Exam One Study Guide.pdf - 1 N5315 Advanced Pathophysiology Altered Cellular Function and Cancer Module 1 Module Core Concepts and Objectives with

Exam One Study Guide.pdf - 1 N5315 Advanced Pathophysiology...

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Unformatted text preview: 1 N5315 Advanced Pathophysiology Altered Cellular Function and Cancer Module 1 Module Core Concepts and Objectives with Advanced Organizers Cellular Physiology H elpful youtube link: 1. Analyze the steps of the action potential. (axon hillock is where action potential begins) a) Depolarization: resting cell is stimulated (graded potential) through voltage­regulated channels, cell becomes more permeable to Na, net movement of Na from outside the cell to inside the cell, membrane potential decreases (negative value to zero) b) Once threshold potential is reached an action potential will occur resulting in depolarization, the sodium gates open, sodium rushes into the cell, this causes membrane potential to reach zero and become more positive (depolarization) c) Repolarization: negative polarity of the membrane potential is reestablished, Na voltage gated channels close and K voltage gated channels open, membrane permeability to Na decreases and the potassium permeability increases, resulting in K to move from inside the cell to outside the cell, this causes the membrane potential to become more negative d) Na+­K+ pump return the membrane to the resting potential by pumping potassium back into the cell and Na out of the cell 2. Discuss how the action potential is altered by calcium and potassium imbalances and the clinical significance. (review figure 3­7 on page 116) Topic Describe the Action Potential How is the action potential altered by a potassium imbalance? How is the action potential altered by a calcium imbalance? Action Potential Physiology Threshold potential: point which depolarization must occur in Action potential carries signal along the nerve or muscle cell and conveys info from one cell to another. Action potential is the membrane Hypokalemia: (<3.5, severe is <2.5) Higher concentration in the ICF, as extracellular K+ is depleted, the intracellular potassium diffuses out of the cell easily, this causes the cell to be Hypercalcemia: (>10­12) high serum calcium level, decreases cell permeability to sodium. This causes the threshold potential to become more 2 order to initiate an action potential (­59mV) Resting membrane potential: neuron at rest, no nerve impulses, ­70mV ­ Nerve impulse travel along the plasma membrane ­ Usually more negative inside the cell, when Na influx occurs inside the cell becomes more positive (depolarization occurs) ­Repolarization occurs when K moves outside the cell (falling phase of action potential) ­ Movement of Na and K, wave of depolarization when opening of Na channels cause depolarization (rise of action potential), open of k channels reflect repolarization (fall of action potential), the hyperpolarization or potential of an active neuron. One that is conducting an impulse. The process of conducting an impulse (action potential) involves a stimulus that activates the neuron ­> the neuron depolarizes ­> then repolarizes. hyperpolarized (more negative). A cell which is normally ­90 mv is now ­100 mv. This causes the cell to be less likely to depolarize or conduct impulses. This causes a decrease in neuromuscular excitability and leads to muscle weakness, smooth muscle atony, paresthesias and cardiac dysrhythmias. Hyperkalemia: (>5.5) I f the ECF potassium increases without any change in the ICF potassium levels, the resting membrane potential of the cell becomes more positive. Normal RMP ­90mv may be ­80mv. The cell is said to be hypopolarized. The cells are more excitable and conduct impulses more easily and more quickly. This causes peaked T waves on a EKG. As K+ rises the RMP will become more positive and it will eventually lead to the RMP equaling the threshold potential, an action potential will not be generated and cardiac positive and is further away from the membrane potential. It takes more stimulus to initiate an action potential. The cells are far less excitable and do not initiate action potential. This causes weakness, hyporeflexia, fatigue, lethargy, confusion, encephalopathy, shortened QT segment, and depressed w idened T waves on EKG. Hypocalcemia: (<8.5) l ow serum Ca+, increases cell permeability to Na, thus causing a progressive depolarization. The threshold potential becomes more negative and is closer to the resting membrane potential. The cells are more likely and more frequently to initiate an action potential. Cells are more excitable. T his results in tetany, hyperreflexia, circumonal 3 standstill will occur. Also, paresthesias, seizures paralysis and and dysrhythmias. paresthesias. * Both high and low K+ alter RMP and result in weakness, cardiac dysrhythmias and paresthesias. refractory period after the action potential (can not trigger an action potential) Cellular Adaptation Patterns 1. Analyze the differences between cellular adaptation patterns. Adaptation : process cells undergo to adapt to their environment and protect themselves, may be physiologic or pathologic a. Differentiate between the etiology and the pathophysiology of atrophy, hypertrophy, hyperplasia, dysplasia, and metaplasia and identify an example of each. Disease Etiology Pathophysiology Example Atrophy Decrease/ shrinkage in cellular size; An increase in catabolism of the intracellular organelles that causes a reduction of the structural components of the cell (less mitochondria, myofilaments, ER) Oxygen consumption and amino acid uptake are rapidly reduced. Caused by Up­regulation of proteasome (protein degrading complex)­ is characteristic of atrophic muscle changes. Ubiquitin­proteasome pathway­ primary pathway of protein catabolism where protein is first conjugated to ubiquitin (small protein) and then degraded by proteasomes Atrophic changes increase hydrolytic enzymes (which are present in autophagic vacuoles to prevent uncontrolled cellular destruction) Thus the Physiologic: Thymus gland shrinks during childhood Pathologic: Skeletal muscle atrophy due to paralysis (disuse atrophy) Atrophy occurs most often in skeletal muscle, heart, secondary sex organs, brain 4 Hypertrophy decreased workload, pressure, use, blood supply, nutrition, hormone stimulation or nerve stimulation. vacuoles proliferate as needed to protect the uninjured organelles from the injured organelles and are eventually taken up and destroyed by lysosomes (see p. 7). Certain contents of the autophagic vacuole may resist destruction by lysosomal enzymes and persist in membrane­bound residual bodies. Physiologic Atrophy: occurs with early development, normal and expected process Pathologic Atrophy: Occurs due to decrease in workload, blood supply, nutrition, hormonal stimulation, nerve stimulation, not normal and a cellular response to a harsh environment in which the cell is living Increase in size of cells and the size of the affected organ Caused by hormonal stimulation or Increases the cellular protein in plasma membrane, ER, myofilaments, and mitochondria. Nucleus also enlarges increasing synthesis of DNA. Cardiomegaly (left­sided, or right­sided or both, depends on where the “stretch” is happening at in the heart), 5 Hyperplasia increased functional demand; Mechanical signals: stretch Trophic signals: g rowth factors, vasoactive agents Physiologic: Heart: Moderate endurance training, pregnancy Pathologic: Heart­ secondary to HTN or valvular dysfunction * Only in cells that can undergo mitosis Increased number of cells due to increased rate of cellular division d/t severe/prolonged stress Physiologic: An increase in tissue mass after damage or partial resection ( Compensatory Hyperplasia­ adaptive Physiologic­ Compensatory­ Liver regeneration in response to hepatocyte growth factor, callus on mechanism that enables hands in response to certain organs to mechanical regenerate ex. Liver with stimulus, hepatocyte growth factor, Hormonal­ uterus epithelial cells (callus in enlargement during response to mechanical pregnancy. stimulus), ) ( Hormonal Hyperplasia: Pathologic­ cannot Uterus and Breast tissue happen in nerve during pregnancy) tissue (replaced by glial cells). Cardiac Pathologic: Response to tissue replaced by an injury in the injury has scaring (like in been severe or prolonged Myocardial infarct) (Pathologic abnormal proliferation of normal cells, can be effect endometrial of hormonal stimulation or hyperplasia p.53) the effects of growth hormones on target cells. ID’d by pronounced enlargement of nucleus, clumping of chromatin and If you remove one kidney, the other enlarges to meet new demand. Heart, Kidneys, Skeletal Muscle most common · h yperplasia of the endometrium secondary to imbalance of estrogen & progesterone ( endometriosis) à over 6 the presence of one or more nucleoli. secretion of estrogen ( Hyperestrogenism) · S ymptoms of hyperestrogenism in women may consist of menstrual irregularities, amenorrhea, abnormal vaginal bleeding, and enlargement of the uterus and breasts; if left untreated could lead to high risk of estrogen sensitive cancers later in life ( Breast cancer) Dysplasia *Not a true adaptive process* (aka: Atypical Hyperplasia) Abnormal cell growth of mature cells (size, shape, organization); due to persistent severe cell injury or irritation Disordered cell growth (mild, mod, severe) Strongly associated with neoplastic growth, however, dysplasia not indicate cancer and may not advance to cancer Epithelial cells of cervix (Pap Smear) and respiratory tract hyperplasia is a strong predictor of breast cancer ***Atypical Metaplasia Reversible replacement of one mature cell by another; Cell exposed to chronic stress, injury or irritation A stimulus induces a reprogramming of stem cells (which exist in most epithelial or of undifferentiated mesenchymal (tissue from embryonic mesoderm) cells present in connective tissue. The stem cells differentiate a new cellular pathway because of signals generated by cytokines and growth factors in the cell’s environment. Barrett’s Esophagus (d/t acid stress) Bronchial metaplasia d/t smoking *can be reversed if smoking is stopped 7 b. Identify a physiologic and pathophysiologic example for atrophy, hypertrophy, hyperplasia, dysplasia, and metaplasia. Disease Physiologic Example Pathologic Example Atrophy Shrinking of thymus gland during childhood Disuse atrophy­skeletal muscle atrophy occurring when a person is immobilized for a prolonged period of time such as in paralysis Hypertrophy One cell that undergoes stress ­ changes to become larger Skeletal muscle hypertrophy from doing heavy work or weight lifting exercises Surgically removing one kidney results in the other kidney increasing in size to compensate for the increased workload Cardiomegaly resulting from an increased workload in hypertensive patients or patients with heart valve problems Hyperplasia One cell that undergoes stress ­ reproduces like crazy Physiologic compensatory hyperplasia­­removal of part of the liver leads to hyperplasia of hepatocytes and liver regeneration Physiologic hormonal hyperplasia­­uterine and mammary gland enlargement during pregnancy Endometrial lining undergoes hyperplasia in response to estrogen secretion, but is halted by release of progesterone; once this balance is disturbed, estrogen secretion is unopposed by progesterone and the endometrial lining will undergo hyperplasia and increased risk for endometrial cancer Dysplasia abnormal changes in size, shape “Pre­cancer”; pap smears show and organization of mature cells. dysplastic c ells of the cervix All of which are pathological. and need laser or surgical treatment or close observation Metaplasia­ Replacement of normal columnar ciliated epithelial cells of the the bronchial lining by stratified squamous epithelial cells. The newly formed epithelial cells do not secrete Occurs when prolonged exposure to inducing stimulus (cigarette s moking), cancerous transformation can occur. Barrett’s Esophagus 8 mucous or have cilia, causing loss of vital protective mechanism. However, it does provide to protect against cigarette smoke. **Transformation of the endocervix (transformation zone) throughout the life span (changes from childhood during puberty and then as part of normal aging) ** ** Found on internet not in book or lecture. Mechanisms of Cellular Injury 2. Analyze the mechanisms and outcomes of cellular injury. ● Active cell Injury/ Reversible Injury­ Immediate response of “entire” cell, Loss of adenosine triphosphate (ATP), swelling of cell, detachment of ribosomes, autophagy of lysosomes. May progress into irreversible injury but there is no precise “point of no return” ● Irreversible Injury­“Point of no return” structurally when severe vacuolization of mitochondria occurs and Ca ++ m oves into the cell, including mitochondrial membrane damage ● Pathologic Calcification­ dystrophic and metastatic calcification ● Chronic Cell Injury­ Persistent stimuli response may involve only specific organelles or cytoskeleton (e.g., phagocytosis of bacteria) ● Injurious stimuli­ chemical agents, lack of sufficient oxygen (hypoxia), free radicals, infectious agents, physical and mechanical factors, immunologic reactions, genetic factors, and nutritional imbalances. ● Both chemical and hypoxic injury can lead to disruption of selective permeability of the plasma membrane; reduction or cessation of cellular metabolism; lack of protein synthesis damage to lysosomal membranes with leakage of destructive enzymes into the cytoplasm; enzymatic destruction of cellular organelles; cellular death (exhibited by nuclear changes); and phagocytosis of the dead cell by cellular components of the acute inflammatory response ● Common Themes in cell Injury and cell death (pg55 table 2­2) ○ ATP depletion­ Loss of mitochondrial ATP and decreased ATP synthesis; results include cellular swelling, decreased protein synthesis, decreased membrane 9 transport, and lipogenesis, all changes that contribute to loss of integrity of plasma membrane ○ O2 and O2 derived free radicals­ Lack of oxygen progresses cell injury in ischemia, activated oxygen species are generated (free radicals, H2O2, NO) cause destruction of cell membranes and cell structure ( reperfusion injury ) WBC are especially affected. ○ Intracellular calcium and loss of calcium steady state­ Normally intracellular cytosolic calcium concentrations are very low; ischemia and certain chemicals cause an increase in cytosolic Ca ++ c oncentrations; sustained levels of Ca ++ continue to increase with damage to plasma membrane; Ca ++ c auses intracellular damage by activating a number of enzymes ○ Defects in membrane permeability­ early loss of selective membrane permeability found in all forms of cell injury a. Differentiate between the etiology, clinical manifestations and pathophysiology of cellular injuries caused by hypoxia, free radicals, and ethanol. Cellular Injury Etiology Clinical Manifestations Pathophysiology Hypoxic Injury Decreased amount of oxygen in air (high altitudes, asphyxiation, or drowning); loss of hemoglobin or its function (hemorrhage or sickle cell anemia); decreased production of RBCs (iron deficiency anemia and leukemia); cardiopulmonary diseases; ischemia (most common) Cell death with cell specific release of intracellular enzymes that we can use labs to identify and diagnose organ damage; creatine kinase (muscle cells, including the heart), LDH (muscle cells, liver cells, lung cells, heart, RBCs, and brain), AST and ALT (found in liver cells), and troponin (cardiac cells), Hypoxia can induce inflammation and Caused by arteriosclerosis and thrombosis. Progressive hypoxia is better tolerated than anoxia such as an embolus.(The body can adapt) Lack of oxygen delivered to the cell causes a decrease in mitochondrial function which causes a decreased production of ATP and increases anaerobic metabolism (which generates ATP from g lycogen stores) 10 inflamed lesion can become hypoxic. ­ Acid hydrolases from leaking lysosomes are activated in reduced pH of the injured cell and they autodigest cytoplasmic and nuclear componenets. and eventually anaerobic metabolism will stop (after glycogen stores are depleted) and the cell will die; reduction in ATP levels impairs the sodium potassium pump and sodium calcium exchange leading to an increase in intracellular sodium and calcium and potassium will leave the cell; water begins to follow sodium into the cell and cause the cell to swell along with ER dilation which leads to ribosomal d etachment which causes a decrease in protein synthesis. If O2 is not restores v acuolation (formation of vacuoles) within the cytoplasm, swelling of lysosomes, and marked swelling of the mitochondria resulting from mitochondrial membrane damage. Continued hypoxia leads to accumulation of Ca which activates multiple enzyme 11 systems, including proteases, nitric oxide synthase, phospholipases, and endonuclease, resulting in cytoskeleton disruption, membrane damage, activation of inflammation, DNA and chromatin degradation, ATP depletion, and eventual cell death due to the calcium stimulating cell enzymes that cause apoptosis. Free Radical and Reactive Oxygen Species Free radicals­­molecules with an unpaired electron in its outer shell making it unstable and highly reactive and oxidized; to try to stabilize, it steals an electron from another molecule and the molecule it stole from becomes a free radical ROS (reactive oxygen species)­called oxidative stress ­produced as a Cellular injury and eventually death; aging and disease; ROS have a role in development of heart disease, Alzheimer’s Disease, Parkinson’s Disease, prion disease and Amyotrophic Lateral Sclerosis ROS play major roles in the initiation and progression of cardiovascular alterations associated with hypertension, hyperlipidemia, diabetes ROS cause (1)lipid peroxidation (destroying the unsaturated fatty acids of lipids causing cell membrane damage and an increased permeability of the cell membrane), (2) alteration to proteins which maintain ion pumps and cellular transport, (3) alterations of DNA including breaking of single strands and causes less protein synthesis, chromatin destruction, and 12 byproduct of ATP production and will overwhelm the mitochondria and exhaust intracellular antioxidants; also produced by absorption of high energy sources such as radiation or UV light, occurrence of endogenous reactions (O2>H20) or enzymatic metabolism of exogenous chemical or drugs ­ mellitus, ischemic heart disease, chronic heart failure, and sleep apnea. ­ROS may trigger inflammatory responses by activating endothelial cells, leukocytes, and platelets. damaged mitochondria (greatest source and target of ROS) Antioxidants are our body’s defence against ROS. Enzymes such as superoxide dismutase decompose ROS. The endothelium (inner lining) of blood vessels uses n itric oxide to signal the surrounding smooth muscle to relax, thus resulting in v asodilation and increasing blood flow: up­ regulation of adhesion molecule production in the endothelium can be accomplished by ROS, which diminishes nitric oxide (NO) synthase (synthesizes NO) activity & promotes NO breakdown→ decreased vasodilation of vessels→ increased vasoconstriction, vascular smooth muscle proliferation. Hypercoagulability, thrombosis Ethanol Metabolized to acetaldehyde in the cytoplasm of the cell of the liver with the help of ADH (acetaldehyde) and then to acetate in Adverse effects on liver and nutritional deficiencies including magnesium, vitamin B6, thiamine, and phosphorus, elevated triglyceride levels ­Pyruvate changes to lactic acid (lactic acidosis); ­oxaloacetate converts to malate (prevents gluconeogenesis and 13 the mitochondria; oxidized niacin (NAD+) is reduced to NADH thus increasing the NADH/NAD + ratio in the liver and hepatosteatosis (fatty liver); ketoacidosis; acute effects­­ CNS depression, reversible liver and gastric changes. Chronic effects­­fatty infiltration, hepatomegaly, liver necrosis, suppressed fatty acid oxidation liver failure, alcoholic hepatitis, and cirrhosis. Wernicke encep...
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