Test 2- Cell Injury Flashcards
1
Q
Reversible cell injury
– Morphologic correlates:
A
Reversible cell injury
– Morphologic correlates:
- Cellular swelling
- Fatty changes (lipidosis)
2
Q
Irreversible cell injury and cell death
– Morphologic correlates:
A
– Morphologic correlates:
• Necrosis
- Apoptosis
- Other types of cell death
3
Q
Acute cell swelling- other names
A
AKA: hydropic degeneration; hydropic change;
cytotoxic edema (CNS); ballooning degeneration (epidermis)
4
Q
Highly vulnerable to hypoxia & cell swelling:
A
Highly vulnerable to hypoxia & cell swelling:
cardiomyocytes
proximal renal tubule epithelium
hepatocytes
endothelium
CNS neurons ,oligodendrocytes, astrocytes(cytotoxic edema)
5
Q
Definition of acute cell swelling
A
- Early,sub-lethal manifestation of cell damage, characterized by ↑ cell size & volume due to H2O overload
- Most common and fundamental expression of cell injury
6
Q
Etiology of acute cell swelling
A
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
7
Q
Pathogenesis of acute cell swelling
A
less oxygen and ATP production decreases
8
Q
Gross appearance of acute cell swelling
A
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”)
9
Q
A
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).
10
Q
Histologic appearance of cellular swelling !
A
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!
11
Q
A
Epidermis - ballooning degeneration (extreme variant of hydropic degeneration)
Etiology : Swinepox virus- pox viruses in general
12
Q
Ultrastructural changes of cellular swelling
A
- 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
13
Q
Which parts of the cell are the most important for cellular swelling?
A
mitchondrial swelling
ER swelling
clumping of clear chromatin
general swelling
14
Q
Hydropic change, Fatty change (Cell swelling)
A
due to ↑uptake of H2O & then to diffuse disintegration of organelles and cytoplasmic proteins
15
Q
Hypertrophy (Cell enlargement)
A
• the cell enlargement is caused by ↑ of normal organelles
16
Q
Prognosis of cellular swelling
A
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)
17
Q
Lipofuscin in a cell
A
evidence of previous injury (e.g. neuron)
seen in cells with a longer lifespan
18
Q
Definition of fatty change
A
- sub-lethal cell damage characterized by intracytoplasmic fatty vacuolation
- maybe preceded or accompanied by cell swelling
19
Q
All major classes of lipids can accumulate in cells:
A
- Triglycerides
- Cholesterol/cholesterol esters
- Phospholipids
- Abnormal complexes of lipids and carbohydrates (lysosomal storage diseases)
20
Q
Lipidosis
A
- 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
21
Q
Etiology of fatty change
A
Main causes: hypoxia, toxicity, metabolic disorders
Seen in abnormalities of synthesis, utilization and/or mobilization of fat
22
Q
A
Etiology of fatty change
23
Q
A
fatty change
24
Q
Pathogenesis of fatty change
A
- impaired metabolism of fatty acids
- accumulation of triglycerides
- formation of intracytoplasmic fat vacuoles
25
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.
26
only form in which triglycerides can be transported out of the hepatocytes
Lipoproteins
27
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
28
fatty change
29
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
30
Ketone bodies
Ketone bodies: are alternative fuel for cells
Produced in the liver by mitochondria
Convertion of acetyl CoA from fatty acid oxidation=LIPOLYSIS
31
Hepatic lipidosis
Nutritional disorders:
obesity
protein-calorie malnutrition (impaired apolipoprotein synthesis)
starvation (↑mobilization of triglycerides)
32
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
33
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
34
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.
35
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
36
Necrotic change ultrasound histologically grossly
Necrotic change:
Ultrastructurally – less than 6 hours
Histologically – 6 to 12 hours
Grossly – 24 to 48 hours
37
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)**
38
Light microscopy nuclear change
39
Ultrastructural changes for coagulative necrosis
40
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
41
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
42
Patterns of tissue necrosis:
May provide clues about the underlying cause
Do not reflect underlying mechanisms but are used by
pathologists and clinicians
43
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**
44
Infarct: localized area of coagulative necrosis
45
• •
Coagulative (coagulation) necrosis
46
• •
Coagulative (coagulation) necrosis
47
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
48
Skeletal muscle: Degeneration and necrosis
Cause: Vitamin E/selenium deficiency
Condition Synonyms: Nutritional myopathy, white muscle disease
49
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
50
Liquefactive necrosis - gross
Sheep, brain stem
MDx: Bilateral symmetrical encephalomalacia
51
Leukoencephalomalacia
52
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**
53
Horse: Equine Leukomyelitis
MDx: Multifocal necrohemorrhagic (leuko) myelitis
Etiology: **Sarcocystis neurona**- protozoan
Edx- protozoan leukomyelitis
54
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).
55
Liquefactive necrosis – gross
Goat: Pituitary gland abscess
necrotic material is frequently creamy yellow because of the presence of dead WBCs = PUS
56
Abscess
57
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
58
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
59
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
60
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
61
Gangrenous necrosis
“Dry” gangrene
62
“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
63
“Wet” gangrene
64
Caseous necrosis
“caseous” (cheeselike)
friable (crumble) white: area of necrosis
necrotic debris represents dead WBCs
Possible causes:
** Mycobacterium**
** Corynebacterium**
** Fusobacterium**
** fungal infections**
65
Corynebacterium pseudotuberculosis- SHEEP
Disease name: Caseous lymphadenitis
66
Caseous necrosis
Abscesses
67
Cow, MDx: Multifocal caseous pneumonia Name of disease: Tuberculosis
68
Compared with coagulation necrosis, caseous necrosis is
Compared with coagulation necrosis, caseous necrosis is **chronic**
69
Caseous Necrosis is often associated with
Caseous Necrosis is often associated with poorly degradable lipids of bacterial origin
70
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
71
Caseous necrosis – Histology
72
Caseous necrosis – Histology
73
Fat necrosis
Three types:
1. enzymatic necrosis
2. traumatic necrosis of fat
3. necrosis of abdominal fat
74
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**)
```
75
Cat, Pancreatic fat necrosis
76
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).
77
2. Traumatic necrosis of fat
2. Traumatic necrosis of fat
- Dystocia
- Subcutaneously in inter-muscular fat @ sternum - recumbent cattle
78
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...
79
Fat necrosis, cow, abdominal cavity
80
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
81
Fibrinoid necrosis
82
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
83
Is there inflammation in necrosis?
NO!!!!
84
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)
85
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
86
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
87
Apoptosis
88
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
89
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
90
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
91
Pro-apoptotic proteins:
Pro-apoptotic proteins:
**Bim, Bid, Bad** [BH3-only proteins]: Sensors of damage/stress
**Bak, Bax:** effectors
92
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- 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
93
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)**
94
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
95
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**
96
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**
97
Necrosis vs Apoptosis
98
Reversible
99
Irreversible
100
Reversible
101
Irreversible
102
cogulation necrosis
103
necroptosis
certain forms of necrosis( necroptosis) also genetically programmed- by a distinct set of genes
combo of inflammation and apopotosis
104
apoptotic bodies
105
Is necrosis physiologic or pathologic?
PATHOLOGIC!!!
106
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.**
