Test 2- Cell Injury Flashcards
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:
cardiomyocytes
proximal renal tubule epithelium
hepatocytes
endothelium
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
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”)
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 !
liver
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!
Epidermis - ballooning degeneration (extreme variant of hydropic degeneration)
Etiology : Swinepox virus- pox viruses in general
Ultrastructural changes of cellular swelling
- Plasma membrane alterations, such as blebbing, blunting, and
loss of microvilli
2. Mitochondrial changes, including swelling and the appearance of small amorphous densities
- Dilation of the ER, with detachment of polysomes; intracytoplasmic myelin figures may be present (see later)
- Nuclear alterations, with disaggregation of granular and fibrillar elements
Kidney, epithelial cell
Which parts of the cell are the most important for cellular swelling?
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
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)
Lipidosis
- 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
Etiology of fatty change
fatty change
Pathogenesis of fatty change
- impaired metabolism of fatty acids
- accumulation of triglycerides
- 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.
only form in which triglycerides can be transported out of the hepatocytes
Lipoproteins
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
fatty change
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:
obesity
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
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?
Myocardium
- 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
Ultrastructural changes for coagulative necrosis
Necrosis: Gross appearance
Pale, soft, friable and
sharply demarcated
from viable tissue by a zone of inflammation
Turkey,
MDx: Hepatitis, multifocal to coalescing, subacute, severe, necrotizing Et: Histomonas meleagridis
Name of Disease: Blackhead
Light microscopy changes of necrotic cells in CYTOPLASM
Cause
Denatured proteins:
Loss of RNA
Loss of glycogen particles
Enzyme-digested cytoplasm organelles
Appearance
↑ binding of eosin (pink)
Loosing basophilia
Glassy homogeneous
Vacuolation and moth eaten appearance
Calcification may be seen
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
Infarct: localized area of coagulative necrosis
• •
Coagulative (coagulation) necrosis
• •
Coagulative (coagulation) necrosis
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
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
Liquefactive necrosis - gross
Sheep, brain stem
MDx: Bilateral symmetrical encephalomalacia
Leukoencephalomalacia
Leukoencephalomalacia
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
Horse: Equine Leukomyelitis
MDx: Multifocal necrohemorrhagic (leuko) myelitis
Etiology: Sarcocystis neurona- protozoan
Edx- protozoan leukomyelitis
Sheep
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).
Liquefactive necrosis – gross
Goat: Pituitary gland abscess
necrotic material is frequently creamy yellow because of the presence of dead WBCs = PUS
Abscess
Abscess
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
- Septic: (the majority) =infection, release of enzymes from WBCs and infectious agent (Pyogenic bacteria, e.g.: Staphylococcus aureus)- MOST
- 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
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
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
“Wet” gangrene
Caseous necrosis
“caseous” (cheeselike)
friable (crumble) white: area of necrosis
necrotic debris represents dead WBCs
Possible causes:
Mycobacterium
Corynebacterium
Fusobacterium
fungal infections
Corynebacterium pseudotuberculosis- SHEEP
Disease name: Caseous lymphadenitis
Caseous necrosis
Abscesses
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 areaeosinophilic 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
Caseous necrosis – Histology
Caseous necrosis – Histology
Fat necrosis
Three types:
- enzymatic necrosis
- traumatic necrosis of fat
- necrosis of abdominal fat
- Enzymatic necrosis:
- 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**)
Cat, Pancreatic fat necrosis
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).
- Traumatic necrosis of fat
- Traumatic necrosis of fat
- Dystocia
- Subcutaneously in inter-muscular fat @ sternum - recumbent cattle
- Necrosis of abdominal fat (cattle):
- Necrosis of abdominal fat (cattle): - unknown cause
Mesentery, omentum, retroperitoneum, Extreme cases intestinal stenosis(reduction of intestinal muscosa)
Channel island Breeds…
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
Fibrinoid necrosis
Apoptosis
- 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?
NO!!!!
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
Apoptosis
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
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 cytoplasminitiates 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
- Death domain
- 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- 8active 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
TOO LITTLE
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
Reversible
Irreversible
Reversible
Irreversible
cogulation necrosis
necroptosis
certain forms of necrosis( necroptosis) also genetically programmed- by a distinct set of genes
combo of inflammation and apopotosis
apoptotic bodies
Is necrosis physiologic or pathologic?
PATHOLOGIC!!!
Necroptosis
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.
