Cellular Adaptations, Cell Injury & Cell death BY: Gebru T, MD

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… - The normal cell is confined to a fairly normal range of function & structure. It is nevertheless able to handle normal physiologic demands, maintaining steady state called homeostasis.

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… Cellular adaptation It is a new but altered steady state which preserves the viability of the cell & modulates its function as it responds to a stimuli. Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment.

… Hyperplasia It is an increase in number of cells in an organ or tissue , usually resulting in increased volume of the organ or tissue Hyperplasia takes place if the cellular population is capable of synthesizing DNA or able to undergo mitotic division Usually, it occurs together with hypertrophy It can be physiologic or pathologic

… Physiologic Hyperplasia Hormonal hyperplasia which increases the functional capacity of a tissue when needed. e.g. Proliferation of glandular epithelium of the female breast during pregnancy & puberty or physiologic hyperplasia that occurs in pregnant uterus

… 2. Compensatory hyperplasia, which increases tissue mass after damage or partial resection E.g.2 when a liver is partially resected, mitotic activity in the remaining cells begins as early as 12 hours later, eventually restoring the liver to its normal weight. .

… Pathologic hyperplasia Most are caused by excessive hormonal stimulation or growth factors acting on target cells e.g. Endometrial hyperplasia Pathologic hyperplasia constitutes a fertile soil in which cancerous proliferation may eventually arise.

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… Hypertrophy It refers to an increase in the size of cells , resulting in an increase in the size of the organ The increase in size is due to synthesis of more structural components It can be physiologic or pathologic & is caused by increased functional demand or by specific hormonal stimulation - E.g. the enlargement of the left ventricle in hypertensive heart disease & the increase in skeletal muscle during strenuous exercise

… A, Gross appearance of a normal uterus (right) and a gravid uterus (left) that was removed for postpartum bleeding. B, Small spindle-shaped uterine smooth muscle cells from a normal uterus. Compare this with (C) large, plump hypertrophied smooth muscle cells from a gravid uterus

… Atrophy Shrinkage in the size of the cell by loss of cell substance Atrophy can be physiologic or pathologic Physiologic atrophy is common during early development although atrophic cells may have diminished function, they are not dead. .

…. Atrophy results from decreased protein synthesis and increased protein degradation in cells. Protein synthesis decreases because of reduced metabolic activity. Atrophy is also accompanied by increased autophagy, with resulting increases in the number of autophagic vacuoles.

… Pathologic atrophy can be local or generalized The common causes of atrophy are the following Decreased work load (Atrophy of disuse) Loss of innervation (denervation atrophy) Diminished blood supply Inadequate nutrition Loss of endocrine stimulation Aging Pressure

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…. Metaplasia It is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type It may represent an adaptive substitution of cells that are sensitive to stress by cell types better able to withstand the adverse environment

… The most common metaplasia is columnar to squamous. The normal ciliated columnar epithelial cells of the trachea & bronchi are often replaced focally or widely by stratified squamous epithelial cells in cigarette smokers Metaplasia from squamous to columnar type may also occur. Esophageal squamous epithelium is replaced by intestinal – like columnar under the influence of refluxed gastric acid

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Cell Injury Causes of cell injury Oxygen deprivation Physical agents Chemical agents & Drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalance

Mechanisms of cell injury The most important targets of injurious stimuli are Aerobic respiration involving mitochondrial oxidative phosphorylation & production of ATP The integrity of cell membranes Protein synthesis The cytoskeleton The integrity of the genetic apparatus of the

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… REVERSIBLE CELL INJURY The injury will cease when the stimulus is removed Two patterns can be recognized under the light microscope  1.Cellular swelling the first manifestation of injury it appears whenever the cells are incapable of maintaining ionic & fluid homeostasis & is result of loss of function of plasma membrane energy dependant ion pumps  

… 2. Fatty change It is manifested by the appearance of small & large lipid vacuoles in the cytoplasm & occurs in hypoxic & various toxic injury. It is principally seen in cells involved in & dependent on fat metabolism such as hepatocytes & myocardial cell

… IRREVERSIBLE CELL INJURY  With persistent stimuli/ damage ---- cell can not recover so irreversible injury occurs Irreversibly injured cells undergo changes that are recognized as cell death.  Cell death:- is the ultimate result of cell injury & is one of the crucial event in the development of disease. with cell death, there are marked changes with in the cell  

… There are two types of cell death Necrosis Apoptosis

… occurs after abnormal stress like ischemia or other injuries Necrosis It refers to a spectrum of morphologic changes that follow cell death in a living tissue resulting from the progressive degradative action of enzymes in lethally injured cells. occurs after abnormal stress like ischemia or other injuries it is always pathologic

.. Types of necrosis 1. Coagulative necrosis - Most often results from sudden interruption of blood supply to an organ. - It is, in early stages, characterized by general preservation of tissue architecture -characteristic of hypoxic death of cells in all tissues except the brain.

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… 2. Liquefactive necrosis - It is characterized by digestion of tissue. It shows softening & liquefaction of tissue. It characteristically results from ischemic injury to the CNS. It also occurs in suppurative infections characterized by formation of pus. -liquefaction completely digests the dead cells, resulting in transformation of the tissue into a liquid viscous mass.

… 3. Gangrenous necrosis - It is due to vascular occlusion & most affects the lower extremities & the bowel. - It is called wet gangrene if it is complicated by bacterial infection which leads to superimposed liquefactive necrosis. Dry gangrene if there is only coagulative necrosis without liquefactive necrosis.

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… 4. Caseous necrosis It is type of necrosis most often seen in foci of tuberculous infection The term caseous is derived from the cheesy white gross appearance of the area of necrosis On microscopic examination, the necrotic focus appears as amorphous granular debris Unlike coagulative necrosis, the tissue architecture is completely obliterated.

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… Apoptosis It is a pathway of cell death that is induced by tightly regulated intracellular program in which cells destined to die activate enzymes that degrade the cells’ own nuclear DNA & nuclear & cytoplasmic proteins The plasma membrane of the apoptotic cell remains intact, but the membrane is altered in such a way that the cell and its fragments become avid targets for phagocytes.

… Morphology The following morphologic features characterize cells undergoing apoptosis Cell shrinkage Chromatin condensation Formation of cytoplasmic blebs & apoptotic bodies Phagocytosis of apoptotic cells or cell bodies usually by macrophages

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Features of Necrosis and Apoptosis Cell size Enlarged (swelling) Reduced (shrinkage) Nucleus Pyknosis - karyorrhexis - karyolysis Fragmentation into nucleosome size fragments Plasma membrane Disrupted Intact; altered structure, especially orientation of lipids Cellular contents Enzymatic digestion; may leak out of cell Intact; may be released in apoptotic bodies Adjacent inflammation Frequent No Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Often physiologic, means of eliminating unwanted cells; may be pathologic after some forms of cell injury, especially DNA damage

Intracellular accumulations Cholesterol Atherosclerosis – Cholesterol & cholesterol esters fill smooth muscle cells & macrophages within the intimal layer of the aorta & large arteries Xanthoma – intracellular accumulation of cholesterol within macrophages in the subepithelial connective tissue of the skin & in tendons Cholesterolosis – focal accumulation of cholesterol laden macrophages in the lamina propria of the gallbladder

… Pigments Pigments are colored substances , some of which are normal constituents of cells (e.g. melanin) whereas others are abnormal Pigments can be endogenous or exogenous

… Exogenous pigments Accumulation of carbon or coal dust cause blacken lung tissue & involved lymph nodes – anthracosis . When inhaled , it is picked up by alveolar macrophages & transported into the regional LNs Tattooing is a form of localized exogenous pigmentation of the skin. The pigments inoculated are phagocytosed by dermal macrophages and reside for the remainder of the life of the embellished.

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… Endogenous pigments A. Melanin Melanin is a brownish-black pigment produced by the melanocytes found in the skin. Increased melanin pigmentation is caused by sun tanning & certain diseases. e.g. nevus, or malignant melanoma. Decreased melanin pigmentation is seen in albinism & vitiligo.

… B. Bilirubin Bilirubin is a yellowish pigment, mainly produced during the degradation of hemoglobin. Excess accumulation of bilirubin causes yellowish discoloration of the sclera, mucosa, & internal organs. Such a yellowish discoloration is called jaundice.

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… C. Hemosiderin -Hemosiderin is an iron-containing pigment derived from ferritin. - It can be local or systemic derangement. - It accumulates in tissues in excess amounts in certain diseases. :

… Pathologic calcification It is the abnormal tissue deposition of calcium salts There are two forms of pathologic calcification Dystrophic calcification Metastatic calcification

… Dystrophic calcification It is occurs in previously damaged tissue It occurs in areas of necrosis (coagulative , liquefactive, caseous, enzymatic necrosis of fat) , atheroma, in aging or damaged heart valves - Typically, occurs despite normal serum calcium and in the absence of derangements in calcium metabolism.

…. Metastatic calcification It occurs in normal tissue whenever there is hypercalcemia. There are four principal causes of hypercalcemia Increased secretion of parathyroid hormone with subsequent bone resorption Destruction of bone tissue occurring with primary tumors of bone marrow (multiple myeloma) or diffuse skeletal metastasis Vitamin D – related disorders Renal failure

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