CELL INJURY, APOPTOSIS AND NECROSIS

CONCEPTS IN CELL INJURY

• Cell injury results from a disruption of one or more of the cellular components that maintain cell viability.

• Cell injury is common to all pathologic processes.

CONCEPTS IN CELL INJURY

• Cell injury may be reversible, result in cell adaptation, or lead to cell death.

• Injury at one point induces a cascade of effects.

CAUSES OF CELL INJURY -THE PATIENT’S VIEW

• Hypoxia

• Infectious agents

• Physical injury

• Chemicals/drugs

• Immune response

• Genetic derangement

• Nutritional imbalance

• Ischemia ("ischemic hypoxia"; "stagnant hypoxia"): Loss of arterial blood flow (*  literally, "holding back the blood")

• Local causes – Occlusion of the arteries that bring in fresh blood – Occlusion of the veins which allow blood to leave, so

that fresh blood can flow in – Shunting of arterial blood elsewhere ("steal

syndromes"; "Robin Hood" syndromes)

• Systemic causes – Failure of the heart to pump enough blood

Hypoxemia: Too little available oxygen in the blood

Oxygen problems ("hypoxic hypoxia") Too little oxygen in the air Failure to properly ventilate the lungs Failure of the lungs to properly oxygenate the blood Failure of the heart to pump enough blood through the lungs Tremendously increased dead space (i.e., pulmonary thromboembolus)

Hemoglobin problems ("anemic hypoxia") Inadequate circulating red cell mass ("anemia") Inability of hemoglobin to carry the oxygen (carbon monoxide poisoning, methemoglobinemia) "High affinity" hemoglobins that will not give up their oxygen to the tissues

Direct Physical ActionMajor problems are hemorrhage & ischemia

INFECTIOUS DISEASE

Primary HerpesCandidiasis

Tuberculosis Actinomycosis

PHYSICAL INJURY

Thermal Burn Traumatic ulcer

CHEMICAL/DRUG INJURY

GingivalHyperplasia

Asprin Burn

GENETIC DERANGEMENTS

Down's Syndrome

Ehlers-Danlos

Cancer

NUTRITIONAL IMBALANCE

Diabetes

Scurvy

Reversible Injury

• Mitochondrial oxidative phosphorylation is disrupted first Decreased ATP – Decreased Na/K ATPase gain of

intracellular Na cell swelling– Decreased ATP-dependent Ca pumps

increased cytoplasmic Ca concentration– Altered metabolism depletion of glycogen– Lactic acid accumulation decreased pH– Detachment of ribosomes from RER

decreased protein synthesis

• End result is cytoskeletal disruption with loss of microvilli, bleb formation, etc

HYPOXIA - ISCHEMIA MODEL

Impaired function of the plasma membrane

ATP-dependentNa+ pump

Na+ influxCa++ influxK+ efflux

H2O influx

Cellular swellingMembrane blebs and loss of villiER swelling

Irreversible Injury

• Mitochondrial swelling with formation of large amorphous densities in matrix

• Lysosomal membrane damage leakage of proteolytic enzymes into cytoplasm

• Mechanisms include:– Irreversible mitochondrial dysfunction

markedly decreased ATP– Severe impairment of cellular and organellar

membranes

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Cell Injury

• Membrane damage and loss of calcium homeostasis are most crucial

• Some models of cell death suggest that a massive influx of calcium “causes” cell death

• Too much cytoplasmic calcium:– Denatures proteins– Poisons mitochondria– Inhibits cellular enzymes

Clinical Correlation

• Injured membranes are leaky

• Enzymes and other proteins that escape through the leaky membranes make their way to the bloodstream, where they can be measured in the serum

Reactive oxygen and nitrogen species ROS/RNSFree radical – each molecule or its fragment, which can exists independently And contains one or two unpaired electronsReactive oxygen species - species, which contain one or more oxygen atoms and are much more reactive than molecular oxygen

ROS/RNSFree radicals

superoxide radical

hydroperoxyl radical

hydroxyl radical

nitric oxide

hydrogen peroxide

Free Radicals

• Free radicals have an unpaired electron in their outer orbit

• Free radicals cause chain reactions

• Generated by:– Absorption of radiant energy– Oxidation of endogenous constituents– Oxidation of exogenous compounds

Examples of Free Radical Injury

• Chemical (e.g., CCl4, acetaminophen)

• Inflammation / Microbial killing

• Irradiation (e.g., UV rays skin cancer)

• Oxygen (e.g., exposure to very high oxygen tension on ventilator)

• Age-related changes

Mechanism of Free Radical Injury

• Lipid peroxidation damage to cellular and organellar membranes

• Protein cross-linking and fragmentation due to oxidative modification of amino acids and proteins

• DNA damage due to reactions of free radicals with thymine

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IRREVERSIBLE CELL INJURY

Definition:Necrosis is local death of cells while the individual is a life

followed by morphological changes in the surrounding living tissue, (cell placed immediately in fixative are dead but not necrotic).

Causes of cell necrosis: most common causes of cell death are viruses, ischaemia, bacterial toxins, hypersensitivity, and

ionizing radiation.

Morphologic change in necrosis:The changes don’t appear in the affected cells by light microscopy

before 2-6 hours according to the type of the affected tissue.

NECROSIS

Changes in the cytoplasm:

i. Swelling and granularity of the cytoplasm

ii. Loss of cellular membrane

iii. Fusion of cells

Nuclear changes: Occur due to hydrolysis of

nucleoproteins:

i. Pyknosis i.e. the nucleus becomes shrunken condensed and deeply stained.

ii. Karyorrhexis: rupture of nuclear membrane with fragmentation of the nucleus.

iii. Karyolysis: the nucleus dissolves and disappears.

Finally the affected tissue changes to homogeneous eosinophilic mass with nuclear debris.

TYPES OF NECROSIS

The variable types of necrosis differ as regards causes, gross and microscopic pictures.

(1) Coagulative necrosis:It is mainly caused by sudden ischaemia e.g. infarction of

heart, kidney and spleen. The protein of the affected tissue becomes denaturated.

Grossly, it appears dry pale opaque. It is triangular ? subcapsular with the base towards the capsule of the affected organ. This is due to the fan like distribution of the supplying blood vessels. The infarct area is surrounded by narrow zone of inflammation and congestion.

Microscopically, the structural outline of the affected tissue is preserved but the cellular details are lost.

TYPES OF NECROSIS

(2) Liquifactive necrosis

The necrosed tissue undergoes rapid softening e.g. infarction of the nervous tissue which has abundant lysosomal enzymes. Also, this type of necrosis occurs in case of suppurative inflammation (Abscess) where liquefaction occurs under the effect of proteolytic enzymes of PNLs liquefaction of the amoebic abscess occurs due to the effect of strong proteolytic enzymes and hyaluronidase secreted by E. Histolytica.

Grossly: the affected tissue appears as homogenous amorphous substance. Microscopically: it appears as homogenous eosinophilic structure.

.

The two lung abscesses seen here are examples of liquefactive necrosis in which there is a liquid center in an area of tissue injury. One abscess appears in the upper lobe and one in the lower lobe. Liquefactive necrosis is typical of organs in which the tissues have a lot of lipid (such as brain) or when there is an abscess with lots of acute inflammatory cells whose release of proteolytic enzymes destroys the surrounding tissues.

Lung Abscess: Microscopic appearance (Liquefactive Necrosis)

(3) Caseous necrosis:• It is characteristic of tuberculosis. The necrotic

tissue undergoes slow partial liquefaction forming yellow cheesy material.

• Microscopically, it shows amorphous granular eosinophilic material lacking the cell outlines.

• Unlike coagulative necrosis, the necrotic cells do not retain their cellular outlines, and do not disappear by lysis, as in liquifactive necrosi

• Grossly, the caseous material resembles clumpy cheese, hence the name caseous necrosis.

• The cause of necrosis in TB is hypersensitivity reaction caused by the tuberculoprotein content of the cell wall of Mycobacterium..

Caseous necrosis with granulomatous inflammation

T.B LUNG : (Large Area Of Caseous Necrosis)

AREA ,YELLOW-WHITE AND CHESSY

(4) Fat necrosis it is necrosis of adipose tissue including

two types:

a) Traumatic: caused by trauma to adipose tissue e.g. breast and subcutaneous tissue.

b) Enzymatic: which occurs in case of acute haemorrhagic pancreatitis.

Obstruction of the pancreatic duct leads to release of lipase which splits the fat cells of the omentum into fatty acid (combine with Ca giving chalky white calcification) and to glycerol which is absorbed in the circulation.

(5) Fibrinoid necrosis This is characterized by swelling, fragmentation, increased eosinophilia of collagen fibers and accumulation of mucopolysaccharides and fibrin due to vascular exudation of fibrinogen at the site of lesion, e.g.:

a) Collagen diseases (Rheumatic fever, Rheumatoid, Sclerodermia, Lupus erythematosus and Polyarteritis nodosa).

b) In the wall of blood vessels in malignant hypertension

(6) Zenker’s necrosis:

Of the rectus abdominus muscle and

diaphragm as a complication of :bacterial infection particularly typhoid

fever.

The striated muscles lose its striation, swell and fuse together in homogeneous structureless mass.

Gangrene

• Gangrene is defined as the gradual destruction of living tissue, due to an obstruction in the supply of blood and oxygen to an area of the body (Pipkin and Janelli, 2000)

Obstruction of the blood supply to the bowel is almost followed by gangrene.

(7) Gangrenous necrosis:

The tissue in this case have undergone ischaemic cell death and coagulative necrosis followed by liquifactive action of putrefactive organisms. When coagulative pattern is dominant the process is termed dry gangrene.

When the liquifactive action of the bacteria

is more pronounced it is called wet gangrene.

“Dry Gangrene”

"wet gangrene in patient with Diabetes millitus”

CLOSTRIDIAL GANGRENE

• (including "gas gangrene"), a dread complication of dirty, blood-deprived wounds. The clostridia digest tissue enzymatically and rapidly, often transforming it into a bubbly soup.

FOURNIER'S GANGRENE

•  Fournier's gangrene, bacterial gangrene of the scrotum (the dreaded "black sack disease")

ApoptosisDefinition:• It is programmed death of cells in living tissues. It is

an active process differing from necrosis by the following points:

• Occurs in both physiological and pathological conditions.

• Starts by nuclear changes in the form of chromatin condensation and fragmentation followed by cytoplasmic budding and then phagocytosis of the extruded apoptotic bodies.

• Plasma membrane are thought to remain intact during apoptosis until the last stage so does not initiate inflammatory reaction around it.

•ROBBIN’S BASIC PATHOLOGY, 7TH EDD, MAJOR