Cell injury & Cell death (1)

Mechanisms:
1* Reversible cell injury : damaging stimulus function. & morph. changes Hallmarks of reversible injury : * oxidative phosphorilation * adenosin triphosphate (ATP) * cellular swelling : caused by ** changes in ion concentrations ** water influx

Cell injury & Cell death (2)

2* Irreversible injury & cell death :

Stimuli damage irreversible injury

e.g. : ischemic myocardium * structural change, e.g.: amorphous densities in mitochondria * functional change, e.g. : loss of membrane permeability Signs of cells that have suffered irrever. injury

Irreversibly injured cells invariably undergo morphologic changes that recognized as cell death Two types of cell death : NECROSIS & APOPTOSIS Differ in : * morphologic * mechanisms * role in disease and physiology NECROSIS is always a pathologic process, APOPTOSIS serves many normal functions & not necessarily associated with cell injury

Causa Cell injury (1)

1. Oxygen deprivation (hypoxia) * inadequate oxygenation of the blood due to cardiorespiratory failure * Loss of the oxygen-carrying capacity of the blood : anemia, CO poisoning 2. Physical agents : * Mechanical trauma * Extremes of temperatue (burns or deep cold) * Sudden changes in atmospheric preassure * Radiation * Electrical shock

Causa Cell injury (2)

3. Chemical agents and drugs :
glucose / salt in hypertonic concentration oxygen in high concentrations poisons : arsenic, cyanide, mercury salts pollutants, insecticides, herbicides industrial hazards : CO, asbestos alkohol & narkoba.

4. Infectious agents :
Virus rickettsiae -bacteria fungi parasites (tapeworms)

5. Immunologic reactions :
Anaphylactic reaction foreign protein / drug Autoimmune disease reactions to endogenous self-antigens

Causa Cell injury (3)

6. Genetic derangements * Trisomy 21 Down syndrome * Sickle cell anemia 7. Nutritional imbalance :

* protein-calorie defisiensies
* vitamins defisiensies * excesses of lipid : obesity, atherosclerosis * metabolic disease: diabetes

Principles that are relevant to most forms of cell injury

The cellular response to injurious stimuli depends on the type of injury, its duration and its severity. * chemical toxin : doses and duration * ischemia : severity and duration The consequences of cell injury depend on the type, state, and adaptability of the injured cell. striated muscle cell in the leg >< muscle cell of the heart

Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components.

The most important targets of injurious stimuli are : 1. Aerobic respiration involving mitochondrial oxydative phosphorylation & production of ATP 2. The integrity of cell membranes, on which the ionic & osmotic homeostasis of cell & its organelles depends 3. Protein synthesis 4. The cytoskeleton 5. The integrity of the genetic apparatus of the cell

Figure 1-10 Cellular and biochemical sites of damage in cell injury.

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2007 Elsevier

Mechanism of Cell Injury

* ATP depletion & decrease ATP synthesis * Mitochondrial damage * Influx of Intracellular Calcium & loss of Calcium Homeostasis * Accumulation of Oxygen-derived Free Radicals (Oxydative Stress) * Defects in Membrane Permeability

Two patterns of reversible cell injury can be recognized under the light microscope : Cellular swelling Fatty change

Cellular swelling
Loss of function of plasma membrane energydependent ion pumps incapable of maintaining ionic & fluid homeostasis. When it affects many cells in organ : pallor, turgor , weight . Microscopic : small clear vacuoles within the cytoplasm Synonym : hydropic change / vacuolar degeneration

Fatty change / Steatosis

Abnormal accumulations of triglycerides within parenchymal cells. Principally encountered in cells involved in & dependent on metabolism : hepatocyte, myocardial cells. Causes : toxins, protein malnutrition, diabetes mellitus, obesity, anoxia, alcohol abuse. Microscopic : small or large vacuoles in the cytoplasm. To identify the fat : stained with Sudan IV or Oil Red-O

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Downloaded from: Robbins & Cotran Pathologic Basis of Disease (on 11 February 2005 04:43 PM) 2005 Elsevier

NECROSIS
Spectrum of morphologic changes that follow cell death in living tissue. Largely resulting from progressive degradative action of enzymes on the lethally injured cell The morphologic appearance is the result of denaturation of intracellular protein and enzymatic digestion of the cell.

Morphology :
Nuclear changes due to nonspesific breakdown of DNA : 1. Karyolysis : the basophilia of the chromatine may fade, a change that presumably reflects DNase activity. 2. Pyknosis : characterized by nuclear shrinkage & increased basophilia (the DNA apparently condenses into a solid, shrunken basophilic mass.

3. Karyorrhexis : the pyknotic or partially pyknotic nucleus undergoes fragmentation. With the passage of time (a day or two), the nucleus in the necrotic cell totally disappears. When denaturation is the primary pattern, coagulative necrosis develops. In the instance of dominant enzyme digestion, liquefactive necrosis develops.

The process of coagulative necrosis, with preservation of the general tissue architecture, is characteristic of hypoxic death of cells in all tissues except brain. CASEOUS NECROSIS : distinctive form of coagulative necrosis, is encountered most often in foci of tuberculous infecrtion. caseous = cheesy white gross appearance of the area of necrosis

Figure 1-19 Coagulative and liquefactive necrosis. A, Kidney infarct exhibiting coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture. B, A focus of liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with white cells and cellular debris, creating a renal abscess that obliterates the normal architecture.

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Figure 1-20 A tuberculous lung with a large area of caseous necrosis. The caseous debris is yellow-white and cheesy.

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LIQUEFACTION NECROSIS : is characteristic of focal bacterial or, occasionally fungal infections, because microbes stimulate the accumulation of inflammatory cells. e.g. Central Nerve System often evokes liquefaction necrosis. Liquef. Necrosis completely digests the dead cells liquid viscous mass. Acute inflamm. dead white cells creamy yellow material = pus

GANGRENOUS NECROSIS

Usually applied to a limb, (the lower leg) lost its blood supply undergone coagulation necrosis. Bacterial infection (+) coagulative nec. modified by liquefactive action of the bacteria & attracted leucocytes (so called wet gangrene)

APOPTOSIS
Is pathway of cell death that is induced by tightly regulated intracellular pogram Cells destined to die activate enzymes that degrade the cells own nuclear DNA and nuclear and cytoplasmic proteins. The cells plasma membrane remain intact, but its structure is altered the apoptotic cells become an avid target for phagocytosis.

Before its contents have leaked out the dead cell is rapidly cleared no elicit an inflammatory reaction in the host. Apoptosis is fundamentally different from necrosis. Apoptosis and necrosis sometimes coexist, and they may share some common features and mechanisms.

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Apoptosis in physiologic situations

* The programmed destruction of cell during embryogenesis.
* Hormone-dependent involution in adult ** endometrial cell breakdown during the M cycle, ** ovarian follicular atresia ** regression lactating breast after weaning ** prostatic atrophy after castration * Cell deletion in proliferating cell populations

* Death of host cells that have served their purpose ** neutrophils in acute inflammatory response ** lymphocytes at the end of an immune response * Cell death induced by cytotoxic T cells, a defence mechanism against viruses and tumors (eliminate virus-infected and neoplastic cells)

Apoptosis in Pathologic Conditions

* Cell death produced by a variety of injurius stimuli :

radiation, cytotoxic drugs, heat, hypoxia * Cell injury in certain viral disease viral hepatitis * Pathologic atrophy in parenchymal organs after duct obstruction : pancreas, parotid gland * Cell death in tumors

Morphology
* Cell shrinkage * Chromatin condensation * Formation of cytoplasmic blebs and apoptotic bodies * Phagocytosis of apoptotic cells or cell bodies, by macrophage

Features of Necrosis and Apoptosis

Feature
Cell size Nucleus

Necrosis
Enlarge (swelling) Pyknosis karyorrhexis karyolysis Disrupted

Apoptosis
Reduced (shrinkage) Fragmentation into nucleosome size fragments Intact; altered structure, especially orientation of lipids Intact; may be released in apoptotics bodies

Plasma membrane

Cellular contents

Enzymatic digestion; may leak out of cell

Adjacent inflammation
Physiologic or pathologic role

Frequent
Invariably pathologic (culmination of irreversible cell injury)

No
Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage

TERIMA KASIH & SELAMAT BELAJAR