Cell death

Cell death is a critical process to remove potentially harmful cells from the body of multicellular organisms. Various types of cell death includes –

Necrosis (Cell death with inflammation) –

Definition- Necrosis refers to pathological cell death associated with inflammation.
Microscopic examination-
Pink (eosinophilic)
Inflammation present

Types of necrosis –

Coagulative necrosis –

  • This is the most common type of necrosis.
  • Mechanism of action of coagulative necrosis – Denaturation of proteins.
  • Solid organs that are affected in coagulative necrosis –
    Heart (most commonly affected)
  • Morphology – Due to decreased blood supply, presence of infarct is seen in coagulative necrosis.
  • Microscope – Ghost cells seen in microscopic examination which gives a tombstone appearance.
  • During microscopic examination, tissue architecture and outline is preserved and details are lost.

Liquefactive necrosis / Colliquative necrosis –

  • Liquefactive necrosis refers to the pattern of cell death in which death of the cells occur within hours and the cells transform into a thick, sticky liquid.
  • The cells may appear creamy yellow due to presence of pus.
  • Solid organs that are affected in liquefactive necrosis –
  • The organs are rich in hydrolytic enzymes which makes them the common organs to be affected in Liquefactive necrosis.
  • Cause – Infectious agents (bacteria, virus, fungi)
  • Tissue architecture does not remain preserved.
  • Example – Abscess

Caseous necrosis –

  • As the word caseous means cheese, caseous necrosis has a cheesy appearance.
  • Caseous necrosis is a mixture of coagulative and liquefactive necrosis.
  • In this necrosis – coagulative necrosis >>>>>> liquefactive necrosis
  • Solid organs affected in caseous necrosis – Lungs
  • Example- Tuberculosis, fungal infection, syphilis

Fat necrosis –

  • Fat necrosis refers to the death of fat tissue due to any injury, trauma or loss of blood supply.
  • There is hydrolysis and rupture of adipocytes, causing release of neutral fat which changes into glycerol and free fatty acids which forms a complex with calcium to form calcium soaps.
  • Microscopy – Amorphous, granular and basophilic
  • Example –
    Breast – Any trauma to breast leads to breakdown of fat that causes release of free fatty acids which further leads to saponification.
    Omentum – due to acute pancreatitis

In case of pancreatitis, if the injury is inside the pancreas it leads to liquefactive necrosis and in case of peri pancreatic fat it is fat necrosis.

Fibrinoid necrosis –

  • Fibrinoid necrosis is characterised by deposition of fibrin like material.
  • Microscopy – Brightly eosinophilic, hyaline like deposition in the cell wall .
  • Encountered in immune complex reaction or antigen antibody reaction.
  • Example –
    PAN (polyarteritis nodosa)
    RHD (rheumatic heart disease)

Gangrene –

  • Gangrene is a type of necrosis with superadded putrefaction.
  • This leads to blackish discolouration of the organs and is foul smelling.
  • There are two main types of gangrene –
    Dry gangrene
    Wet gangrene
Dry gangrene –
  • This form of gangrene begins in distal part of a limb due to ischemia.
  • The gangrene spreads slowly upwards until it reaches a point where the blood supply is adequate to keep the tissue viable.
  • A line of separation is formed at this point between the gangrenous part and the viable part.
Wet gangrene –
  • Wet gangrene occurs naturally moist tissues and organs such as the bowel, lung, mouth, cervix, vulva, etc.
  • Example –
    Diabetic foot
    Bed sores that occurs in bed ridden patients.

Zenker’s degeneration –

  • This is a type of coagulative necrosis.
  • Example – Typhoid or enteric fever
  • It leads to complications in skeletal muscles like rectus abdominis and diaphragm.

Apoptosis –

  • Apoptosis is caspase dependent programmed cell death.
  • This can be physiological or pathological unlike necrosis which is only pathological.
  • Physiological apoptosis –
  • Digit formation in baby.
  • Endometriosis
  • Neutrophil clearance
  • Pathological apoptosis –
  • Councillman bodies – seen in case of viral hepatitis.
  • Civatte/ Colloid/ Cytoid bodies – seen in the case of lichen plants.

Mechanism of apoptosis –

The mechanism of apoptosis include two major steps that are initiation and execution.

Initiation –
  • This includes the role of caspase 8,9,10. There are two pathway for initiation that include intrinsic and extrinsic pathway.
  • IntrinsicThis is also known as mitochondrial pathway.
  • As the name clearly suggests this pathway includes the mechanisms of apoptosis occurring within the cell.
  • When a cell undergoes stress, stress sensors like BIM,BID,BAD,NOXA,PUMA get signals and increase proapoptotic factors within the cell and decrease antiapoptotic factors.
  • On the surface of mitochondria, cytochrome c and apaf1 (apoptosis activating factor) collectively form apoptosome, which is a wheel like hexamer and it activates procaspase 9 to caspase 9.
  • Other proapoptotic factors in mitochondria includes SMAC/DIABLO.

  • Extrinsic – This is also known as the death receptor pathway.
  • This is the mechanism of apoptosis happening on the surface of the cell.
  • In this process, cell wanting to die have CD95/fas and the supporting T-cell have CD95 ligand /fas ligand.
  • During the process, trimerisation of CD95/fas occurs on the surface of the cell which activates fadd(fas associated death domain). This fadd activates procaspase 8,10 into caspase 8,10. FLIP is the inhibitor of this process, so it is as antiapoptotic factor.
Execution –
  • This includes the role of caspase 3,6,7
  • This step includes activation of several enzymes Including –
  • Phospholipase
  • Protease
  • Endonuclease – This breaks DNA after every 180-200 bp, known as intranucleosomal cleavage.
  • After execution call falls off into apoptotic bodies. These apoptotic bodies generates EAT ME signals (C1q, Thromospondin, Phosphatidyl serine) which triggers macrophages for phagocytosis.
  • The process of engulfment of apoptotic bodies by macrophages is known as Efferocytosis.
  • During this process,PS flipping is seen that is, in normal cell phosphatidyl serine is present in inner layer of cell membrane but in apoptotic cell it reaches outer layer of the cell membrane.
  • Scott syndrome is a condition arising due to defect in PS flipping.
  • Survival of cancer cells is due to release of CD47 which is a DO NOT EAT ME signal.

Identification of apoptosis –

  • MARKER– Annexin V (PS flipping test)
  • MICROSCOPE – Nuclear chromatin condensation
  • STAIN – Tunel stain (TdT dUTP Nick End Labelling)
    Positive- Apoptosis Negative – Necrosis
  • Gel electrophoresis – Step ladder pattern