Cell Injury 2

ATP

essential for nearly all synthetic & degradative processes in the cell

key ATP dependent functions

• membrane transport

• protein synthesis

• lipogenesis

• phospholipid turnover via deacylation-reacylation rxns

mild ischemi

• decreased oxidative phosphorylation → decrease ATP

• failure of Na+/K+ pump → Na+ & water influx → cellular & organelle swelling (reversible)

severe/prolonged ischemia

• mitochondrial swelling (increase Ca2+ influx into cytosol & mitochondria)

• rupture of plasma & lysosomal membranes

• cell death by necrosis & apoptosis

reperfusion injury

• restoring blood flow → may recover reversible injuredcells

• can worsen injury due to oxidative stress, calcium overload, complement activation

mechanisms of membrane damage in cell injury

• decreased O2 & increased cytosolic Ca2+ are typically seen in ischemia

• ROS, which are often produced on reperfusion of ischemic tissues also cause membrane damage

early changes in cell injury

• decrease ATP synthesis

• loss of membrane integrity

• defective protein synthesis

• cytoskeletal damage

• DNA damage

irreversible injury to cells

• extensive damage to all cellular membranes

• swelling of lysosomes

• mitochondrial vacuolation w/ decreased ATP-generating capacity

necrosis

• spectrum of morphologic changes following cell death in living tissues, caused primarily by enzymatic digestion of lethally injured cells

• causes local inflammatory response

• extensive damage to the plasma membrane

• associated w/ collateral tissue damage

apoptosis

• form of programmed cell death

• eliminates unwanted/ damaged cells precisely

• mediated by a coordinated internal program involving gene products

• plasma membrane remains intact > no inflammation*

• occurs w/out causing damage to surrounding tissue

hallmarks of irreversible injury

• inability to reverse mitochondrial dysfunction (loss of oxidative phosphorylation)*

• profound disturbances in membrane function (loss of plasma membrane integrity & damage to internal membranes)*

• lysosomal membrane injury > leakage of lysosomal enzymes into the cytoplasm > leads to autodigestion of cell components

is there a delay in the progression of cell injury?

yes, there is a delay between the initial stress & visible morphologic changes of injury or death

cellular swelling (cloudy swelling, hydropic change, vacuolar degeration)

• gross appearance: affected organs become heavy & pale

• microscopic appearance: cytoplasm contains small, clear vacuoles

• vacuoles represent swollen segments of the endoplasmic reticulum filled w/ fluid

• mechanism: loss of ionic & fluid homeostasis, failure of ATP dependent membrane ion pumps

fatty change

• occurs in hypoxic injury, toxic & metabolic injuries

• morphology: cytoplasm contains small/ large lipid vacuoles

• commonly affected cells: cells involved in fat metabolism especially hepatocytes & myocardial cells

• less universal vs cell swelling

plasma membrane alterations

• blebbing, blunting, & distortion of microvilli

• formation of myelin figures

• loosening of intercellular junctions

mitochondrial changes

• swelling of mitochondria

• appearance of amorphous, phospholipid-rich densities

ER changes

• dilatation of the ER

• detachment of ribosomes

• disaggregation of polysomes

nuclear alterations

disaggregation of granular & fibrillar nuclear elements

autolysis

lysosomes of the dead cells themselves

heterolysis

lysosomes of infiltrating inflammatory leukocytes

morphologic changes

delayed; seen after 4-12 hrs post injury

biochemical changes

occur earlier; detected as early as 2 hrs post cell death

troponin

most specific; Myocardial infarction

CPK-MB

myocardial infarction

LDH

general tissue injury, including MI

transaminases (AST, ALT)

hepatitis

amylase & lipase

pancreatitis

alkaline phosphatase (ALP)

biliary tract obstruction

cytoplasmic changes in necrotic cells

• increased eosinophilia

• glassy, homogenous appearance

• vacuolated “moth-eaten” cytoplasm

• calcification

nuclear changes in necrosis

• karyolysis

• pyknosis

• karyorrhexis

coagulative necrosis

• occurs when protein denaturation predominates

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