02_Cell Injury_Q and A_Jonathan Flashcards
Distinguish reversible from permanent and lethal cell injury.
• Reversible injury leads to altered cell composition such that if and when the offensive stimulus is removed, the cell will restore its original function
• Hallmarks include: reduced oxidative phosphorylation with resultant depletion of energy stores in the form of ATP, cell swelling due to ion concentrations, alterations in cytoskeletal structures, organelles, and mitochondria
o Examples of reversible ischemic injury include
• Mitochondrial swelling
• Membrane blebs
• Increased cell volume
• Cytoskeletal disorganization
• Influx of Ca, Na, H2O
• Efflux of K
• Decrease in protein synthesis and increase in lipid deposition
• Irreversible injury leads to either a permanently altered cell or cell death
o Ex: Mitochondria
• become porous and enter a low energy state.
• Lose enzymatic systems and cannot recover normal function.
• Swell and Ca precipitate forms (pathologic calcification)
• Apoptosis cascade may begin
What are the three causes of cell death?
- apoptosis
- necrosis
- (also autophagy during nutrient deprivation)
What is necrosis?
- When damage to membranes is severe, lysosomal enzymes enter the cytoplasm and digest the cell, and cellular contents leak out
- This is always a pathologic process
What is Apoptosis?
- a form of cell death that is characterized by nuclear dissolution, fragmentation of the cell without complete loss of membrane integrity, and rapid removal of the cellular debris
- This is sometimes a pathologic process and sometimes a normal cell function
Details: apoptosis and necrosis sometimes have similar causes. Apoptosis can sometimes lead to necrosis. Autophagy can sometimes be similar to apoptosis.
Details: apoptosis and necrosis sometimes have similar causes. Apoptosis can sometimes lead to necrosis. Autophagy can sometimes be similar to apoptosis.
What are the causes of cell injury?
- O2 deprivation aka hypoxia
- Physical agents (temperature, pressure, radiation, electric shoc)
- Chemical agents
- Infectious agents (microbiology to large tapeworms)
- Immune reactions
- Genetic derangements (ex: decreased life span of RBCs)
- Nutritional imbalances
What are two features of reversible cell injury that can be recognized under the light microscope?
- cellular swelling
* fatty change
What causes cellular swelling?
• lack of ATP causes ion pumps to not function and osmotic imbalance occurs
What causes fatty change?
- found usually in cells that depend on fat metabolism: heart, liver, and others
- Several mechanism (check back later)
What are the ultracellular changes of reversible cell injury?
- plasma membrane: blebbing, blunting, loss of microvilli
- mitochondria: swell and have small amorphous densities
- dilation of the ER and detachment of ribosomes
- nuclear alterations: desegregation of granular and fibrillar elements
- may include increased eosinophillic staining
What is the mechanistic cause of necrosis?
• denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell
See Table 1-2 page 13 robbins for differences between necrosis and apoptosis.
See Table 1-2 page 13 robbins for differences between necrosis and apoptosis.
What digests the contents of necrotic cells?
- lysosomes from the necrotic cells
- lysosomes from inflammatory leukocyte
- Note: this takes hours, so may not occur in sudden infarct. Instead, cellular components from the heart are released into the blood stream
What are the ultrastructural changes in general necrosis?
• increased esosinophilia due to the loss of cytoplasmic RNA (blue) and increased denatured proteins
• glassy homogenous: loss of glycogen
• dead cells may be replaced by myelin figures (from damaged cell membranes)
• calcification
• discontinuous cell and organelle membranes
• very large mitochondria
• Nuclear changes (3)
o Karyolysis (fade of basophilia)
o Pyknosis (nuclear shrinkage)
o Karyorrhexis (nuclear fragmentation)
What are the six types of necrosis?
- Coagulative necrosis
- Liquefactive necrosis
- Gangrenous necrosis
- Caseous necrosis (cheese-like)
- Fat necrosis
- Fibrinoid necrosis
What are the features of Coagulative necrosis?
- denaturation of proteolytic enzymes, so much of the structure of the cells remain intact.
- Eosinophilic, anucleate cells
Ischemia can lead to coagulative necrosis in all organs except? Why?
- the brain
* Why?
What degrades the coagulative necrosis?
- note: may persist for weeks
* degraded by leukocytes
What are the characteristics of liquefactive necrosis?
- digestion of dead cells, resulting in a viscous mass
- seen in focal bacterial or fungal infections because microbes stimulate the accumulation of leukocytes, which then digest the necrotic cells
- Pus
- Infarction of the brain produces liquifactive necrosis
What are the characteristics of Gangrenous necrosis?
- a type of liquifactive necrosis
- usually on a limb that lacks circulation
- bacteria invade and attract leukocytes, which digest the tissue
What are the characteristics of Caseous necrosis?
- classically in tuberculosis infections with granuloma
- caseous = cheese-like
- white, appears like it can be broken into pieces like cheese
- collection of fragmented or lysed cells and amorphous granular debris within a distinctive inflammatory border (granuloma)
What are the characteristics of fat necrosis?
- focal areas of fat destruction from the release of pancreatic lipases in the pancrease or peritoneal cavity
- occurs during acute pancreatitis
- lipases split fat esters ==> fat combines with Ca to form chalky white areas of saponification
- see Robbins page 17, figure 1-14
What is fibrinoid necrosis?
- antigen-antibody complexes deposit in blood vessels
- Immune complexes leak out of the vessels bound to fibrin
- Result in bright pink and amorphous H&E stain, called “fibrinoids”
- Seen in vasculitis
Term: dystrophic calcification come back later
Term: dystrophic calcification come back later
What are the basic principles of Cell Injury?
- cellular response depends on the nature of the injury, duration, and severity
- consequences of cell injury depend on the type, state, and adaptability of the injured cell
- cell injury results from different biochemical mechanisms action on cell components
What are the different biochemical mechanisms action on cell components that cause cell injury?
- ↓ATP
- Mitochondrial damage
- ↑ Ca
- ↑ ROS
- Membrane damage
- Protein misfolding and DNA damage
What are the causes and effects of ↓ATP?
• cause: reduced O2 or nutrients, mitochondrial damage
• effects:
o Na/K pump (ouabain sensitive) effects ion balance
o Cellular energy metabolism altered (glycolysis, etc..)
o Ca pump ==> increased intracellular Ca
o Reduction in protein synthesis and increase in protein misfolding
What are the causes and effects of mitochondrial damage?
• Causes: ↑ Ca, ↑ ROS, hypoxia
• Effects:
o Mitochondrial membrane ==> loses H gradient
o Cytochrome C release ==> caspase cascade
What are the sources of ↑intracellular Ca?
- cell injury lets in extracellular Ca
- mitochondrial Ca
- Smooth ER
What are the effects of ↑ Ca?
• ↑ mitochondrial permeability • May induce apoptosis via direct activation of caspases • activation of many cellular processes o phospholipase o protease o endo-nuclease o ATPase
What causes Free Radicals?
• normal byproducts of redox reactions o O2 superoxide o H2O2 peroxide o –OH • radiation • inflammation • metabolism of exogenous drugs • Transition metals • NO
What removes free radicals?
• Antioxidants • Lower Fe and Cu levels • Radical-Scavenging systems o Catalase o Superoxide dismutase o Glutathione peroxidase
What are the effects of free radicals? Pg 22
- Lipid peroxidation in plasma and organelle membranes
- Oxidative modification of proteins
- Lesions on DNA
Know: apoptosis occurs as part of normal physiology as well as pathology
Know: apoptosis occurs as part of normal physiology as well as pathology
What are the benefits of Apoptosis in pathological conditions.
• eliminates cells without eliciting a host reaction, thus limiting collateral tissue damage.
What are some common pathological states that recruit apoptosis?
• Growth factor deprivation
• DNA damage
• Protein misfolding
• Cell death in certain infections (esp viral)
o CTL-mediated via FasL and TNF
• Pathological atrophy in parenchymal organs after duct obstruction
What are the morphological features of Apoptosis?
- Cell shrinkage
- Chromatin condensation ==> then nucleus breaks up ==> fragments
- Cytoplasmic blebs and apoptotic bodies
- Phagocytosis of apoptotic cells or cell bodies, usu by macrophages
- Plasma membranes remain intact until last stages
What are biochemical features of apoptosis?
- caspase cascade
- DNA and protein breakdown
- Membrane alteration and recognition by phagocytes
What are the mechanisms of apoptosis? (intrinsic then extrinsic)
Robbins pg 28 and 29
• Intrinsic: Cell injury (Growth Factor withdrawal, DNA damage, protein misfolding) ==> Bcl-2 sensors ==> Bcl-2 effectors (Bax and Bak) ==> mitochondrial release of Cytochrome C and other pro-apoptotic proteins ==> initiator caspases ==> exocutioner caspases ==> nuclear and cytoskeleton breakdown
o Note: Bcl-2 and Bcl-x are inhibitors of Bax and Bak
o Bcl-2 and Bcl-x are anti-apoptotic
• Extrinsic: Fas or TNF receptor ==> FADD ==> procaspase-8 ==> exocutioner caspases
What is Steatosis?
- abnormal accumulations of triglycerides within parenchymal cells
- LV, heart, muscle, and KD
What are the causes of steatosis?
- usu alcohol abuse and nonalcoholic fatty liver disease
- excess accumulation of tryglycerides within the liver may result from excessive entry or defective metabolism and export of lipids
- defects induced by alcohol alter mitochondrial and microsomal functions ==> increased synthesis and reduced breakdown of lipids
- CCL4 and protein malnutrition cause fatty change by reducing apoprotein synthesis
What is the morphology of fatty LV?
- development of lipososomes
* small vacuoles
What are the features of Hyaline Change?
- alteration within cells or extracellular space that gives a homogeneous, glassy, pink appearance with H and E
- does not represent a specific accumulation (its related to many things)
What is hemosiderin?
- hemoglobin-derived, golden yellow brown, granular pigment
* storage form of iron
How is iron stored in cells?
• stored in association with apoferritin to form apoferritin micelles
When there is ↑ Fe, ferritin forms hemosiderin granules
When there is ↑ Fe, ferritin forms hemosiderin granules
Local excess ==> from hemorrhages in tissues ==> RBCs are phagocytosed ==> Fe accumulates
Local excess ==> from hemorrhages in tissues ==> RBCs are phagocytosed ==> Fe accumulates
Systemic overload of Fe ==> deposited in organs (process called hemosiderosis)
Systemic overload of Fe ==> deposited in organs (process called hemosiderosis)
What are the main causes of hemosiderosis?
- increased absorption of Fe
- hemolytic anemias
- repeated blood transfusions
What is hemochromatosis?
• excessive accumulation of Fe
o deposited in LV, Pancreas, heart, and joints
• Primary hemochromatosis: homologous recessive disorder ==> excessive iron absorption
• Secondary hemochromatosis/hemosiderosis: acquired disease
Why is excessive iron toxic?
- lipid peroxidation via Fe free radicals
- stimulates collagen formation in hepatic stellate cells
- interaction with O free radicals which damage DNA
What is the morphology of hemochromatosis?
• deposition of hemosiderin in LV and pancreas, and others
• cirrhosis
• pancreatic fibrosis
• In the Liver
o Iron ==> golden brown ==> stain blue with Prussian blue stain
o Iron is a direct hepatoxin, therefore inflammation is absent (not necessary for damage)
Classic triad of hematochromatosis (often occurs late)
- pigment cirrhosis with hepatomagaly
- skin pigmentation
- diabetes
Is there treatment for hematochromatosis?
Hematochromatosis is a genetic disease that is treatable with bleeding and reduced iron intake.
What are the 3 forms of alcoholic liver disease?
- hepatic steatosis
- alcoholic hepatitis
- cirrhosis
What is the morphology of hepatic steatosis?
- microvesicular or macrovesicular globules displace nucleus
- organ becomes enlarged, yellow, and greasy
- chronic alcohol use cause fibrous tissue around veins and sinusoids
Is hepatic steatosis reversible?
• completely reversible upon abstension
What are the morphological features of Cirrhosis?
- final and irreversible form of alcoholic liver
- usu slow and insidious
- yellow-tan ==> brown, shrunken, nonfatty organ
- fibrous septa extend through the sinusoids from central to portal regions
- parenchymal micronodules ==> mixed micronodule macronodule pattern ==> ischemia ==> obliterates nodules ==> tough pale scar tissue
- resembles viral hepatitis cirrhosis
How does alcohol cause steatosis?
- Alcohol dehydrogenase and acetyladelhyde DH ==>↑ NADH ==> shunt substrates away from catabolism and toward lipid synthesis
- Impairs assembly and secretion of lipoproteins ==> ↓ lipid export
- ↑ peripheral catabolism of fatty acids ==> ↑ delivered FA to the liver
The effect of EtOH on hepatic lipid metabolism
- Mobilization of fatty acids from body stores
- Decreased fatty acid oxidation
- Increased triglyceride synthesis
- Decreased lipoprotein synthesis
- Decreased transport, glycosylation and secretion of VLDL
What are Mallory’s bodies?
- Characteristic, but not specific of, alcoholic liver disease.
- Accumulations of cytokeratin intermediate filaments eosinophilic
