Apoptosis | cell death | gangrene | types of gangrene | Difference between gangrene - apoptosis| important question)| mnemonic |caspases,

 Apoptosis 

Apoptosis/programmed cell death: 

Apoptosis is a type of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate intrinsic enzymes that degrade the cells' genomic DNA and nuclear and cytoplasmic proteins. 

Causes/examples of apoptosis: 

▶Physiological causes: 

1) The removal of supernumerary cells (in excess of the required number) during development / programmed cell death during embryogenesis: 

Cell death is critical for involution of primordial structures & remodeling of maturing tissues, e.g. during- 

• ➤Implantation. 
• ➤Organogenesis.
• ➤Developmental involution & 
• ➤Metamorphosis. 

2) Involution of hormone-dependent tissues on hormone withdrawal: e.g. 

• ➤Endometrial cell breakdown during the menstrual cycle.
• ➤ Ovarian follicular atresia in the menopause.
• ➤The regression of the lactating breast after weaning & 
• ➤Prostatic atrophy after castration. 

3) Cell turnover in proliferating cell populations:To maintain a constant number of cells (cellular homeostasis); e.g.

• ➤Immature lymphocytes in the bone marrow & thymus. 
• ➤B-lymphocytes in the germinal centers that fail to express useful antigen receptors. 
• ➤ Epithelial cells in the intestinal crypts. 

4) Elimination of potentially harmful self-reactive lymphocytes: To prevent immune reactions against one's own tissues. 

5) Death of host cells that have served their useful purpose: Due to withdrawal of survival signals, e.g. 

• ➤Neutrophils in an acute inflammatory response & 
• ➤ Lymphocytes at the end of an immune response. 

▶Pathological causes: 

Apoptosis eliminates cells that are injured beyond repair. 

1) Apoptosis of injured cell due to DNA damage: By radiation & cytotoxic anti-cancer drugs can damage DNA. Apoptosis of such type of injured cell is a protective mechanism to prevent their conversion into malignant transformation. 

2) Apoptosis of cells in which there are accumulation of misfolded proteins: This type of apoptosis occurs in the endoplasmic reticulum (ER stress) due to gene mutation. 

3) Cell death in certain infections: Particularly in case of viral infections; e.g. Adenovirus, HIV, hepatitis infections etc. 

4) Cell death in tumors. 

5) Pathologic atrophy & apoptosis in parenchymal organs after duct obstruction: e.g. in the pancreas, parotid gland & kidney. 

▶Morphologic features of apoptosis: 

1) Cell shrinkage: 

• ➤Cell size: Smaller than normal cell.
• ➤Cytoplasm: Dense.
• ➤ Organelles: Relatively normal but tightly packed.
• ➤Cell membrane: Remain intact during apoptosis, but in the last stage of apoptosis it becomes permeable. 

2) Chromatin condensation: 

✔ This is the most characteristic feature of apoptosis. 

✔ The chromatin aggregates peripherally (under the nuclear membrane) and transformed into dense masses of various shapes and sizes. 

✔ The nucleus itself may break up, producing two or more fragments. 

3) Formation of cytoplasmic blebs & apoptotic bodies:

 The apoptotic cell first shows extensive surface blebbing, then undergoes fragmentation into membrane-bound apoptotic bodies composed of cytoplasm and tightly packed organelles, with or without nuclear fragments. 

4) Phagocytosis of apoptotic cells or cell bodies: 

✔ Phagocytosis occurs usually by macrophages. 

✔ The apoptotic bodies are rapidly ingested by phagocytes and degraded by the phagocyte's lysosomal enzymes. 

▶Pathogenesis/ mechanism of apoptosis: 

Apoptosis is the endpoint of an energy-dependent cascade of molecular events and results from the activation of enzymes called caspases. 

▶Initiation phase/signaling pathways that initiate apoptosis: 

During this period, some caspases become catalytically active. Two distinct pathways converge caspase activation, e.g. 

a) The intrinsic (mitochondrial) pathway of apoptosis: 

• ➤The intrinsic / mitochondrial pathway is the major mechanism of apoptosis.
• ➤It results from increased permeability of the mitochondrial outer membrane with consequent release of death-inducing (pro-apoptotic) molecules from the mitochondrial intermembrane space into the cytoplasm.
• ➤The release of mitochondrial pro-apoptotic proteins is tightly controlled by the BCL2 family of proteins.
• ➤The mitochondrial pathway leads to activation of the initiator caspase-9. 

b) Extrinsic/death receptor-initiated pathway of apoptosis: 

• ➤This pathway is located in cell membrane & initiated by engagement of plasma membrane death receptors on a variety of cells.
• ➤Death receptors are members of the TNF receptor family & a related protein called Fas that contain a cytoplasmic domain involved in protein-protein interactions that is called the death domain because it is essential for delivering apoptotic signals.
• ➤The death receptor pathway leads to activation of the initiator caspases 8 & 10. 

❖ Execution phase: 

Caspases trigger the degradation of critical cellular components. 

• ➤The enzymatic death program is set in motion by rapid and sequential activation of the executioner caspases (e.g. caspase 3 & 6) act on many cellular components.
• ➤These activated caspases cleave an inhibitor of a cytoplasmic DNase→ make the DNase enzyme active → DNase enzyme induces cleavage of DNA.
• ➤Caspases also degrade structural components of the nuclear matrix and thus promote fragmentation of nuclei. 

❖Removal of dead cells: By phagocytosis. 

Figure: Mechanism of apoptosis.

Figure: The intrinsic (mitochondrial) pathway of apoptosis. 

 

Caspases: 

❖They are named so, because they are cysteine proteases that cleave proteins after aspartic residues. 

❖Like many proteases, caspases exist as inactive proenzymes, or zymogens. 

❖They must undergo enzymatic cleavage to become active. 

❖The presence of cleaved, active caspases is a marker for cells undergoing apoptosis. 

❖The activation of caspases depends on a finely tuned balance between production of pro- apoptotic and anti-apoptotic proteins. 

Caspases/enzymes responsible for apoptosis: 

1) Initiation phase: 

• ➤Intrinsic / mitochondrial pathway: Caspase 9. 
• ➤Extrinsic / cell membrane death receptor pathway: Caspases 8 & 10. 

2) Execution phase: Caspase 3 & 6. 

Differences between necrosis and apoptosis: 

Gangrene 

Gangrene: Gangrene means macroscopic death (necrosis) of tissue with superadded putrefaction. 

Types: 

1. Dry gangrene.
2. Wet/moist gangrene.
3. Gas gangrene: It is a specific moist gangrene caused by Clostridium perfringens in most cases. 

❖ Signs of gangrene: 

• ✓ Changes of colour: Pale, bluish, purple & finally black.
• ✓ Loss of temperature.
• ✓ Loss of sensation.
• ✓ Loss of pulsation.
• ✓ Loss of function. 

❖ Some gangrene-related terms: 

• ✓ Noma: A gangrenous lesion of the vulva or mouth (when it is alternatively called cancrum oris) occurring usually in malnourished children after an infectious disease such as measles. 
• ✓ Postoperative synergistic gangrene: Which implicates the anterior abdominal wall and thighs.
• ✓ Fournier's gangrene: A fulminating lesion of the scrotum, which is usually completely destroyed, so that the testes are left exposed. 

Dry gangrene: 

❖ Causes of dry gangrene: Occurs due to lack of arterial blood supply. 

1) Changes in arterial wall: 

• ✓ Diabetic gangrene (commonest example). 
• ✓ Thromboangitis obliterans (Buerger's disease). 
• ✓ Atherosclerosis.
• ✓ Arteriosclerosis. 

2) Spasm of artery: 

• ✓ Raynaud's disease.
• ✓ Ergot poisoning. 

3) Obstruction of the lumen of the artery: 

• ✓ Thrombosis.
• ✓ Embolism. 

4) Pressure effect: Pressure from outside by tumour, tight plaster. 

➤Site: Usually occurred in distal part of extremity. Usually, gangrene starts at the great toe. 

➤Pathogenesis of dry gangrene: 

Dry gangrene occurs due to impairment of the arterial supply, (But venous drainage remains intact)

↓ 

Due to impairment in the arterial supply, ischaemic coagulative necrosis occurs 

↓ 

The gangrenous area appears cold, dry, shriveled, mummified and black due to iron sulphide and foul smelling 

↓

Iron is derived from haemolysed RBC and H2S from putrefaction by involved saprophytes 

↓ 

There is a line of demarcation between necrotic tissue and the healthy inflammatory zone 

➤ Zones of dry gangrene: 3 zones of dry gangrene- 

1. Zone of granulation tissue over necrotic area.
2. Zone of inflammation
3. Zone of demarcation: It separates necrotic tissue from inflammatory zone formed by contraction of granulation tissue and is the guideline for amputation. 

❖ Causes of dry gangrene:

 Mnemonic → RESTED 

• ➤ R = Raynaud's disease,
• ➤ E = Embolism,
• ➤ S = Senile atherosclerosis,
• ➤ T Thrombosis,
• ➤ E = Ergot poisoning, 
• ➤ D= Diabetic arteritis. 

Buerger's disease  

Buerger's disease/ thromboangitis obliterans:

• ✓ Involves small and medium-sized arteries and veins.ib zomradesenvoll you t2.0
• ✓ Involves the extremities.
• ✓ Recurrent neutrophilic vasculitis with micro-abscess formation.
• ✓ Segmental thrombosis leads to vascular insufficiency. 

Vessels affected in Buerger's disease: 

❖ Medium and small sized vessels: e.g.

1. Dorsalis pedis.
2. Posterior and anterior tibialis.
3. Radial artery,
4. Ulnar &
5. Digital artery. 

❖ Rarely mesenteric, cerebral and coronary vessels may be affected. 

Pathology of the Buerger's disease: 

Localized inflammation in the walls of arteries & veins

 ↓

 Thrombosis 

↓

Occlusion of the lumen (or obliteration)

 ↓

Ischaemia, ulceration & gangrene 

Wet gangrene 

Moist gangrene/wet gangrene: 

➤ Sites of wet gangrene: 

1) Commonest site: Intestine is the commonest site. Wet gangrene in the intestine occurs in- 

• ➤ Strangulated hernia.
• ➤ Intussusception.
• ➤ Volvulus & 
• ➤ Trombosis in mesenteric artery. 

2) Bed sores. 

3) Lungs. 

4) Other sites: Vulva, scrotum, anterior abdominal wall, thigh etc. 

❖ Pathogenesis of wet gangrene: 

It develops due to obstruction of both arterial supply & venous drainage particularly in moist areas

↓ 

The gangrenous part is moist, blackish and offensive in smell

↓ 

There is no line of demarcation  

➤ Differences between dry gangrene and moist gangrene: 

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