Pathology Lec 3 PDF

 ‫ةماـو ةحارجو بط سويكولكب‬ ‫ردممملا ضـمممارا – ررـمممارا ةممميع )باركورد( سمممكوب‬ ‫)‪M.B.Ch.B FICMS- Pathology (Hematology‬‬  CELL INJURY AND CELL DEATH Cell injury results when cells are exposed to 1. Persistent stress so that the affected cells are no longer a...

 ‫ةماـو ةحارجو بط سويكولكب‬ ‫ردممملا ضـمممارا – ررـمممارا ةممميع )باركورد( سمممكوب‬ ‫)‪M.B.Ch.B FICMS- Pathology (Hematology‬‬  CELL INJURY AND CELL DEATH Cell injury results when cells are exposed to 1. Persistent stress so that the affected cells are no longer able to adapt or 2. Inherently damaging agents. Reversible cell injury occurs when the injurious agent is mild but persistent or severe but short lived. In this type of injury the functional and morphologic changes are reversible. With continuing damage, there is irreversible injury, at which time the cell cannot recover even with the removable of the injurious agent i.e. it dies.  Causes of Cell Injury include: 1. Oxygen deprivation (Hypoxia): insufficient supply of oxygen, interferes with aerobic oxidative respiration and is a common cause of cell injury and death. Causes of hypoxia include: a. Ischemia i.e. loss of blood supply in a tissue due to interference with arterial flow or reduced venous drainage. This is the most common cause of hypoxia b. Inadequate oxygenation of the blood, as in pneumonia or chronic bronchitis c. Reduction in the oxygen-carrying capacity of the blood, as in anemia or carbon monoxide (CO) poisoning.  2. Chemical agents: various poisons cause damage by affecting either membrane permeability, or the integrity of the cellular enzymes. Environmental toxins as pollutants, insecticides, CO, alcohol and drugs can cause cell injury. 3. Infectious agents including viruses, bacteria, rickettsiae, fungi and parasites. 4. Immunologic reactions; these are primarily defensive in nature but they can also result in cell and tissue injury. Examples include autoimmune diseases & allergic reactions. 5. Genetic defects including gross congenital malformations (as in Down syndrome) or point mutations (as in sickle cell anemia).  6. Nutritional imbalances: nutritional deficiencies are still a major cause of cell injury. Protein-calorie & vitamins insufficiencies are obvious example. 7. Physical agents: trauma, extremes of temperatures, radiation, electric shock, and sudden changes in atmospheric pressure all are associated with cell injury. 8. Aging: this leads to impairment of replicative and repair abilities of individual cells that result in a diminished ability to respond to damage and, eventually, the death of cells and of the individual Factors affect cell injury: The outcomes of the interaction between injurious agents & cells depend on: 1. The injurious agent: its type, severity, and the duration of its application to the cells. 2. The cells exposed to the injury: its type, adaptability, and their genetic makeup. The above are exemplified by the following facts Low doses of toxins or a brief duration of ischemia may lead to reversible cell injury, whereas larger toxin doses or longer ischemic intervals may result in irreversible injury and cell death.  The same injury has different outcomes depending on the cell type; thus, striated skeletal muscles in the leg resist complete ischemia for 2 to 3 hours without irreversible injury (as in applying a tourniquet to stop severe uncontrolled bleeding from a limb trauma), whereas cardiac muscles die after only 20 to 30 minutes of severe acute ischemia. Individuals who inherit variants of the same gene that encode an enzyme that degrades a particular toxin show differences in the speed (rate) of toxins degradation. This explains the different outcomes that may occur when different individuals are exposed to the same dose of a given toxin.  The most important targets of injurious agents are 1. Mitochondria (the sites of ATP generation) 2. Cell membranes, which influence the ionic and osmotic homeostasis of the cell 3. Protein synthesis (ribosomes) 4. The cytoskeleton (microtubules, and various filaments) 5. The genetic apparatus of the cell (nuclear DNA) ATP Depletion ATP, the energy fuel of cells, is produced mainly by oxidative phosphorylation of ADP within the mitochondria. In addition, the glycolytic pathway can generate ATP in the absence of oxygen using glucose derived either from the circulation or from the hydrolysis of intracellular glycogen (anerobic glycolysis). The major causes of ATP depletion are: 1. Reduced supply of oxygen and nutrients 2. Mitochondrial damage 3. The actions of some toxins (e.g., cyanide) High-energy phosphate in the form of ATP is required for virtually all synthetic and degradative processes within the cell, including membrane transport, protein synthesis, phospholipid turnover, etc. Mitochondrial Damage Mitochondria can be damaged by increases of cytosolic Ca2+, reactive oxygen species, and oxygen deprivation, and so they are sensitive to virtually all types of injurious stimuli, including hypoxia and toxins. There are two major consequences of mitochondrial damage: Failure of oxidative phosphorylation with progressive depletion of ATP, culminating in necrosis of the cell. Leakage of cytochrome c that is capable of activating apoptotic pathways. Influx of Calcium Cytoplasmic free calcium is normally maintained by ATP-dependent calcium pump (transporter) at concentrations that are10,000 times lower than the concentration of extra-cellular calcium or intracellular mitochondrial and ER calcium. Ischemia and certain toxins cause an increase in cytoplasmic calcium concentration, initially because of release of Ca2+ from the intracellular stores, and later resulting from increased influx across the plasma membrane. Accumulation of Oxygen-Derived Free Radicals (Oxidative Stress) These are designated as reactive oxygen species (ROS) are units with a single unpaired electron in their outer orbit. When generated in cells they enthusiastically attack nucleic acids, cellular proteins and lipids. ROS are produced normally in cells during mitochondrial respiration and energy generation, but they are degraded and removed by cellular defense systems. When their production increases or the defense systems are ineffective, the result is an excess of these free radicals, leading to a condition called oxidative stress. Cell injury in many circumstances involves damage by free radicals; these include: 1.Reperfusion injury 2.Chemical and radiation injury 3.Toxicity from oxygen and other gases 4.Cellular aging Inflammatory cells mediated tissue injury DEFECTS IN MEMBRANE PERMEABILITY Early loss of selective membrane permeability leading ultimately to overt membrane damage is a consistent feature of most forms of cell injury (except apoptosis). The plasma membrane can be damaged by ischemia, microbial toxins, complement components- mediated lysis, etc. The most important sites of membrane damage during cell injury are : the mitochondrial membrane. the plasma membrane. membranes of lysosomes. Damage to DNA & 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. A similar reaction is triggered by improperly folded (configured) proteins, which may be the result of inherited mutations or through free radicals. These mechanisms of cell injury typically cause apoptosis Morphologic features of cell and tissue injury All harmful influences exert their effects first at the molecular (subcellular) or biochemical level. Function may be lost long before morphologic changes of cell injury become obvious. For example, myocardial cells fail to contract after 1 to 2 minutes of ischemia, although they do not die until after 20 to 30 minutes of ischemia. These myocytes do not appear morphologically dead by electron microscopy until after 3 hours and by light microscopy after 6 to 12 hours. The cellular changes associated with reversible injury can be repaired once the injurious agent is removed. Changes associated with irreversible injury (as with persistent or excessively severe injury) are irreversible even with the removal of the injurious agent, i.e. their occurrence signals the point of no return, and the cell inevitably dies.  There are two changes that characterize irreversible injury (cell death) 1. manifested as lack of oxidative phosphorylation leading to ATP depletion 2. including not only the outer cell membrane but also the membranes that surround intracytoplasmic lysosomes. This results in liberation of the harmful lysosomal enzymes into the cytoplasm, which in turn leads to dissolution of vital cellular structures.  Morphologic examples of reversible injury 1. Cellular swelling (hydropic change or vacuolar degeneration): This is due to impairment of energy-dependent ion pumps of the plasma membrane. This leads to influx of sodium (with water) into the cell and departure of potassium out. It is the first manifestation of almost all forms of cell injury. Microscopically, there are clear vacuoles (of water) within the cytoplasm. 2. Fatty change: This is manifested by the appearance of lipid vacuoles in the cytoplasm. It is principally encountered in cells participating in fat metabolism such as hepatocytes; as in alcoholic liver disease, malnutrition & total parenteral nutrition.