1. Cell Injury and Cell Death

2. Cell Injury
If the cells fail to adapt under stress, they undergo certain changes called cell injury.
The affected cells may recover from the injury (reversible) or may die (irreversible).

5. Causes of Cell Injury Oxygen deprivation (hypoxia) Physical agents
Chemical agents
Infections agents
Immunologic reactions
Genetic defects
Nutritional imbalances

6. Hypoxia & Ischaemia

7. Morphology of Cell Injury
Reversible:
Cellular swelling and vacuoles formation
(Hydropic changes)
Changes at this stage EM - blebbing of the plasma membrane, swelling of mitochondria and dilatation of ER
Nuclear alterations
Fatty change

11. Sequence of events in reversible injury
reduced oxidative phosphorylation and ATP production in the mitochondria
increased anaerobic metabolism (glycolysis)  reduced glycogen stores and increased production of Lactic acid
decreased intracellular pH - clumping of nuclear DNA
decreased activity of Na+ pump (ATP-dependent)
generalized edema (increased intracellular Na+ and H20)
detachment of ribosomes from ER - reduced protein synthesis
surface blebs, mitochondrial swelling

17. Cloudy swelling, Kidney
Hydropic change or vacuolar degeneration.
Appears whenever cells are incapable of maintaining ionic and fluid homeostasis.
The first manifestation of almost all forms of cell injury.
Reversible injury.

23. Fatty Change
Hepatic lipid accumulation is characterized by intracellular accumulation of triglycerides, and due to the failure of metabolic removal.
Defects in fat metabolism are often induced by alcohol consumption, and also associated with diabetes, obesity, and toxins.
Fatty change is most often seen in the liver (and heart), and is generally reversible.

26. Morphology of Cell Injury
Irreversible (Necrosis):
The changes are produced by enzymatic digestion of dead cellular elements, denaturation of proteins and autolysis (by lysosomal enzymes)
Cytoplasm - increased eosinophilia
Nucleus - nonspecific breakdown of DNA leading to pyknosis (shrinkage), karyolysis (fading) and karyorrhexis (fragmentation).

29. Irreversible Injury disruption of plasma membrane
disintegration of DNA, RNA, and phospholipids
rupture of lysosomes and leakage of lysosomal enzymes into the cytoplasm  enzymatic digestion of cellular components
influx of Ca+2 into the intracellular space

32. Irreversibility Inability to reverse mitochondrial dysfunction
Profound disturbances in membrane function

33. Reversible Injury:
Cellular Swelling, Vacuolar Degeneration, “Hydropic Change” – appearance of clear, vacuolated cytoplasm (due to generalized edema, mitochondrial edema, dispersion of ribosomes, and presence of surface blebs)
“Fatty Change” – appearance of lipid vacuoles in the cell cytoplasm
Irreversible Injury:
binding of eosin to denatured proteins causes increased cytoplasmic eosinophilia  more pink
loss of DNA, RNA, glycogen causes decreased basophilia  less blue
nuclear changes: karyolysis (faded), karyorrhexis (fragmentation), pyknosis (shrinkage)

35. MECHANISMS OF FREE RADICAL-INDUCED CELL INJURY
Free radicals are chemical species with a single unpaired electron in an outer orbit. Free radicals are highly reactive with cell membranes and nucleic acids. They may by initiated by:
absorption of radiant energy
enzymatic metabolism of exogenous chemicals or drugs
redox reactions of normal metabolism:
superoxide anion radical from mitochondria and cytochrome p450
hydrogen peroxide from peroxysome catylases
hydroxyl ions from ionization of water
transition metals
nitric oxide

37. MECHANISMS OF FREE RADICAL-INDUCED CELL INJURY
Free radicals cause:
lipid peroxidation of membranes
oxidation of proteins
DNA damage

43. Cells can be damaged by a variety of mechanisms.
Hypoxia causes loss of ATP production secondary to oxygen deficiency and can be caused by ischemia, cardiopulmonary failure, or decreased oxygen-carrying capacity of the blood.
The response of cells can range from adaptation to reversible injury to irreversible injury with cell death.
Intracellular sites and systems particularly vulnerable to injury include DNA, ATP production, cell membranes, and protein synthesis.
Reversible cell injury is primarily related to decreased ATP synthesis by oxidative phosphorylation, leading to cellular swelling and inadequate protein synthesis.
Irreversible cell injury often additionally involves severe damage to membranes, mitochondria, Iysosomes, and nucleus.