Molecular Targets of Cellular Injury

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Cell injury is associated with damage to the structural and functional molecules of the cell. Although any biologically important molecule in a cell can be the target of injury producing stress, four biochemical systems are particularly vulnerable: (1) the cell membrane, (2) energy metabolism, (3) protein synthesis, and (4) genes. Because many of the biochemical systems of the cell are inter-dependent, injury at one site typically causes secondary injury to other cellular processes.

·         Cell Membrane Integrity. Selectively permeable lipid membranes are essential for maintaining the internal environment of cells. By controlling what molecules enter and leave the cell, the plasma membrane helps conserve important resources, and keeps the cell in osmotic equilibrium with extracellular fluid. Energy-dependent protein "pumps" embedded in the plasma membrane establish differences in ion concentrations and electrical charge between the inside and outside of the cell (resting membrane potential). The resting membrane potential is particularly important for nerve and muscle function. The function of intracellular organelles such as mitochondria, lysosomes, and the endoplasmic reticulum also depend on the integrity of their lipid membranes.

Cell membranes can be disrupted by degrading phospholipids - the primary molecular component of biologic membranes. Damage to the plasma membrane increases the cell’s permeability to sodium and water. This causes the cell to swell, and may even lead to disruption of the cell (lysis). Potassium may leak out of the cell affecting its ability to maintain resting membrane potential. Injury to the limiting membrane of mitochondria impairs energy metabolism. Lysosomal injury releases hydrolytic enzymes into the cytoplasm leading to auto-digestion of cellular proteins. Damage to the endoplasmic reticulum interferes with protein synthesis and the intracellular transport of biologically important compounds.

·         The Role of Calcium. Cells also use energy-dependent membrane "pumps" to keep the intracellular concentration of calcium ions very low. If cell membranes are injured, calcium ions can move from the extracellular fluid, and from intracellular storage sites, into the cytoplasm. The consequence of increased cytosolic calcium is activation of a class of enzymes known as protein kinases. This leads to the activation of other enzymes such as phospholipases, ATPases, proteases, and endonucleases which attack and break down critical components of the cell (lipid membranes, ATP, cytoskeletal proteins, DNA).

·         Aerobic Respiration and ATP Production. Cells require a constant energy supply, mainly in the form of ATP, to drive metabolism and biosynthetic reactions. Depriving the cell of oxygen (hypoxia), or disturbing mitochondrial function, interferes with the cell’s ability to utilize oxygen to generate adequate amounts of ATP. This, in turn, impairs the ability of the cell to utilize nutrients to synthesize structural and functional proteins necessary for maintaining the cell. Depletion of ATP also shifts energy metabolism towards anaerobic glycolysis. In addition to being less efficient in terms of energy production, glycolysis is also accompanied by the accumulation of inorganic phosphate and lactic acid which lowers the pH inside the cell. This "acidosis" interferes with enzyme functioning and can damage nuclear DNA.

·         The Role of Oxygen-derived Free Radicals (Reactive Oxygen Species). While oxygen is vital for normal energy metabolism, it also plays a special role in cell injury. When mitochondria generate energy by reducing molecular oxygen to water, small amounts of partially reduced forms of oxygen (superoxide, hydrogen peroxide, and hydroxyl radicals) are produced in the process (fig.2.) These "free radicals" are short-lived molecules containing an unpaired electron in an outer orbital - an electron that is not contributing to normal intramolecular bonding. These are essentially "free chemical bonds" which are energetically unstable and highly reactive. Free radicals are generally transient products of oxidation-reduction reactions or result when a covalent bond is broken and one electron from each pair remains with each atom. Although free radicals play an important physiologic role in intracellular oxidation-reduction reactions and the bacteria killing function of white blood cells, they can also interact with biologically important molecules - removing electrons or hydrogen atoms and disrupting covalent bonds. Fortunately, cells normally produce only very small amounts of oxygen-derived free radicals, and they also have molecular scavengers (anti-oxidants) to neutralize them before they can do any harm.

However, when cells are injured, large amounts of free radicals can accumulate - rapidly depleting anti-oxidants - and allowing free radicals to react with critical biochemical components of the cell. Free radicals can attack the double bonds of unsaturated phospholipids in cell membranes which eventually degrade the structural integrity of cell membranes. Free radicals also impair the functions of enzymes by causing fragmentation of polypeptide chains or the cross-linking of sulfhydryl (-SH) groups in proteins. Free radicals also cause strand breaks or abnormal cross-linking in DNA.

Functional and Structural Proteins. Denaturation of cellular enzymes or structural proteins can severely impair cellular functions.

• Almost all vital cellular processes are dependent on enzymes - protein catalysts that facilitate biochemical reactions inside the cell. Without enzymes, synthesis and metabolic reactions would occur too slowly to be useful to the cell.
• Damage to structural proteins can impair the intracellular transport system of cells and disrupt the supportive protein cytoskeleton of cells.

Genetic Apparatus. Damage to the cell’s DNA interferes with cell replication, and impairs the synthesis of important structural and functional proteins.

ATP depletion and membrane damage are particularly lethal events. They are probably the central factor in the pathogenesis of irreversible cell injury.

Disease-producing cellular stresses (Pathological Stimuli)

• Hypoxia. Depriving tissues of oxygen is one of the more common mechanisms for cellular injury. Hypoxia can result from interrupted blood supply (ischemia), inadequate oxygenation of blood due to pulmonary disease or hypoventilation, inability of the heart to adequately pump blood (heart failure), or impaired oxygen carrying capacity of the blood (anemia, carbon monoxide poisoning, etc.). As noted above, hypoxia depletes cellular ATP and generates oxygen-derived free radicals.

• Chemical injury. A very large number of drugs and environmental chemical agents are capable of causing cell injury. The list includes inorganic compounds, ions, and organic molecules - including byproducts of normal metabolism and toxins synthesized by microorganisms.

Two basic mechanisms of chemical injury are recognized: (1) A compound can react directly with some critical molecular component of the cell interfering with its function. For example, cyanide inactivates the enzyme cytochrome oxidase in mitochondria required for aerobic respiration. (2) A compound that is itself harmless to cells can be rendered toxic when it is metabolized and converted to a toxic substance (such as a free radical). This is the way in which acetaminophen overdose is toxic to the liver.

• Physical agents. Many forms of physical injury can be harmful to cells and tissues. Common examples include: (1) Mechanical injury (crush injury, fractures, lacerations, hemorrhage). (2) Extremes of heat or cold (burns, heat stroke, heat exhaustion, frostbite, hypothermia). (3) Ionizing or non-ionizing radiation - (x-rays, radioactive elements, ultraviolet radiation). (4) Electric shock. (5) Sudden changes in atmospheric pressure (blast injury, decompression injury in divers). (6) Noise trauma.

• Infection. This very common category of cell injury results from the parasitization of the body by pathogenic viruses, bacteria, fungi, protozoa, or helminths. Pathogenic organisms produce disease by either: (1) replicating inside host cells and disrupting the structural integrity of the cell (direct cytopathic effect - e.g., herpes virus), (2) producing a toxin that is harmful to host cells (e.g., clostridia and diphtheria), or by (3) triggering an inflammatory or immune response that inadvertently injures host cells caught in the “cross fire” between the immune system and invading microorganism (e.g., rheumatic fever, tuberculosis).

• Immune reactions. Exaggerated immune reactions (anaphylaxis, allergy), or the inappropriate targeting of the body's own cells by the immune system (autoimmunity) can result in acute or chronic inflammation and cell injury. Abnormal suppression of the immune system can increase vulnerability to microbial invasion.

• Nutritional imbalance. Deficiencies or excesses in normal cellular substrates (e.g., calories, proteins, carbohydrates, minerals, vitamins) can produce problems such as obesity, malnutrition, scurvy, iron deficiency anemia, etc.

• Genetic derangements. Inherited or acquired mutations in important genes can alter the synthesis of crucial cellular proteins leading to developmental defects, or abnormal metabolic functioning. Acquired mutations to somatic cells during life can affect cell differentiation and replication leading to diseases such as cancer.