Cellular Injury

Definition and Causes of Cellular Injury and Adaptation

normal cell is in homeostatic steady state

stresses and some pathologic stimuli bring on adaptations and an altered steady state

could lead to hypertrophy, hyperplasia, atrophy
steady state lower then a certain threshold leads to cell death

cell injury in two phases: sublethal (reversible); acute lethal (irreversible)

causes: hypoxia, anoxia, toxins, chemicals, infections, immunologic, metabolic, genetic, physical trauma

cell death: loss of enzymatic and metabolic function except release of lysosomal hydrolytic enzymes

necrosis: secondary changes (hydrolytic breakdown) that lead to obvious cellular debris, etc (i.e. scar)

ultimate fate may be calcification, dessication, liquifaction, phagocytosis

Ischemia (little blood flow) and Hypoxia (little oxygen)

anoxia (no oxygen): Þ anerobic metabolismÞ dec ATP Þ dec pH (lactate) and Na/ Ca influx Þ swelling Þ cell lysis

free radical damage: from chemicals, smoke, anesthetics, etc; especially in presence of transition metals

leads to lipid peroxidation, DNA damage, protein cross-linking, glutathione depletion
antioxidants: vitamins A, C, E (inactive free radical reactions)

acetaminophen: converted to toxic metabolite in liver, depletes glutathione, liver necrosis

alcohol: metabolized to acetaldehyde and FA ethyl esters

leads to fatty liver, cell vacuolization, Mallory body, cirrhosis (scarring)

Histology of Necrosis

swelling of cells, mito, ER

vacuolization

deposits of:

lipid
protein (e.g., kidney epithelial cells in proteinuria)
glycogen (diabetes; glycogen storage disease)
lipofuscin (indigestible yellow-brown products of free radical and lipid peroxidation damage)
melanin
hemoglobin products (hemosiderin, hematin, bilirubin)

"hyaline change": a catch-all term describing a glassy, homogeneous acellular appearance

dystrophic calcification: results from calcium deposition in dead tissue

metastatic calcification: calcium deposits resulting from hypercalcemia

Systemization of Necrosis

(1) coagulation necrosis – retention of cellular outlines despite complete nuclear dissolution, increased eosinophilia due to protein degeneration

seen in severe hypoxia
most common form of necrosis
denaturation and solidification of cytoplasm
may reflect ischemia (early stages of MI), acute chemical injury
eventual fragmentation and phagocytosis of cell; nuclei disappear

(2) liquifaction necrosis – massive infiltration of inflammatory cells (pus)

may result from release of hydrolytic enzymes or focused bacterial infection Þ cell walls and internal structures destroyed (i.e. brain)

(3) caseous necrosis – no cell outlines; granular, cheesy appearance

depends on effects of bacterial products, i.e. TB
combination of coagulation and liqufaction

(4) fat necrosis – amorphous granular basophilic deposits

release of lipase, production of FFA, saponification (creation of soaps i.e. with Ca)
acute pancreatitis

Cell Injury

Sites of Cell Injury

cell membrane, ER, mito, cytoskeleton
aerobic respiration
synthesis of structural and enzymatic proteins
integrity of DNA

Necrosis

decreased metabolism Þ decreased pH and ATP productionÞ Ca⁺⁺ influx Þ phospholipase action and membrane degeneration

decreased ATP Þ loss of transprort processes Þ swelling and lysis

decreased pH Þ intracellular release of lysosomal enzymesÞ decreased basophilia

protein efflux: i.e. in MI, can detect CPK and LDH as evidence before EKG

membrane damage may be the line between reversible and irreversible damage

Apoptosis – important in regulation of normal cell population density

programed cell death; different from necrosis: cells disappear without a trace

stimulation of endogenous endonuclease activity that leads to cleavage of nuclear chromatin

i.e. endometrium (menstruation), thymus degeneration; TNFa Þ apoptosis of endometrium

events:

cell shrinkage
nuclei fragment and blebs form
apoptotic bodies taken up by macrophages or other cells

no inflamation

stimulated by withdrawl of tropic factors; positive stimuli (p53); Bcl-2 inhibits

karyorrhexis: fragmentation of chromatin

Subcellular Alterations in Cell Injury

lysosomes: heterophagy and autophagy
hypertrophy of smooth ER
cytoskeletal abnormalities:

Alzheimer’s disease
Mallory body: eosinophilic inclusion in liver cells composed of intermediate filaments (alcoholic hepatitis)
Chediak-Higashi syndrome
immotile cilia syndrome