Cell death

2 types of cell death

Necrosis

Apoptosis

Necrosis (definition + associated with , & results from)

Necrosis

• Def: pathologic process where cells rupture and release content into extracellular space causing local inflammation

• Associated with: Loss of memb integrity & cellular content leakage and dissolution of cells

• Necrosis results from severe cell injury

Key features of necrosis

1. Membrane dissolution

• cellular memb breakdown (plasma & lysosomal

2. Enzyme leakage:

• Lysosomal enzyme escape into cytoplasm → digest cellular components worsening injury

3. Inflammatory response:

• Cytokine release → induces inflammation

4. Immune activation

• Phagocytosis of cell debris

• Inflammatory cells release more proteolytic enzyme cause more tissue injury

Morphological changes of Necrosis (Cytoplasmic and nuclear)

Cytoplasmic: ↑Eosinophilia due to ↑binding of eosin to denatured cytoplasmic protein

Nuclear: Due to breakdown of DNA and chromatin

• Pyknosis = Nuclear shrinkage & DNA condense into solid shrunken mass

• Karyorrhexis = Pyknotic nucleus fragmentation

• Karyolysis = Complete dissolution

Coagulative Necrosis: (Description,Mostly seen, Examples and describe the gross and microscopic image below)

• Characteristic of hypoxia induced cell death most commonly by ischemia

• Its called infarction seen mostly in solid organs like kidney and heart

Eg: Myocardial infarction, Renal infarction

A. Gross image = Kidney infarction (yellow) with outlines preserved

B Microscopic image = Normal kidney (N) and Necrotic cells of infarct (I). Necrotic cells show persevered outlines with loss of nuclei

Liquefactive Necrosis (Def, cause, Associated with, Example)

Def: Dead cells disintegrate and affected tissue is liquified

Causes: Dead cells digested by released enzymes in necrosis from bacterial, fungal infections & in brain ischemic infarcts (even if sterile)

Associated with: cellular destruction and pus formation

Eg: Cerebral infarction (ischemia in brain is liquefactive not coagulative)

1. Liquefactive necrosis in brain tissue

2. Pus formation

Caseous necrosis (Def, characteristic of, gross/ microscopically, peripheral collection)

Def: Dead tissue breaks down creating cheesy consistency on gross exam

Characteristic of : TB, some fungal infections (eg:histoplasmosis)

Microscopically: Collection of fragmented/lysed cells with amorphous granular pink (eosinophilic) appearance.

(Often) peripheral collection: macrophages forming granuloma

Gross: Large area of caseous necrosis containing yellow-white cheesy debris

Microscopically: Granuloma shows central necrosis surrounded by multiple Langerhans- giant cells, epitheliod cells and lymphocytes

Gangrenous necrosis (Def , Types + gross examination)

Def:

Death of soft tissue (applied for limb lost its blood supply)

• Results from ischemia (eg: diabetic vasc disease affecting lower limbs)

Types

1. Dry gangrene : Dead tissue intact

2. Wet gangrene : Tissue liquifies (especially after bacterial infection)

3. 

Gross: Gangrenous necrosis is a dark/black colour

Fat necrosis (def, causes, clinical context, gross, microscope, types)

a. Def: Local areas of fat destruction

b. Causes: (usually) Activated pancreatic lipase release into pancreatic tissue and peritoneal cavity

c. Clinical context: Common in acute pancreatitis

d. Gross appearance:

Fatty acid released from necrotic cells + calcium → Fat saponification

Produces chalky white, visible lesions

e. Microscopic: Shadowy outlines of necrotic fat cells surrounded by basophilic Ca deposits. Also has inflammatory reaction.

f. Types: Enzymatic (fat necrosis by pancreatic enzymes), Traumatic (traumatic fat necrosis of breast)

Enzymatic Fat necrosis

Traumatic fat necrosis of breast

Fibrinoid necrosis (Def , Causes/Mech)

Def: Microscopic pattern of necrosis seen mostly commonly in cell mediated reactions

Causes/Mechanism: Deposition of immune complexes (antigen+ antibodies) & extravasated plasma protein in blood vessel walls.

Laboratory diagnosis of necrosis

Lab diagnosis of necrosis relies on detecting ↑ intracellular protein serum levels that leak out due to cell memb damage.

Eg of diagnostic markers:

1. Troponin → diagnose myocardial infarction

2. Transaminases (ALT,AST) → Diagnose liver disease

3. Pancreatic enzyme (amylase, lipase…) → Diagnose pancreatitis

Apoptosis (Def, Purpose, Key feature, Physiological and Pathological example)

Def: Apoptosis is form of programmed cell death (cellular suicide)

Purpose: Eliminate (/remove) cells no longer needed or damaged beyond repair

Key feature: Occurs without eliciting (harmful) inflammatory response

Physiological and Pathological apoptosis examples

• Physiological = eg: During development for removal of excess cells during embryogenesis

• Pathological = eg: Eliminate cells with DNA damage by radiation, cytotoxic agents etc

1. Apoptosis mech involves activation of caspases (enzyme)

2. Activated caspases → activation of nucleases degrade DNA & other enzymes that destroy necleoproteins and cytoskeletal proteins.

2 distinct pathways involved on caspase activation

1. Mitochondrial pathway

2. Death receptor pathway

Mitochondrial pathway = Cell injury → Bcl 2 family effectors (Bax, Bak) → Mitochondria → cytochrome c → initiator caspases

Death receptor pathway = Receptor ligand interactions → Adapter proteins → initiator caspases

Morphology of apoptosis

• Cell shrinkage

• Condensation of nuclear chromatin

• Formed apoptotic bodies by fragmentation of cells and nuclei

• Fragments are memb bound and contain cell organelles

• Phagocytosis of apoptopic bodies by phagocytes

Necrosis vs Apoptosis ( Cell size , Nucleus, Plasma memb, Cell contents, Adjacent inflammation, Physiological or pathological)

Feature (N = necrosis , A = Apoptosis

1. Cell Size :

N = Enlarged swelling

A = Reduced (shrinkage)

2. Nucleus

N = Pyknosis → Karryohexis → Karyolysis ,

A = Fragmentation → Nuclosome sized fragment

3. Plasma membrane

N = Disrupted

A = Intact (altered struct especially lipid orientation)

4. Cellular contents

N = Enzymatic digestion (may leak out of cell)

A = Intact (may be released in apoptotic bodies)

5. Adjacent inflammation

N = Frequent

A = No

6. Physiological/ Pathological role

N = Pathological (culmination of irreversible cell injury)

A = Often Physiological (eliminate unwanted cells) may be pathological after some forms of cell injury especially DNA and protein damage