Cell Injury Robert Low MD PhD

sites within cells that are easily injured reversibility of injury and complete recover adaptation to chronic injury cell death-necrosis vs apoptosis Hypoxic injury-starving cells/tissues for oxygen; problems of too much oxygen and cell damage from oxygen radicals Cell and tissue injury produce human disease Injury-acute vs chronic

#1 Human disease occurs because of injury to cells/tissue

Cell Injury– Damage or alteration of one or more cellular components 1. Many types of injury we incur are tissue specific because of anatomic relationships and the tissue tropism of chemical and infectious agents. 2. Cell injury perturbs cell physiology; the cell does not function at full capacity.

Basic Types of Tissues 1. Epithelium 2. Muscle (skeletal, smooth, cardiac) 3. Nerve (CNS, PNS) 4. Connective (bone, cartilage, soft tissue, adventitia, ligaments, blood and lymph, etc)

#2 Most human disease results from injury to Epithelium

Epithelium arises from each of three germ layers 1. Cells cover external surfaces (skin); line internal closed cavities, secretory glands and tubes- -GI, respiratory, GU tracts- -that communicate with external surfaces 2. Also includes liver, exocrine pancreas, parotid glands, thyroid, parathyroid, epithelium of kidney 3. Also: vascular endothelium, mesothelium

#3 Injury to one tissue usually affects the adjacent or underlying tissue as well

Cell Injury Produces: 1. Signs - abnormal physical findings 2. Symptoms - complaints experienced by the patient

Cell Injury Produces: (cont) 3. Morphologic change - A visual change in the cell shape or appearance, seen when cells are stained and viewed by light microscopy; or examined by E.M. in the injured tissue; or seen “grossly” with the naked eye.

Outcomes from cell injury depend upon: 1. Type of injury 2. Severity of the injury 3. Duration of the damage 4. Type of cell being injured- Some cell types sustain injury better than others; some tissues (e.g. liver) have a capacity to regenerate.

Cell Injury: Vulnerable Sites 1. Cell membranes 2. Mitochondria 3. Endoplasmic reticulum 4. Nucleus

Cell Membrane- why so easily injured 1. Membrane faces the external environment: sustains “trauma”, extracellular oxidants, proteases, etc. 2. Requires a constant supply of ATP for normal function (ion pumps). 3. Lipid molecules in the membrane are easily oxidized and support and oxidative chain reaction called lipid peroxidation.

Consequences of Injury 1. No long term effects- - the cell damage is repaired, the effects of the injury are reversible. 2. The cell ”adapts” to the damaging stimulus. 3. The cell dies, undergoing necrosis. The damage is irreversible.

Reversible Cell Injury Examples: 1. Cell swelling – usually accompanies all types of injury. Results from an increase in water permeability. Reverses once membrane function is restored. 2. Increase in extracellular metabolite because of a biochemical derangement. Ex.: Increase in extracellular glycogen in diabetes.

Reversible Cell Injury (cont) Examples: 3. Fatty change in liver. Vacuoles of fat accumulate within the liver cell following many types of injury: alcohol intoxication, chronic illness, diabetes mellitus, etc. Due to: An increase in entry of free fatty acids. An increase in synthesis of free fatty acids. An increase in synthesis of free fatty acids. A decrease in fatty acid oxidation. A decrease in fatty acid oxidation.

Adaptation- the cell responds successfully to the injurious stimulus Examples: 1. Hypertrophy- the cell increases in size. Ex.: cardiac myocytes of the left ventricle increase in size from essential hypertension. 2. Atrophy- the cell decreases in size because of a loss of cell substance.

Causes of Cell Atrophy 1. Loss of blood supply or innervation 2. Loss of endocrine factors (ex. TSH) 3. Decrease in the workload 4. Aging, chronic illness

Cell Death Necrosis Apoptosis

Morphology of Necrosis

Coagulative Necrosis Dead cell remains a ghost-like remnant of its former self-classically seen in an MI.Dead cell remains a ghost-like remnant of its former self-classically seen in an MI.

Pyknosis Intensely dark staining and shrunken nucleus, seen in a necrotic (dead) cell.

Karyorrhexis Fragmentation of pyknotic nucleus.

Karyolysis Extensive hydrolysis of the pyknotic nucleus with loss of staining. Represents breakdown of the denatured chromatin.

Liquefactive Necrosis The dead cell undergoes extensive autolysis, caused by the release of lysosomal hydrolases (proteinases, DNases, RNases, lipases, etc.) Seen classically in the spleen and brain following infarction. Seen classically in the spleen and brain following infarction.

Caseous Necrosis Seen in Tuberculosis (mycobacterium tuberculosis). Type of necrosis seen within infected tissues characterized as soft, friable, whitish-grey (resembles the milk protein casein).

Fat Necrosis Leakage of lipases from dead cells attack triglycerides in surrounding fat tissue and generate free fatty acids and calcium soaps. These soaps have a chalky-white appearance. Seen in the pancreas following acute inflammation.

Causes of Cell and Tissue Injury 1. Physical agents 2. Chemicals and drugs 3. Infectious pathogens 4. Immunologic reactions 5. Genetic mutations 6. Nutritional imbalances

Causes of Cell and Tissue Injury (cont) 7. Hypoxia and Ischemia- cell injury resulting from inadequate levels of oxygen. Many important causes: A. Inadequate blood supply B. Lung disease C. Heart failure D. Shock

Why So Important? All cells in the body require a continuous supply of oxygen in order to produce ATP via oxidative phosphorylation in mitochondria. ATP is absolutely critical for life.

Susceptibility of specific cells to ischemic injury- - Neurons: 3 to 5 min. Cardiac myocytes, hepatocytes, renal epithelium: 30 min. to 2 hr. Cells of soft tissue, skin, skeletal muscle: many hours

Hypoxic Injury- changes which are reversible 1. Decrease in extracellular ATP levels 2. Decrease in the Na pump, with cell swelling 3. Increase in glycolysis, with a decrease in intracellular pH 4. Decrease in protein synthesis

Hypoxic Injury- changes which are irreversible 1. Activation of lysosomal enzymes. (recall that lysosomal enzymes are active at low pH, ca. pH 4-5) 2. Degradation of DNA and protein. 3. Influx of calcium. (recall that calcium activates many lipases and proteases)

Hypoxic cells are exposed to damage from oxygen radicals- 1. Hypoxic patients are given high levels of oxygen. This oxygen is toxic to the cells lining the alveolar spaces in the lung because the high 0 2 produces oxygen radicals.

Hypoxic cells are exposed to damage from oxygen radicals- (cont) 2. Hypoxic tissues are often infiltrated with PMNs. PMNs have enzymes, myleoperoxidases, which produce activated oxygen

Hypoxic cells are exposed to damage from oxygen radicals- (cont) 3. Hypoxic tissues are often reperfused once the blood supply is restored. Xanthine oxidase, produced from proteolysis during hypoxia, generates free radicals when the 0 2 is brought back to normal levels.

H + H SOD GOOD/BAD REACTION

BAD REACTIONS H H. + 0H. (very reactive) FE ++ + H FE H. + 0H - H H. + 0H FENTON REACTION HABER-WEISS REACTION

GOOD REACTIONS 1212 GLUTATHIONE PEROXIDASE 2 H H H. + 2 GSH2 H GSSG H GSH 2 H GSSG