Cellular Injury and Adaptation PDF

Cellular Injury and Adaptation Dr Sara Hassan Homeostasis The tendency toward a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes. Homeostasis refers to the body’s ability to maintain a stable internal environm...

Cellular Injury and Adaptation Dr Sara Hassan Homeostasis The tendency toward a relatively stable equilibrium between interdependent elements, especially as maintained by physiological processes. Homeostasis refers to the body’s ability to maintain a stable internal environment  Homeostasis and Cell Function Homeostasis refers to the balance, or equilibrium within the cell or a body. Keeping a stable internal environment requires constant adjustments as conditions change inside and outside the cell. The adjusting of systems within a cell is called homeostatic regulation. Because the internal and external environments of a cell are constantly changing, adjustments must be made continuously to stay at or near the set point (the normal level or range).  Homeostasis is a dynamic equilibrium rather than an unchanging state.  Cells are active participants in their environment, constantly adjusting their structure and function to accommodate changing demands and extracellular stresses ,they maintain normal homeostasis. Causes Of Cellular Injury 1. Hypoxia Is the most common cause of injury. It occurs when lack of oxygen prevents the cell from synthesizing sufficient atp by aerobic oxidation. Major mechanisms leading to hypoxia are ischemia, cardiopulmonary failure, and decreased oxygencarrying capacity of the blood (e.G., Anemia). Ischemia, due to a loss of blood supply, is the most common cause of hypoxia and is typically related to decreased arterial flow or decreased venous outflow (e.g., atherosclerosis, thrombus, thromboembolus). 2. Pathogens: Viruses Bacteria Parasites Fungi Prions Pathogens can injure the body by direct infection of cells, production of toxins, or host inflammatory response. 3. Immunologic dysfunction: includes: Hypersensitivity reactions Autoimmune diseases 4. Congenital disorders: Are inherited genetic mutations (e.g., inborn errors of metabolism). 5. Chemical injury Can occur with drugs, poisons (cyanide, arsenic, mercury, etc.), pollution, occupational exposure (CCl4, asbestos, carbon monoxide, etc.), and social/lifestyle choices (alcohol, smoking, IV drug abuse, etc.) 6. Physical forms of injury Include trauma (blunt/penetrating/crush injuries, gunshot wounds, etc.), burns, frostbite, radiation, and pressure changes. 7. Nutritional or vitamin imbalance: Inadequate calorie/protein intake Excess caloric intake Vitamin deficiencies Hypervitaminosis  Cellular Changes During Injury Cellular responses to injury include: 1. Adaptation (hypertrophy or atrophy, hyperplasiaor metaplasia) 2. Reversible injury 3. Irreversible injury and cell death (necrosis, apoptosis, or necroptosis). The cellular response to injury depends on several important factors, including: 1. The type of injury 2. Duration (including pattern) of injury 3. Severity and intensity of injury 4. Type of cell injured 5. The cell’s metabolic state 6. The cell’s ability to adapt  The intracellular targets that are susceptible to injury are: 1. DNA 2. Production of ATP via aerobic respiration 3. Cell membranes 4. Protein synthesis Important mechanisms of cell injury are as follows: 1. Damage to DNA, proteins, lipid membranes, and circulating lipids (LDL) can be caused by oxygen-derived free radicals 2. ATP depletion. 3. Increased cell membrane permeability 4. Influx of calcium 5. Mitochondrial dysfunction 1. Free radicals Damage to DNA, proteins, lipid membranes, and circulating lipids (LDL) can be caused by oxygen-derived free radicals, including: Superoxide anion (O2 –) Hydroxyl radical (OH ) Hydrogen peroxide (H2O2) Protective factors against free radicals include: Antioxidants: Vitamins A, E, and C Superoxide dismutase: Superoxide → hydrogen peroxide Glutathione peroxidase: Hydroxyl ions or hydrogen peroxide → water Catalase: Hydrogen peroxide → oxygen and water 2. ATP depletion Several key biochemical pathways are dependent on ATP. Disruption of Na+/K+ or Ca++ pumps cause imbalances in solute concentrations. Additionally, ATP depletion increases anaerobic glycolysis that leads to a decrease in cellular pH. Chronic ATP depletion causes morphological and functional changes to the ER and ribosomes. 3. Increased cell membrane permeability: Several defects can lead to movement of fluids into the cell, including formation of the membrane attack complex via complement, breakdown of Na+/K+ gradients (i.e., causing sodium to enter or potassium to leave the cell), etc. 4. Influx of calcium Calcium is a second messenger, which can activate a wide spectrum of enzymes. These enzymes include proteases (protein breakdown), ATPases (contributes to ATP depletion), phospholipases (cell membrane injury), and endonucleases (DNA damage). Mitochondrial dysfunction Mitochondrial dysfunction causes decreased oxidative phosphorylation and ATP production, formation of mitochondrial permeability transition (MPT) channels, and release of cytochrome c (a trigger for apoptosis). Cellular Adaptations To Stress Definition : Adaptations are reversible changes in the number, size, phenotype, metabolic activity, or functions of cells in response to changes in their environment achieving a new steady state and preserving viability and function Types: Physiologic adaptations usually represent responses of cells to normal stimulation by hormones or endogenous chemical mediators (e.g., the hormone- induced enlargement of the breast and uterus during pregnancy. Pathologic adaptations are responses to stress that allow cells to modulate their structure and function and thus escape injury  The principal adaptive responses are: 1. Hypertrophy. 2. Hyperplasia. 3. Atrophy. 4. Metaplasia. If the adaptive capability is exceeded or if the external stress is inherently harmful, cell injury develops. 1.Hypertrophy Is an increase in cell size and functional ability due to increased synthesis of intracellular components. There are no new cells; just bigger cells, enlarged by an increased amount of structural proteins and organelles. Hypertrophy can be: Physiologic Pathologic Hypertrophy and hyperplasia can also occur together, both result in an enlarged (hypertrophic) organ.  Thus, the massive physiologic enlargement of the uterus during pregnancy occurs as a consequence of estrogen-stimulated smooth muscle hypertrophy and smooth muscle hyperplasia  In contrast, the striated muscle cells in both the skeletal muscle and the heart can undergo only hypertrophy in response to increased demand because in the adult they have limited capacity to divide Examples of pathologic cellular hypertrophy include the cardiac enlargement that occurs with hypertension or aortic valve disease Physiologic hypertrophy of the uterus during pregnancy. A, Gross appearance of a normal uterus (right) and a gravid uterus (removed for postpartum bleeding) (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus (left) compared with large plump cells in gravid uterus (right).  Causes of hypertrophy include: 1. Increased mechanical demand can be physiologic (striated muscle of weight lifters) or pathologic (cardiac muscle in hypertension). 2. Increased endocrine stimulation plays a role in puberty (growth hormone, androgens/estrogens, etc.), gravid uterus (estrogen), and lactating breast (prolactin and estrogen).  Hypertrophy is mediated by growth factors, cytokines, and other trophic stimuli and leads to increased expression of genes and increased protein synthesis. 2. Hyperplasia Is an increase in the number of cells resulting in increase in the size of the organ. Hyperplasia takes place if the cell population is capable of replication It may occur with hypertrophy and often in response to the same stimuli. Hyperplasia can be physiologic or pathologic  Two types of physiologic hyperplasia are : 1. Hormonal hyperplasia, The proliferation of the glandular epithelium of the female breast at puberty and during pregnancy. 2. Compensatory hyperplasia Hyperplasia that occurs when a portion of the tissue is removed or diseased. For example, 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  The stimuli for hyperplasia in this setting are polypeptide growth factors produced by remnant hepatocytes After restoration of the liver mass, cell proliferation is "turned off" by various growth inhibitors  Pathologic hyperplasia : Most forms of pathologic hyperplasia are caused by excessive hormonal or growth factor stimulation. For example, after a normal menstrual period there is a burst of uterine epithelial proliferation that is normally tightly regulated by stimulation through pituitary hormones and ovarian estrogen and by inhibition through progesterone.  However, if the balance between estrogen and progesterone is disturbed, endometrial hyperplasia ensues, a common cause of abnormal menstrual bleeding.  Hyperplasia is also an important response of connective tissue cells in wound healing, in which proliferating fibroblasts and blood vessels aid in repair. In this process, growth factors are produced by white blood cells (leukocytes) responding to the injury and by cells in the extracellular matrix For example, papillomaviruses cause skin warts and mucosal lesions composed of masses of hyperplastic epithelium.  Here the growth factors may be produced by the virus or by infected cells It is important to note that in all these situations, the hyperplastic process remains controlled. It is this sensitivity to normal regulatory control mechanisms that distinguishes benign pathologic hyperplasias from cancer in which the growth control mechanisms become dysregulated or ineffective, 3.Atrophy Shrinkage in the size of the cell by the loss of cell substance is known as atrophy. When a sufficient number of cells is involved, the entire tissue or organ diminishes in size, becoming atrophic although atrophic cells may have diminished function, they are not dead.  Causes of atrophy include : 1. decreased workload (e.g., immobilization of a limb to permit healing of a fracture), 2. loss of innervation, 3. diminished blood supply, 4. inadequate nutrition, 5. loss of endocrine stimulation 6. and aging (senile atrophy)  Although some of these stimuli are physiologic (e.g., the loss of hormone stimulation in menopause) and others pathologic (e.g., denervation) the fundamental cellular changes are identical  Atrophy results from decreased protein synthesis and increased protein degradation in cells. In many situations, atrophy is also accompanied by increased autophagy, with resulting increases in the number of autophagic vacuoles.  Autophagy ("self-eating") is the process in which the starved cell eats its own components in an attempt to find nutrients and survive  4.Metaplasia Metaplasia is a reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type. In this type of cellular adaptation, cells sensitive to a particular stress are replaced by other cell types better able to withstand the adverse environment. Metaplasia is thought to arise by genetic "reprogramming" of stem cells rather than transdifferentiation of already differentiated cells  Epithelial metaplasia is exemplified by the squamous change that occurs in the respiratory epithelium in habitual cigarette smokers. Although the metaplastic squamous epithelium has survival advantages, important protective mechanisms are lost, such as mucus secretion and ciliary clearance of particulate matter  Metaplasia in chronic gastric reflux, the normal stratified squamous epithelium of the lower esophagus may undergo metaplastic transformation to gastric or intestinal-type columnar epithelium  Metaplasia may also occur in mesenchymal cells but less clearly as an adaptive response. For example, bone is occasionally formed in soft tissues, particularly in foci of injury.