Cell Death

CELL DEATH

Common type of necrosis after exogenous stimuli. •Swelling, denaturation and coagulation of proteins •Breakdown of cellular organelles •Cell rupture

NECROSIS The sum of the morphologic changes that follow cell death in living tissue and organ: • Denaturation of proteins. • Enzymatic digestion of organelles and cytosol.

AUTOLYSIS • Enzymatic digestion by lysosomal enzymes of the dead cells themselves. HETEROLYSIS • Digestion by lysosomal enzymes of immigrant leukocytes.

Three pattern of nuclear changes Karyolysis (DNase activity) Pyknosis (DNA condensation) Karyorrhexis (fragmentation of pyknotic nucleus)

Morphologic appearance of necrosis • Increased eosinophilia: Loss of RNA in the cytoplasm Increased binding of eosin to denatured cytoplasmic protein • More glassy homogeneous appearance Loss of glycogen particles • Vacuolated and moth-eaten cytoplasm • Calcification of necrotic cells

TYPES OF CELL DEATH • necrosis Coagulation necrosis Caseous necrosis Gangrene

Liquefaction necrosis( fat necrosis) Fibrinoid necrosis

• Apoptosis

Coagulation necrosis Denatures of both structural and enzymatic proteins by injury or the subsequent increasing intracellular acidosis.

Caseous necrosis A subtype of coagulation necrosis White and cheesy Tuberculosis Completely obliterated tissue architecture

Gangrene A subtype of coagulation necrosis Dry gangrene Wet gangrene Gas gangrene

Liquefactive necrosis Bacterial or fungal infections Central nervous system Amebiasis

Fat necrosis Traumatic Activated pancreatic lipases

Fibrinoid degeneration Deeply eosinophilic • Collagen diseases • Necrotic vasculitis • Malignant hypertension

APOPTOSIS (Programmed cell death) • Programmed destruction of cells during embryogenesis. • Hormone dependent involution of tissues in the adult. • Cell deletion in proliferating cell populations (intestinal crypt epithelium), tumors, and lymphoid organs.

• Pathologic atrophy in parenchymal organs after duct obstruction. • Cell death by cytotoxic T cells. • Cell injury in certain viral diseases. • Cell death produced by a variety of injurious stimuli given in low doses (e.g. mild thermal injury).

MORPHOLOGICAL FEATURES OF APOPTOSIS • Cell shrinkage • Chromatin condensation and fragmentation. • Formation of cytoplasmic blebs and apoptotic bodies. • Phagocytosis of apoptotic bodies by adjacent healthy cells or macrophages. • Lack of inflammation.

Necrosis Stimuli Hypoxia Toxins Histology Cell swelling Coagulation N Disruption of organelles DNA Random breakdown Diffuse

Apoptosis Physical Pathological Single cell Chromatin condensation Apoptotic bodies Internucleosomal

Necrosis Apoptosis Mechanism ATP depletion Gene activation Membrane Endonuclease injury Free radicals Tissue Inflammation No inflammation reaction Phagocytosis of apoptotic bodies

• Fig 1-18

Biochemical features of apoptosis 1.PROTEIN CLEAVAGE: Caspases (cysteine protease) Nuclear scaffold Cytoskeletal protein 2.PROTEIN CROSS-LINKING: Transglutaminase Cytoplasmic protein→shrunken shalls →apoptotic bodies Biochemical features of apoptosis

3. DNA breakdown: 50-300 kb pieces Ca2+, Mg2+ dependent endonucleases DNA oligonucleosomes DNA ladders (also seen in necrosis) 4. PHAGOCYTIC RECOGNITION Receptors on macrophages for the surface components (phosphatidylserine, thrombospondin) on apoptotic bodies.

• Fig 1-19

• Apoptosis-associated genes bcl-2, c-myc, p53

• Fig 1-20

Fates of necrosis • Absorption • Discharge: Erosion Ulcer Sinus Fistula Cavitation • Organization • Encapsulation • Calcification

Chapter Three Repair Section A Regeneration: Completely regeneration Fibrous repair

Regeneration capacity • • •

Labile cells Stable cells Permanent cells

Factors influencing regeneration 1. Cell-cell interaction Conditioned medium Contact inhibition 2. Extracellular matrix Laminin: ↑ Epithelia ↓ Fibroblasts Fibronectin : ↓ Epithelia ↑Fibroblasts 3. Growth factors

GROWTH FACTORS EGF, TGF-A, PDGF, aFGF, bFGF, IGF-1, IGF-2, VEGF, HGF, MG-CSF, M-CSF, G-CSF, ERYTHROPOITIN, ILs, TNF, IFN, NGF.

Section B Fibrous Repair Granulation tissues: • Newly formed capillaries • Fibroblasts • Inflammatory cells

Granulation tissues • Fibrous repair • Organization • Wound healing

• Fig 4-14

• Fig 4-15

Wound healing • Healing by first intention • Healing by second intention • Healing under scab

• Fig 4-18

• Fig 4-19

Systemic factors influencing wound healing: • Nutrition • Metabolic status • Circulatory status • Hormones

Local factors influencing wound healing: • Infection • Mechanical factors • Foreign bodies • Size, location and types of wound