Local Reactions of the Organism PDF

Local reactions of the organism  Cell damage- when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to damaging agents or suffer from intrinsic abnormalities Reversible cell injury - early stages or mild forms of injury the functi...

Local reactions of the organism  Cell damage- when cells are stressed so severely that they are no longer able to adapt or when cells are exposed to damaging agents or suffer from intrinsic abnormalities Reversible cell injury - early stages or mild forms of injury the functional and morphologic changes are reversible if the damaging stimulus is removed. Cell death - continuing damage, the injury becomes irreversible, we have 2 types : necrosis and apoptosis—which differ in their mechanisms, morphology, and roles in disease and physiology  Necrosis- When damage to membranes is severe, enzymes leak out of lysosomes, enter the cytoplasm, and digest the cell, resulting in necrosis Necrosis is the major pathway of cell death in many commonly encountered injuries, such as those resulting from ischemia, exposure to toxins, various infections, and trauma Cellular contents also leak through the damaged plasma membrane into the extracellular space, where they elicit a host reaction (inflammation Always a pathologic process Apoptosis - When a cell is deprived of growth factors, or the cell’s DNA or proteins are damaged beyond repair, typically the cell kills itself It’s characterized by nuclear dissolution without loss of membrane integrity completely Not always associated with pathologic cell damage Doesn’t elicit inflammation Causes of cell damage Oxygen deprivation (hypoxia) Chemical agents ( for example; CO, asbestos) Infectious agents( fungi, bacteria) Immunologic reactions ( autoimmune reactions) Nutritional imbalances Physical agents ( shock , temperature) Aging  Types of cell damage Reversible and irreversible Reversible injury 2 main changes : cellular swelling and fatty change Cellular swelling is the result of failure of energy-dependent ion pumps in the plasma membrane, leading to an inability to maintain ionic and fluid homeostasis Fatty change occurs in hypoxic injury and in various forms of toxic or metabolic injury and is manifested by the appearance of small or large lipid vacuoles in the cytoplasm potentially injurious insults induce specific alterations in cellular organelles, like the ER, which is involved in metabolism of various chemicals, and cells exposed to these chemicals show hypertrophy of the ER as an adaptive response that may have important functional consequences  Cellular swelling first manifestation of almost all forms of injury to cells it causes some pallor (as a result of compression of capillaries), increased turgor, and increase in weight of the organ small, clear vacuoles within the cytoplasm; these represent distended and pinched-off segments of the endoplasmic reticulum (ER). This pattern of nonlethal injury is sometimes called hydropic change or vacuolar degeneration. Fatty change manifested by the appearance of lipid vacuoles in the cytoplasm. It is principally encountered in cells participating in fat metabolism (e.g., hepatocytes, myocardial cells) and is also reversible plasma membrane alterations such as blebbing, blunting, or distortion of microvilli dilation of the ER with detachment of ribosomes and dissociation of polysomes nuclear alterations, with clumping of chromatin. Irreversible cell damage Necrosis Necrosis is the type of cell death that is associated with loss of membrane integrity and leakage of cellular contents culminating in dissolution of cells, largely resulting from the degradative action of enzymes on lethally injured cells The enzymes responsible for digestion of the cell may be derived from the lysosomes of the dying cells themselves and from the lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells  Cytoplasmic changes. Necrotic cells show increased eosinophilia Nuclear changes. Nuclear changes assume one of three patterns, all due to breakdown of DNA and chromatin. Karyolysis - fading of chromatin Pyknosis - shrinkage karyorrhexis - fragmentation Fates of necrotic cells. Necrotic cells may persist for some time or may be digested by enzymes and disappear  Mechanism of cell damage The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity. Thus, low doses of toxins or a brief duration of ischemia may lead to reversible cell injury The consequences of an injurious stimulus depend on the type, status, adaptability, and genetic makeup of the injured cell. (striated skeletal muscle in the leg accommodates complete ischemia for 2 to 3 hours without irreversible injury, whereas cardiac muscle dies after only 20 to 30 minutes. Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components Multiple biochemical alterations may be triggered by any one injurious insult. Depletion of ATP ATP, the energy store of cells, is produced mainly by oxidative phosphorylation of adenosine diphosphate (ADP) during reduction of oxygen in the electron transport system of mitochondria. The activity of plasma membrane ATP-dependent sodium pumps is reduced, resulting in intracellular accumulation of sodium and efflux of potassium. The net gain of solute is accompanied by iso-osmotic gain of water, causing cell swelling and dilation of the ER. increase in anaerobic glycolysis in an attempt to maintain the cell’s energy sources. Failure of ATP-dependent Ca2+ pumps leads to influx of Ca2+  Mitochondrial Damage and Dysfunction Failure of oxidative phosphorylation leads to progressive depletion of ATP, culminating in necr Abnormal oxidative phosphorylation also leads to the formation of reactive oxygen species,  Influx of Calcium Cytosolic free calcium is normally maintained by ATP-dependent calcium transporters at concentrations as much as 10,000 times lower than the concentration of extracellular calcium Ischemia and certain toxins cause an increase in cytosolic calcium concentration Increased cytosolic Ca2+ activates a number of enzymes, with potentially deleterious cellular effects (Fig. 1–17). These enzymes include phospholipases (which cause membrane damage), proteases (which break down both membrane and cytoskeletal protein  Oxidative stress Free radicals are chemical species with a single unpaired electron in an outer orbital. Such chemical states are extremely unstable, and free radicals readily react with inorganic and organic chemicals; Reactive oxygen species (ROS) are a type of oxygen derived free radical whose role in cell injury is well established. ROS are produced in phagocytic leukocytes, mainly neutrophils and macrophages, as a weapon for destroying ingested microbes and other substances during inflammation and host defense Nitric oxide (NO) is another reactive free radical produced in leukocytes and other cells The damage caused by free radicals is determined by their rates of production and removal Cells have developed many mechanisms to remove free radicals and thereby minimize injury. Free radicals are inherently unstable and decay spontaneou The rate of decay of superoxide is significantly increased by the action of superoxide dismutases (SODs) Glutathione (GSH) peroxidases are a family of enzymes whose major function is to protect cells from oxidative damage.  Defective membrane permeability Decreased phospholipid synthesis. The production of phospholipids in cells may be reduced whenever there is a fall in ATP levels, leading to decreased energy-dependent enzymatic activities Increased phospholipid breakdown ROS Cytoskeletal abnormalities. Cytoskeletal filaments act as anchors connecting the plasma membrane to the cell interior, and serve many functions in maintaining normal cellular architecture, motility, and signaling Lipid breakdown products 3 main reactions that cause cell damage Lipid peroxidation of membranes Cross-linking and other changes in proteins DNA damage. Damage to DNA and Proteins Cells have mechanisms that repair damage to DNA, but if this damage is too severe to be corrected (e.g., after radiation injury or oxidative stress), the cell initiates its suicide program and dies by apoptosis Thank you!