Chapter+2+Response+to+Stress%2C+Injury%2C+and+Aging+b.docx

Chapter 2: Cellular Response to Stress, Injury, and Aging Cellular Injury Most diseases begin with cellular injury Cellular injury occurs if a cell is unable to maintain homeostasis in the face of injurious stimuli Two things may happen: Injured cells may recover (reversible injury) or they may die...

Chapter 2: Cellular Response to Stress, Injury, and Aging Cellular Injury Most diseases begin with cellular injury Cellular injury occurs if a cell is unable to maintain homeostasis in the face of injurious stimuli Two things may happen: Injured cells may recover (reversible injury) or they may die (irreversible injury) Injurious stimuli include: chemical agents, lack of oxygen (hypoxia), free radicals, infectious agents, physical and mechanical factors, immunologic reactions, genetic factors, and nutritional imbalances. Modifying factors such as nutritional status can profoundly influence the extent of the injury. Adaptation and cellular function: For a cell to function, the cell must be able to extract and use chemical energy contained within the structure of organic molecules. When a mole of glucose is metabolically broken down in the presence of oxygen into carbon dioxide and water, 686 kcal of energy is released. The energy stored as ATP can be used in a variety of ways, including muscle contraction. Cells must adapt to their environment to escape and protect themselves from injury. These adaptations are common and a central part of many disease states. In early stages of a successful adaptive response cells may have enhanced function, so it’s often hard to know whether it’s a pathologic response versus an extreme adaption to excessive demand. The most significant adaptive changes in cells include atrophy (decrease in size), hypertrophy (increase in size), hyperplasia (increase in cell number), and metaplasia (reversible replacement of one mature cell type by another (less mature) cell type. A common example of pathologic hyperplasia is the abnormal proliferation normal cells in the endometrium caused by an imbalance between estrogen and progesterone (over secretion of estrogen) which caused excessive menstrual bleeding and pain. Because cells are complex units, the mechanisms responsible for cell injury leading to necrosis are numerous and interrelated and depend on a delicate balance between intracellular and extracellular events. Four common biochemical themes are important in understanding cell injury and cell death regardless of the reason for the injury. ATP depletion (loss of mitochondrial ATP and decreased ATP synthesis can lead to decreased protein synthesis, decreased membrane transport, lipogenesis, and cellular swelling Oxygen and oxygen derived free radicals Intracellular calcium and loss of calcium balance Defects in membrane permeability Hypoxic injury Lack of sufficient oxygen is the single most common cause of cellular injury The most common cause of hypoxia is ischemia (reduced blood supply Cellular response to hypoxic injury in heart muscle has been well studied. Within 1 minute after blood supply is interrupted, the heart muscle becomes pale and has difficulty contracting. Within 3-5 minutes, the ischemic portion of the myocardium stops contracting entirely. This is caused by a fast decrease in mitochondrial phosphorylation (which leads to a loss of ATP). This lack of ATP causes an increase in anaerobic metabolism, but glycogen stores can be deleted as well. A reduction in ATP causes the plasma sodium/potassium pumps and sodium/calcium pumps to fail which causes an increase in intracellular sodium and calcium and increases potassium out of the cell. Sodium and water enter cells freely and cellular swelling results (where salt goes water follows). The movement of water and ions into the cell causes the ER to dilate, which causes the ribosomes to detach from the ER. This reduces protein synthesis. If oxygen is restored, the swelling and other disruptions are reversible. If not, there is continued damage including swelling of lysosomes, mitochondria, and cell membranes. This is considered to be the stage where the damage is irreversible. When the PM is damaged, extracellular calcium moves into the cell and accumulates in the mitochondria. If oxygen is restored it may cause reperfusion injury due to free radicals like hydroxyl ion, superoxide, and hydrogen peroxide. Antioxidants can help reduce this damage (superoxide dismutase or SOD, beta-carotene, and vitamin E) OR Antioxidants like superoxide dismutase and vitamin E can decrease the amount of damage. Stress The term stress has been used since the early 1900’s and is considered to be a demand that exceeds a person’s coping abilities, resulting in disturbances of cognition, emotion, and behavior that can affect a person’s wellbeing. There are 3 stages of stress development in GAS (general adaptation syndrome) defined by Hans Selye 1. Alarm (fight or flight mobilized) 2. Stage of resistance or adaptation 3. Stage of exhaustion (marked by onset of diseases of adaptation} Stress response: Scientists now know that the pituitary gland and adrenal cortex are very sensitive to emotional, psychologic, and social influences. The stress response is initiated by the nervous system and the endocrine systems, specifically corticotropin-releasing factor (CRF) from hypothalamus, the sympathetic nervous system, the pituitary gland, and the adrenal gland. Reproduction, growth, and thyroid hormone are suppressed during stress. The adrenal cortex activates during stress due to ACTH and increases the secretion of glucocorticoid (steroid) hormones, primarily cortisol. Cortisol is also known as hydrocortisone and is available as an OTC ointment or cream, and is also available in prescription form as an injectable to treat rashes, pain, (anti-inflammatory). Cortisol mobilizes substances needed for cellular metabolism One of the primary effects of cortisol is stimulation of gluconeogenesis (formation of glycogen from noncarbohydrate sources like amino acids or free fatty acids in the liver). It also enhances the elevation of blood glucose promoted by other hormones like epinephrine and glucagon. It can inhibit uptake of glucose by other body cells; therefore it increases blood glucose levels. It also affects protein metabolism. It can increase the rate of protein synthesis and RNA in liver (anabolic) It has catabolic effects in muscle, lymphoid tissue, adipose tissue, skin, and bone. Cortisol can act as an immunosuppressant by suppressing protein synthesis and synthesis of immunoglobulin, and can reduce eosinophil, lymphocytes, and macrophages. Macrophages are antigen presenting cells (APC) , and suppression of these cells reduces the third line of defense. However, cortisol also suppresses the inflammatory response and is used extensively in therapy. Steroids can slow the healing process and are not to be used on open wounds. Extreme physiologic stressors include psychosocial distress. The person feels a general state of unpleasant arousal after life events that can cause physiologic, emotional, cognitive, and behavior changes. Periods of depression and emotional upheaval are often associated with adverse life events and place the affected individual at risk for immunologic defects including ill health. Variables studied have included bereavement, academic pressures (tests), life events both positive and negative and aging. The most negative effects can overtax the individual’s ability to cope and can cause potential for illness. Takotsubo cardiomyopathy (broken-heart syndrome) in an inflammatory condition that causes the heart (specifically the left ventricle) to enlarge after a period of emotional distress. The main symptoms are sudden chest pain, shortness of breath or fainting - usually after feeling severe stress. Aging: Aging is not considered to be a disease because it is normal, and disease is considered to be abnormal. Humans have a maximal life span between 80 and 100 years. This maximal life span has not changed significantly over time, but life expectancy has increased. After age 65, women outnumber men. Data suggest than men have a life expectancy of 75 years and women have a life expectancy of 80 years (Swedish data from 1950-1987) In USA the female life expectancy is 89 and for men its 87 (better health care?) There are 3 major areas of study suggesting the causes of aging: 1. Cellular changes produced by genetic, environmental, and behavioral factors 2. Changes in cellular regulatory or control mechanisms especially in the cells of neuroendocrine, immune, and central nervous system 3. Degenerative extracellular and vascular alterations Cellular aging Oxidative phosphorylation by mitochondria is reduced, as is the synthesis of nucleic acids, proteins, cell receptors, and transcription factors At the functional level there is a decline in muscular strength, cardiac reserve, nerve conduction time, vital capacity, glomerular filtration rate, and vascular elasticity. The process of aging and longevity is multifaceted, with both genetic and environmental factors playing a role.