing Fumonisin B1 Toxin-Producing Moldy Corn > Sphingolipid Synthesis Inhibition > Direct Cellular Toxicity > Leukoencephalomalacia

Species affected: horse, also chicken, pig (pulmonary edema)

necrosis of white matter of cerebral hemispheres, brain stem and cerebellum


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Horse: Equine Leukomyelitis

MDx: Multifocal necrohemorrhagic (leuko) myelitis

Etiology: Sarcocystis neurona- protozoan

Edx- protozoan leukomyelitis


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Brain, polioencephalomalacia


a. Thiamine deficiency diet (particularly in young animals);
b. Increased ruminal thiaminase activity;
c. Administration of thiamine analogs Amprolium);

d. High levels of sulfur in diet or water;

e. Lead toxicity;
f. Thiaminase containing plants: Bracken fern (Pteridium spp).


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Liquefactive necrosis – gross

Goat: Pituitary gland abscess


necrotic material is frequently creamy yellow because of the presence of dead WBCs = PUS


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A localized collection of pus (liquefied tissue) in a cavity formed by disintegration of tissues surrounded by fibrous connective tissue (not in CNS!)

It is the result of the body's defensive reaction to foreign material


2 types of abscesses

1. Septic: (the majority) =infection, release of enzymes from WBCs and infectious agent (Pyogenic bacteria, e.g.: Staphylococcus aureus)-  MOST

2. Sterile: process caused by nonliving irritants such as drugs

----------likely to turn into firm, solid lumps as they scar, rather than remaining pockets of pus


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Histology of Liquefactive necrosis – e.g.: Abscess

Loss of cellular detail

Cells are granular

Eosinophilic and basophilic debris

Neutrophil nuclei may dominate nuclear debris

No tissue architecture is preserved- opposite of cogaulative necrosis


Gangrenous necrosis

Not a specific pattern of cell death but begins mostly as coagulative necrosis

------------ likely due to ischemia

Term commonly used in clinical practice

It is usually applied to distal extremities (also toes, ear, udder, pinna) involving multiple planes of tissue

“Dry” gangrene – no bacterial superinfection; tissue appears dry


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Gangrenous necrosis


“Dry” gangrene


“Wet” gangrene

Gangrenous necrosis

“Wet” gangrene – bacterial superinfection has occurred;
- tissue looks wet and liquefactive
• by actions of degradative enzymes in the bacteria and the attracted WBCs


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“Wet” gangrene


Caseous necrosis

“caseous” (cheeselike)

friable (crumble) white: area of necrosis

necrotic debris represents dead WBCs

Possible causes:

 Mycobacterium

 Corynebacterium

 Fusobacterium

 fungal infections


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Corynebacterium pseudotuberculosis- SHEEP

Disease name: Caseous lymphadenitis


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Caseous necrosis




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Cow, MDx: Multifocal caseous pneumonia Name of disease: Tuberculosis


Compared with coagulation necrosis, caseous necrosis is

Compared with coagulation necrosis, caseous necrosis is chronic


Caseous Necrosis  is often associated with

Caseous Necrosis  is often associated with poorly degradable lipids of bacterial origin


Histopathology of Caseous Necrosis

Necrotic areaeosinophilic granular cell debris with a rim of inflammatory cells (MQ, ~MNGC)

Obliterated tissue architecture

Dystrophic calcification---- ALSO WITH NECROSIS

--------commonly to occur in center of lesion


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Caseous necrosis – Histology


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Caseous necrosis – Histology


Fat necrosis

Three types:

1. enzymatic necrosis
2. traumatic necrosis of fat

3. necrosis of abdominal fat


1. Enzymatic necrosis:

1. Enzymatic necrosis: AKA: pancreatic necrosis of fat
Action of activated pancreatic lipases in “escaped” pancreatic fluid

Neutral fat (lipase to triglycerides)
Free fatty acids + Ca+ to  Calcium soaps (saponification)


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Cat, Pancreatic fat necrosis


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A.Fat necrosis:

Enzymatic necrosis of fat (fat necrosis), dog with previous bouts of pancreatitis. Necrotic fat often becomes saponified and so grossly the lesion is chalky to gritty and pale white.

B. Pancreas, dog. Note the large area of fat necrosis with acute inflammation and saponification (basophilic areas).


2. Traumatic necrosis of fat

2. Traumatic necrosis of fat
- Dystocia
- Subcutaneously in inter-muscular fat @ sternum - recumbent cattle


3. Necrosis of abdominal fat (cattle):

3. Necrosis of abdominal fat (cattle): - unknown cause

Mesentery, omentum, retroperitoneum, Extreme cases intestinal stenosis(reduction of intestinal muscosa)

Channel island Breeds...


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Fat necrosis, cow, abdominal cavity


Fibrinoid necrosis

special form of necrosis usually seen in immune reactions involving blood vessels

occurs when Ag-Ab complexes are deposited in the walls of arteries

deposits of these “immune complexes,” together with fibrin that has leaked out of vessels, result in a bright pink and amorphous appearance in H&E stains, called “fibrinoid” (fibrin-like) by pathologists


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Fibrinoid necrosis



-  a pathway of cell death (others include cell death with autophagy and keratinocyte cornification

-  induced by a tightly regulated suicide program

-  cells destined to die activate intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins

-  apoptotic cells break up into fragments, called apoptotic bodies, which contain portions of the cytoplasm and nucleus

-  plasma membrane:
 remains intact
 its structure is altered to become “tasty” targets for phagocytes


Is there inflammation in necrosis?



Apoptosis in some physiologic processes

Programmed cell death during embryogenesis

Hormone-dependent involution of organs in the adult (e.g., thymus, uterus- post-parturition)

Cell deletion in proliferating cell populations (intestinal epith. Turnover)

Deletion of auto-reactive T-cells in the thymus (by cytotoxic T-cells)


Apoptosis: Involved in pathologic processes

Tumor necrosis factor (TNF) or Fas ligand (FasL) induction of apoptosis in many cells

DNA damage- i.e. UV damage

Accumulation of misfolded proteins

Cell injury in certain infections: viral

Pathologic atrophy in parenchymal organs after duct obstruction


Apoptosis: Morphology

Cell shrinkage with ↑ cytoplasmic density

Chromatin condensation (pyknosis)

Formation of cytoplasmic blebs and apoptotic bodies (fragmentation)

Phagocytosis of apoptotic cells by adjacent healthy cells


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Apoptosis: Mechanisms

Specific feature: activation of caspases (cyteine proteases family)

 Initiator caspases: 9 & 8
 Executioner caspases: 3 & 6


Intrinsic pathway = mitochondrial pathway

Extrinsic pathway = death receptor-initiated pathw

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Intrinsic pathway

Major mechanism of apoptosis in all mammalian cells

Result of ↑ mitochondrial permeability & release of pro- apoptotic molecules (death inducers) into the cytoplasm

Cytochrome-C: essential for life; released into cytoplasminitiates suicide program of apoptosis

Controlled of release by: pro- and anti-apoptotic members of the Bcl family of proteins


Anti-apoptotic proteins:

- Bcl-2, Bcl-X, Mcl-1

Can directly inhibit Apaf-1 (Apoptotic protease activating factor 1) activation Loss from cells may permit activation of Apaf-1
Apaf-1 binds to apoptosome to activate Caspase-9
Present within the mitochondria membranes and the cytoplasm


Pro-apoptotic proteins:

Pro-apoptotic proteins:

Bim, Bid, Bad [BH3-only proteins]: Sensors of damage/stress

Bak, Bax: effectors


Extrinsic pathway

Initiated by death receptors

Death receptors: members of TNF receptor family

1. Death domain

2. Best known type: TNF receptor (TNFR1) & Fas (CD95)

Fas-L: Expressed on T-cells that identify self Ag & some Cytotoxic-T cells (perforin, granzymes)

Forming a binding site for an adapter protein, that also contains a death domain: FADD (Fas associated death domain)

Ligand for Fas

FADD in turn binds an inactive Caspase- 8active caspase-8

Activation of execution phase of apoptosis

Can be inhibited by protein FLIP (binds pro- caspase-8 but cannot cleave and activate the caspase)

used by some viruses & normal cells to protect themselves from Fas-mediated apoptosis


Removal of apoptotic cells

Apoptotic bodies

edible for phagocytes

expressed phospholipids in the outer layer of the membrane (instead inner leaflet) to be ID by MQ receptors

may become coated w/ natural Ab & proteins of the complement system (C1q)


Apoptotic cells

secrete soluble factors that recruit phagocytes

some express thrombospondin (adhesine glycoprotein that is ID by phagocytes)

MQ may produce proteins that bind to apoptotic cells (not to live cells) for engulfment


Disorders associated with dysregulated apoptosis

A. Disorders associated with defective apoptosis and ↑cell survival (Abnormal cells survive)

- cells w/mutations in p53 are subjected to DNA damage, not only fail to die but are susceptible to the accumulation of mutations because of defective DNA repair, these can give rise to NEOPLASIA

- limphocytes that react against self-Ag
- failure to eliminate dead cells (potential source of self-Ag)

Above seen in autoimmune disorders





B. Disorders associated with increased apoptosis and excessive cell death

B. Disorders associated with increased apoptosis and excessive cell death

Neurodegenerative dz: manifested by loss of specific sets of neurons (apoptosis caused by mutations and misfolded proteins)

Ischemic injury, as in myocardial infarction & stroke

Death of virus-infected cells


Necrosis vs Apoptosis

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cogulation necrosis



certain forms of necrosis( necroptosis) also genetically programmed- by a distinct set of genes


combo of inflammation and apopotosis


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apoptotic bodies


Is necrosis physiologic or pathologic?




Necroptosis (programmed necrosis)
Resembles necrosis morphologically and apoptosis mechanistically as a form of

Necroptosis is triggered by ligation of TNFR1, and viral proteins of RNA and DNA viruses.

Necroptosis is caspase-independent but dependent on signaling by the RIP1 and RIP3 complex.

Occurs in: mammalian bone growth plate; associated with cell death in steatohepatitis, acute pancreatitis, reperfusion injury, and neurodegenerative diseases

Release of cellular contents evokes an inflammatory reaction as in necrosis.