 |  |
|
08-05-2004, 11:03 AM
|
|||
|
|||
|
Studying Pathology from Goljan :)
PATHOLOGY
GOLJAN Chapter 1 CELL INJURY Note: MC= most common; MCC= most common cause; S/S= signs & symptoms; (N)=Normal (I)=Increase (D)=Decrease Treatment=(Rx)  Oxygen (O2) Related Terms1. O2 Content A. Definition: Total amount of Oxygen O2 carried in Blood. B. Formula: O2 Content = 1.34 (Hb) x SatO2 + PaO2 Hb= Hemoglobin; SaO2= O2 Saturation; and PaO2= amount of O2 dissolved in plasma C. Amount of Hb in RBCs is the most important factor for carrying O2 in the blood. 2. PaO2 A. Def: Amount of O2 dissolved in the plasma of arterial blood; a=arterial It is not the O2 attached to Hb in RBCs (SaO2) Decrease in PaO2 is called Hypoxemia (normal: 75-105mmHg) B. PaO2 depends on: O2% in inspired air (21%) Atmospheric Pressure: with high elevation while O2% is still 21% Matched Ventilation/Perfusion in the lungs Normal diffusion of O2 through the Alveolar-Capillary interface. C. Decreased Alveolar PO2 (PAO2) always leads to Hypoxemia D. Hypoxemia always leads to less O2 carried by the Hb in RBCs (SaO2) E. PO2 at the tissue level: PO2 is the driving force for diffusion of O2 from capillaries into the tissue Capillary PO2 must be higher than tissue PO2 for diffusion to occur In hypoxemia, the amount of Oxygen diffused into tissue is decreased 3. SaO2 A. Def: %O2 attached to the 4 Heme groups in Hb within RBCs (N: 94-96%) B. SaO2 is dependent on: - PaO2 - Valence of Heme Iron: Must be Ferrous (+2) to bind O2 - If oxidized to ferric (+3), it cannot bind O2: +3 Iron is called Methemoglobin C. Measurement of SaO2: - Measured non-invasively with a pulse oximeter - In Arterial Blood Gases (ABG), it is usually calculated from the measured PaO2 D. Decreased SaO2 correlates with cyanosis of Skin/Mucous membranes: SaO2<80% produces visible CYANOSIS. 4. ALVEOLAR ARTERIAL (A-a) Gradient-difference between calculated PAO2 and measured PaO2. A. Normally, the (A-a) is less than < 10mmHg; > 30mmHg is medically significant B. Problems with lung ventilation, perfusion, diffusion, and right to left shunting in the hearts always increase the gradient. IMPORTANCE OF OXYGEN:1. Oxygen is an electron acceptor in the oxidative pathway A. If Oxygenation is inadequate; then the oxidative pathway cannot pump protons into the intermembranous space in the mitochondria. B. No protons in the intermembranous space means that none can reenter proton pores in the inner mitochondrial membrane for the synthesis of ATP. 2. Anaerobic glycolysis is the only other source for ATP that does not require the oxidative pathway- produces 2 ATP. HYPOXIC CELL INJURY (Inadequate Oxygenation of tissue with decreased synthesis of ATP) 1. ISCHEMIA A. Def: Decreased arterial blood flow to tissue B. Normal PaO2 and SaO2 C. Causes; Occlusion of an artery (eg. Coronary artery atherosclerosis), MCC: **decreased cardiac output (e.g. left sided heart failure) **oxygen content is normal 2. HYPOXEMIA: decrease in PaO2 A. Respiratory Acidosis: High PACO2 (CO2 retention) always decreases PAO2, PaO2 and SaO2 B. Ventilation Defect: Massive Atelectasis (collapse of the respiratory unit in the lungs) 1. Def: Impaired O2 delivery to the alveoli for gas exchange with decrease in PaO2 and SaO2 Ex: Respiratory Distress Syndrome (RDS) with decreased synthesis of surfactant and subsequent collapse of alveoli; Adult respiratory distress syndrome. 2. Mx: Leads to intrapulmonary shunting of blood: perfusion of alveoli occurs without O2 exchange. Giving 100% O2 does not significantly increase PaO2 3. (D) O2 content, (N) Hb, (D) PaO2, (D) SaO2 C. Perfusion Defect: e.g.: Pulmonary embolus 1. Def: absent blood flow to alveoli (e.g. pulmonary embolus) with decrease in (D) PaO2 and (D) SaO2 2. Increase (I) Dead Space: alveoli contain O2 but there is no gas exchange. 3. Since not all the vessels are occluded, giving 100%O2 raises the PaO2 by allowing more O2 exchange in normally perfused lungs. D. Diffusion Problems: 1. Def: O2 cannot diffuse through the alveolar-capillary interface. e.g.: Interstitial fibrosis, pulmonary edema 2. (D) PaO2 and SaO2 3. HEMOGLOBIN (Hb) RELATED ABNORMALITIES: A. ANEMIA: (D) Hb concentration 1. (D) O2 Content: (D)Hb, (N)PaO2, (N)SaO2 (gas exchange is normal) 2. Iron deficiency is MC Anemia B. METHEMOGLOBINEMIA With Iron Fe+3, HEME cannot bind O2 1. (D)O2 content: (N)Hb, (N)PaO2, (D)SaO2 2. Causes: - HEME group is oxidized by NITRO/SULFA compounds (drugs with NITRITES or SULFUR), water, particularly in the mountains or on farms where the water is often contaminated with Nitrates. - Deficiency of Methemoglobin Reductase 3. Clinical: Cyanotic (not reversed by O2) Blood is chocolate colored from increased deoxyHb Giving 100% Oxygen O2 does not correct the cyanosis 4. Left shifts the ODC 5. (Rx): * IV Methylene Blue (activates Methemoglobin reductase) is the gold standard for Rx. * Ascorbic acid: reducing agent that is used as ancillary therapy (reduces Ferric Fe+3 to ferrous Fe+2) C. CARBON MONOXIDE CO POISONING: 1. Def: CO has high affinity for the HEME group in RBCs, hence lowering the SaO2 without affecting the Hb or the PaO2. CO competes with O2 for binding sites on HEME Iron. 2. (D)O2 Content: (N)Hb, (N)PaO2, (D)SaO2 3. CO poisoning also: Left shifts the O2 dissociation curve (ODC) [or O2 Bind Curve OBC] Inhibits Cytochrome Oxidase in the Oxidative Pathway (electron transport chain (ETC) 4. Causes of CO poisoning: Car exhaust Space heaters Smoke inhalation in fires Wood stoves 5. Rx: 100% O2, which displaces CO from the HEME group 6. S/S: Headache first symptom Cherry red color on skin b/c Carboxyhemoglobin (masks cyanosis) 7. Chronic Effect: Necrosis of Globus pallidus leading to Parkinson-like findings D. FACTORS LEFT-SHIFTING OBC: High affinity of Hb for O2 Left shifted ODC causes tissue hypoxia: (I)affinity for O2 (does not release O2 into blood) i.e. : (D) 2,3-biphosphoglycerate (BPG) Alkalosis CO Methemoglobin (MetHb) Fetal Hb (HbF) Hypothermia E. CLINICAL CORRELATION: Right shifted OBC (decreased affinity of Hb for O2) 1) (I) 2,3 BPG 2) Fever 3) Acidosis 4) High Altitude: Respiratory alkalosis increases the rate of glycolysis, hence increasing conversion of 1,3 BPG into 2,3 BPG, which offsets the effect of Respiratory alkalosis in left-shifting the OBC. 4. PROBLEMS WITH OXIDATIVE PATHWAY IN MITOCHONDRIA Inner mitochondrial membrane pathway transfers electrons to O2 and creates energy to pump protons into the intermembranous space for production of ATP Carbon Monoxide CO and Cyanide CN: CO and Cyanide CN inhibit Cytochrome Oxidase in the ETC Blocks Oxidative pathway in the Mitochondria even though O2 may be present as an electron acceptor. Protons are no longer entering the intermembranous space No ATP is synthesized. Cyanide Poisoning: Systemic asphyxiant Poisoning is common in the setting of combustion of polyurethane products during residential fires Accidental poisoning S/S: - Bitter almond smell to breath Rx of Cyanide Poisoning: - Nitrites: amyl and sodium nitrite--> create Methemoglobin--> MetHb competes with Cytochrome oxidase for cyanide. - Thiosulfate: combines with Cyanide from Cyanmethemoglobin -->nontoxic Thiocyanate. 5. UNCOUPLED OXIDATIVE PHOSPHORYLATION IN MITOCHONDRIA A. Mitochondrial poisons render the entire inner mitochondrial mb permeable and carry protons with them ((D)ATP synthesis): poisons include: Dinitrophenol Pentachlorphenol (used to treat wood to prevent insect invasion) Thermogenin (natural uncoupling agent in newborn brown fat that keeps internal temperature Up) Alcohol and Salicylates also damage the mitochondrial and produce a similar result, but they are not uncoupling agents. Rate of chemical reactions increases to produce more NADH and NADPH--> potential for hyperthermia. 6. ARTERIOVENOUS SHUNTING Direct communication of arterial system with venous system (microcirculation is bypassed): AV fistula from trauma. Effects of a Decrease in cellular ATP1. Cell must utilize anaerobic glycolysis to generate ATP A. In tissue hypoxia, Phosphofructokinase (PFK), the rate limiting reaction in Glycolysis, is activated by: Low citrate: most important factor Increase in Adenosine Monophosphate (AMP) B. Net gain of 2ATP and no gain in NADPH: NADH is converted into NAD+ when pyruvate is converted into lactate NAD+ is used to produce 2 more ATP C. Decrease in Intracellular pH from Lactate production: Denatures cellular enzymes and other proteins (called coagulation necrosis) Produces an increased (I) Anion Gap metabolic acidosis. 2. Impaired Na+/K+ ATPase Pump A. Na+ and water enter the cell producing cellular swelling: first histologic sign of tissue hypoxia. B. This is a Reversible change if O2 is restored. 3. Ribosomes fall off rough the Endoplasmic Reticulum- Decreased protein synthesis Causes of Irreversible Cell Injury due to tissue hypoxia1. Disruption of the cell membrane: Most important factor Lipid Peroxidation by Free Radicals FR: reversed by Vit E 2. Damage to Mitochondria 3. Calcium in Irreversible Cell Injury: Accumulates in the Cytosol: Ca++ ATPase Pump disrupted Activates Enzymes: - Cell Mb Phospholipase (enhances Lipid Peroxidation) - Enzymes in the nucleus (produces Nuclear Pyknosis) Enters mitochondria: produces electron dense deposits and destroys mitochondria Contribuyes to coagulation necrosis along with the intracellular buildup of lactic acid. Summary of sequence in Hypoxic Cell Injury1. Hypoxia: (D)Oxidative Phosphorilation in mitochondria leading to a (D)ATP 2. (D)ATP leads to: (I) Anaerobic glycolysis: (D) intracellular pH from lactic acid, (D)glycogen Dysfunction of Na+/K+ ATPase Pump: Reversible cellular swelling Ribosomes detach from RER: (D) protein synthesis, fatty change-> 3. Irreversible Cell Membrane Injury: Intracellular release of Lysosomal enzymes damages membrane Endogenous activation of phospholipases ( (I)influx of Ca++ into cytosol) with release of toxic lipid products. Cytoskeletal alterations: activation of proteases by Ca++ 4. Irreversible Nuclear changes: Activation of nuclear enzymes by Ca++ Nuclear Pyknosis and lysis 5. Irreversible mitochondrial dysfunction: Entry of Ca++ into mitochondria with activation of phospholipases causing destruction of inner and outer mb Ca++ produces large densities ENZYME MARKERS CELL DEATH Transaminases - Hepatitis Creatine Kinase - Skeletal/cardiac muscle CK:MB - Cardiac muscle Amylase/Lipase - Acute Pancreatitis LDH ½ flip - Myocardial Infarction FREE RADICALS: Unpaired electrons in the outer orbit 1. Examples.- Superoxide: O2* generated FR inactivated by Superoxide Dismutase (SOD) OH* : generated by ionizing radiation and iron Peroxide: Inactivated by catalase and Glutathione (GSH) Drugs/Chemicals: - Acetaminophen (inactivated by GSH) - CCl4 converted into CCl3- 2. Iron Increases the synthesis of OH*: FRs via the Fenton reaction. FRs are the Mx of damage in Iron overload diseases: e.g. Hemochromatosis. 3. Lipofuscin accumulates in cells damage by FRs in the normal aging process and in atrophy: indigestible lipid from lipid peroxidation that gives tissue a brown appearance. 4. Clinical Examples of FR damage: A. O2 Dependent myeloperoxidase (MPO) system in neutrophils/Monocytes B. O2 toxicity due to superoxide FR damage: e.g. Retrolental fibroplasia leading to blindness in newborns C. Ionizing Radiation: Generates Hydroxyl (OH) FRs in tissue from Radiolysis of water in cells Damages DNA with potential for cancer (e.g., Squamous skin cancer) D. Iron overload conditions E. Acetaminophen toxicity***: Acetaminophen is converted by the hepatocyte Cytochrome system into FRs that act on sulfhydril groups in the hepatocyte cell mbs. MCC of Fulminant Hepatic Necrosis due to drugs: See necrosis around central vein in the liver Acetylcysteine/therapy (Mucomyst) replenishes GSH, which neutralizes the drug FRs F. CCl4 poisoning in dry cleaning industry: CCl4 converted by Cytochrome system into CCl3 FR --> Liver cell necrosis with fatty change. APOPTOSIS: Individual cell necrosis 1. Def: genetically determined internal programmed series of events leading to individual cell death. 2. Functions of Apoptosis: A. Hormone-dependent involution of tissue in adults: Involution of lactating cells with withdrawal of Prolactin Endometrial cell breakdown after withdrawal of Estrogen/Progesterone in the menstrual cycle Prostatic atrophy after removal of dihydrotestosterone (castration, drug induced, old age) Atrophy of Thyroid with inhibition of TSH B. Programmed destruction of cells during embryogenesis: Loss of mullerian structures in male fetus by mullerian inhibitory factor or Wolffian structures in female fetus Development of lumens in the intestines C. Involution of the Thymus in an adult D. Cell death related to injurious agents: Viruses (e.g. HBV infected cells) Cell cycle specific chemotherapy drugs Tissue hypoxia Ionizing and UV light radiation E. Death of tumor cells F. Pathologic Atrophy of parenchymal obstruction due to duct obstruction: Atrophy of pancreatic exocrine cells with duct obstruction by thick secretion in Cystic Fibrosis Atrophy of Parotid gland due to stone in the duct G. Cytotoxic T cell-induced death of target cells H. Programmed cell death involved in old age 3. Sequential mechanisms of Apoptosis A. Signals Initiating Apoptosis: Injurious agents: Radiation, free radicals, toxic agents Withdrawal of growth factor or hormones Receptor-ligand interactions on the plasma mb of cells Tumor Necrosis Factor B. Activation of CASPASES, a group of cysteine-proteases that sets into motion an enzymatic death programs: Endonuclease activation leading to nuclear fragmentation (first steps in actual cell death) Activation of proteases that breakdown the cytoskeleton Transglutaminase activation with increased cross-bridging of proteins C. Mitochondrial Injury D. Formation of Cytoplasmic blebs that fragment into apoptotic bodies that are surrounded by cell mb and contain cytoplasm, packed organelles, with or without nuclear fragments E. Phagocytosis of Apoptotic bodies by neighboring cells or macrophages which destroy the bodies in lysosomes. 4. Microscopic appearance: Cell separates away from neighboring cells Deeply Eosinophilic staining cytoplasm Pyknotic nucleus No or minimal inflammatory infiltrate TYPES OF CELL NECROSISNecrosis is widespread damage to tissue as opposed to apoptosis, which is individual cell necrosis. 1. Coagulation Necrosis A. In Coagulation Necrosis the tissues is dead but vague outlines of what used to be living tissue can still be identified: e.g. can identify cardiac muscle, but striations are fading out and nuclei are disappearing B. Coagulation Necrosis is most often due to thrombosis of a vessel (e.g. artery or vein) and less commonly due to the effect of heavy metals (e.g., Lead, Arsenic mercury) on tissue (particularly the proximal tubules of the kidneys) C. The Gross (visible to the naked eye) manifestation of coagulation Necrosis is called and Infarction of which there are two types: Pale Types of Infarction (Increased density of the tissue prevents RBCs from diffusing through the Necrotic tissue) e.g.: heart, kidney, liver (least likely to infarct due to dual portal vein/hepatic artery blood supply), Spleen Hemorrhagic Types of Infarction (loose textured tissue allows RBCs to diffuse through tissue) e.g.: small bowel, Lungs, testicles. D. Dry gangrene: Predominantly coagulation necrosis when there is no infection: e.g. Diabetic food Wet Gangrene: Is predominantly Liquefactive necrosis (see below) when there is infection. 2. CNS Infarcts A. Example of Liquefactive not Coagulative necrosis B. Brain tissue has cells with numerous lysosomes and all the enzymes cannot be denatured by Lactic Acid, hence there is an autocatalytic effect in the cell. C. Brain tissue has very little structural integrity (held together by processes from Astrocytes), therefore the cells breakdown easily and leave a cystic cavity. 3. Liquefactive Necrosis A. Usually refers to neutrophils-dependent enzymatic destruction of tissue B. Examples include: Abscesses : usually staphylococcus aureus owing to coagulase production Cellulitis: usually Group A Streptococcus infections due to Hyaluronidase Wet Gangrene: e.g. Gangrenous toe becomes infected with anaerobes and neutrophils destroy tissue Brain Infarct/abscesses 4. Caseous Necrosis A. Cheese-like material noted on gross exam of tissue: represents lipid material in granulomas from macrophage destruction of typical/atypical TB and systemic fungi B. Other types of Granulomas are non-caseating: Crohns Disease Sarcoidosis 5. Enzymatic Fat Necrosis in Acute Pancreatitis Release of Amylase and Lipase from damaged Pancreas Fatty Acids combine with calcium to form Chalky White areas in the pancreas (called Saponification): Calcium deposits can be seen on X-*** 6. Fibrinoid Necrosis A. Necrosis of Immunologic Injury with protein material appearing like Fibrin B. Examples: Small Vessel Vasculitis: Henoch-Schonlen purpura Rheumatic Heart disease vegetations on Mitral valve Immunocomplex glomerulonephritis: e.g. SLE 7. Gummatous Necrosis in Tertiary Syphilis- Rubbery masses that are very destructive in tissue FATTY LIVER1. Alcohol MCC A. Increased NADH in the metabolism of alcohol causes a build-up of dihydroxyacetone phosphate (DHAP), an intermediate in Glycolisis: DHAP produces Glycerol 3-phosphate, the carbohydrate backbone of TG B. Increased Acetyl CoA in alcohol metabolism is used for fatty acid (FA) synthesis 2. Kwashiorkor Fatty liver due to decreased synthesis of Apolipoproteins necessary to coat very low density lipoprotein (VLDL) 3. Miscellaneous.- CO poisoning Shock Drugs: Tetracycline, Amiodarone Reyes syndrome HEMOGLOBIN - DERIVED PIGMENTS1. Bilirubin A. Unconjugated Type: Lipid soluble: end product of macrophage metabolism of Hb in phagocytosed RBCs e.g.: Rh hemolytic disease of the newborn B. Conjugated type: Water soluble: conjugated in the liver; e.g.: Obstructive Jaundice: stone in the common bile duct. 2. Hemosiderin B. Storage Iron consists of 2 forms: Soluble Ferritin Insoluble Ferritin C. Soluble Ferritin; is the primary Iron storage protein All cells in the body contain Ferritin: Liver and Bone Marrow macrophages are two biggest storage sites. Small amount circulates in blood and correlates with Iron stores in macrophages in the marrow: best screening test for Iron disorders Serum Ferritin is ; decreased in Iron (Fe) deficiency; and Increased in Iron overload disease (Hemochromatosis, Hemosiderosis), Anemia of chronic disease, Sideroblastic Anemia. It cannot be visualized by microscopy and does not take up the Prussian Blue stain for iron. D. Insoluble hemosiderin is a product of Ferritin degradation: Visualized as Golden-yellow granules in the cytosol of cells (e.g. hepatocytes, marrow macrophage) Stains positive with the Prussian Blue Stain See above for hemosiderin excess, Hemosiderin stores are absent in iron deficiency: first finding in Iron deficiency but requires a bone marrow exam to evaluate its stores. 3. Hematin: Black pigment derived from acid effect on Hb Responsible for Black Tarry stools (melena) associated with peptic ulcer disease. DYSTROPHIC CALCIFICATION1. Definition.- Calcium deposition in damaged tissue in the presence of a normal serum calcium/phosphate. (Psammoma bodies-> calcifications occur in Meningiomas.ex. pap. Ca of thyroid or ovaries. 2. Examples: Atherosclerosis plaques Enzymatic fat necrosis (visible in plain films) Damaged cardiac valves (e.g. bicuspid aortic valve) Periventricular calcification in congenital CMV infections (Monckebeigs medial calcification sclerosis. METASTATIC CALCIFICATION1. Def: Increased serum calcium and/or phosphate leading to the deposition of calcium in normal tissue 2. Examples: Nephrocalcinosis, in primary hyperparathyroidism - calcification of tubular basement membranes Calcification of basal ganglia in primary hypoparathyroidism CONGENITAL SPHEROCYTOSISGenetic example of a membrane defect: AD disease with a defect in Spectrin in the cell Mb results in RBCs with too little membrane (spherocytosis) EXAMPLES OF UBIQUINATION OF DAMAGED INTERMEDIATE FILAMENTS1. Mallory Bodies.- Ubiquinated (marked for destruction by Ubiquitin) Keratin intermediate filaments: microscopic feature of alcoholic hepatitis. 2. Lewy body.- Ubiquinated neurofilaments from degenerated Substantia Nigra neurons in Parkinsons disease. 3. Neurofibrillary tangles.- Ubiquinated neurofilaments in the brain in old age/ Alzheimers. CELL TYPES IN TISSUE:1. Labile cells: Contain Stem Cells with >1.5% of the Stem Cells in the cell cycle at any one time. A. Ex: - Bone Marrow Stem Cells - Stratum Basalis of Skin - Intestine- Stem cells at the base of the glands B. These cells are most affected by radiation and S phase chemotherapy drugs due to their high rate of mitotic activity. 2. Stable Cells: cells that are usually in the Go (resting) phase of the cell cycle A. Must be stimulated to enter the G1 phase by: - Hormones (e.g., Estrogen) - Growth factors (e.g. epidermal derived growth factor) - Loss of parenchymal tissue (e.g. removal of liver tissue) B. <1.5% of the cells are in the cell cycle at any one time C. Examples: - Most parenchymal cells in organs; e.g. hepatocytes, renal tubular cells, endothelial cells. - Smooth muscle: not striated or cardiac cells - Astrocytes / other Neuroglial cells D. Stable cells have the capacity to undergo hypertrophy and / or hyperplasia. 3. Permanent Cells: A. cells can not enter the cell cycle B. Ex: Skeletal cardiac muscle can only HYPERTROPHY Neurons CELL CYCLE1. Inactive CDK (Cyclin-dependent Kinase) is activated by Cyclin D (see diagram) A. Cyclin D is synthesized in the G1 phase of the cell cycle: key phase of the cycle B. G1 phase is the most variable phase: this would be the phase that explains either a shorter or longer cell cycle than normal. cdk= Cyclin-dependent Kinase Rb (hypophosphorylated form) inhibits cell from going from G1 to S phase Rb phosphorylated form allows cell to go from G1 to S phase 2n= normal amount of DNA in a cell, 4n is after duplication of the DNA prior to mitosis. Inactivated cdk is activated by cyclin D, which is synthesized in the G1 phase of the cell cycle. The Rb suppressor gene on chromosome 13 produces the Rb protein, which inhibits the cell from moving from the G1 phase into the S phase. When Rb protein is phosphorylated by active cyclin D/cdk complex, the cell passes into the S phase and finishes the cycle. The p53 suppressor gene (guardian of the cell) located on chromosome 17 produces a product that inhibits the active cyclin D/cdk complex, hence preventing phosphorylation of the Rb protein and keeping the cell in the G1 phase for repair of DNA defects, or if they are too extensive, time for apoptosis. Inactivation of the Rb suppressor gene results in the loss of the inhibitory effect of the Rb protein in keeping the cell from entering the S phase. Furthermore, inactivation of the p53 suppressor gene allows the active cyclin D/cdk complex to continually Phosphorylate the Rb protein, which allows the cell to complete enter the S phase and complete cell division. Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell growth and the potential for cancer Hypertrophy is thought to be a block at the G2 phase (tubulin synthesis), while hyperplasia is thought to be a problem after Gm (mitosis) phase such that cell continues to enter the G1 phase and progress through the cycle again. 2. Rb suppressor gene on chromosome 13 produces the unphosphorilated Rb protein. Rb protein prevents the cell from moving from the G1 phase into the S phase: S phase functions include chromosome replication and organelle replication. Phosphorylation of the Rb protein by the active Cyclin D/cdk complex allows the cell to pass into the s phase and finish the cycle which includes the G2 phase (Tubulin synthesized) and the M phase (mitosis). Inactivation of the Rb suppressor gene: Loss of the inhibitory effect of the Rb protein on the cell allows the cells to constantly enter the S phase once they are phosphorylated. 3. p53 Suppressor Gene functions on Chromosome 17 A. Produces a protein product that inhibits active cyclin D/cdk complex 1. Prevents phosphorylation of the Rb protein and keeps the cell in the G1 phase 2. Allows cell to repair any defects in DNA (Guardian of the cell): cells incapable of repair undergo apoptosis B. Inactivation of the p53 suppressor gene: active cyclin D/cdk complex continually phosphorylates Rb proteins and cells continually mitose. 4. Important concept: Inactivation of either the Rb or p53 suppressor gene leads to unrestricted cell growth and the potential for cancer. E6 and E7 gene produces in HPV inactivate both of these suppressor genes. Examples of Growth alterations1. ATROPHY.- Decrease in cell/tissue mass A. Characteristics include: Less organ weight Wrinkled capsular surface Less mitochondria Increase Lipofuscin in cells B. examples: 1. muscle in a cast: disuse of muscle leads to atrophy 2. Thyroid gland in someone taking excess thyroid hormone: decrease in TSH from increase in T4 causes atrophy of thyroid 3. Renal artery atherosclerosis: affected kidney is atrophied, while the contralateral kidney is hypertrophied (compensatory) 4. Compression atrophy of renal cortex by hydronephrosis 5. Carotid artery atherosclerosis: cerebral atrophy due to apoptosis of neurons (called red neurons) in layers 3,5,6 6. Atrophy of pancreatic ducts and islets cells in cystic fibrosis: thick ductal secretions obstruct the lumen leading to glandular atrophy and fibrosis (fibrosis destroys islet cells) 7. Patients on long-term corticosteroids develop atrophy of the zona fasciculate and reticularis in the adrenal cortex, since ACTH does not stimulate aldosterone synthesis. C. Agenesis: anlage (primordial tissue) is absent (e.g. renal agenesis) D. Aplasia: anlage is present but never develops E. Hypoplasia: anlage develops incompletely; however, the tissue that is present is histologically normal. 2. HYPERTROPHY: Increased cell size A. Cell has passed the S phase but cannot enter the Gm phase: cytosol and nucleus is larger (4n) since it contains organelles for two cells. B. Examples include: - Left ventricle hypertrophy - Removal of kidney and hypertrophy of remaining kidney 3. HYPERPLASIA: Increase in number of cells A. Common alteration in hormone excess states B. Can progress to dysplasia and cancer if left unregulated C. examples: 1. Hormone excess states: - Unopposed estrogen endometrial hyperplasia - Prolactine induced lactation - RBC hyperplasia-hypoxia leads to Erythropoietin stimulation of erythroid Stem cell. 2. Persistent injury to tissue: e.g. regenerative nodules in cirrhosis 3. Psoriasis: hyperplasia of squamous epithelium 4. Clinical examples of equal hyperplasia/hypertrophy: - Uterine smooth muscle hyperplasia/hypertrophy in pregnancy - Iodine deficiency leading to a goiter. 4. METAPLASIA: replacement of one adult cell type by another adult cell type, which may be squamous (squamous metaplasia) or glandular (glandular metaplasia) A. Mucous secreting columnar cells normally undergo squamous metaplasia to replace Exocervical Epithelium: may progress to squamous dysplasia/cancer if HPV is present. B. Schistosoma hematobium eggs in submucosal venous plexus in the bladder cause mucosal squamous metaplasia, which may progress to dysplasia/cancer. C. Squamous epithelium in the distal esophagus undergoes glandular metaplasia (mucous secreting cells/Goblet cells) due to acid injury (gastroesophageal reflux disease); this is called Barrets esophagus and may progress into dysplasia and adenocarcinoma. D. In chronic atrophic gastritis due to Helicobacter pylori, normal glandular cells undergo glandular metaplasia with the formation of Goblet cells and Paneth cells, which are cells that are normally present in the intestinal epithelium; this intestinal metaplasia is a precursor for gastric adenocarcinoma. 5. DYSPLASIA: Atypical hyperplasia with the potential for evolving into cancer. A. Dysplasia is a pre-malignant growth alteration B. In the above examples, note that: * Squamous metaplasia may progress into Squamous Cancer & * Glandular metaplasia into Adenocarcinoma. C. Examples of Dysplasia: * ACTINIC (solar) KERATOSIS: A UVB light derived dysplasia that is a precursor for squamous cancer of the skin * CERVICAL DYSPLASIA: Precursor for cervical squamous cancer (usually related to HPV 16 or 18) *LEUKOPLAKIA in the mouth in smokers and/or alcoholics: dysplasia that may progress to squamous cancer. *DYSPLASTIC NEVUS: Atypical nevus that may progress into a malignant melanoma. End of chapter.     
|
|
08-05-2004, 11:33 AM
|
|||
|
|||
|
Inflammation
PATHOLOGY
GOLJAN INFLAMMATION / REPAIR LATIN TERMS FOR ACUTE INFLAMMATION :- Calor (heat) Histamine-dependent vasodilation - Rubor (redness) Histamine-dep vasodilation of arterioles - Tumor (tissue swelling) Histamine-dep. Increase in vessel permeability in venules. - Dolor (pain) due to Prostaglandin E2 and Bradykinin [b]SEQUENCE OF VASCULAR EVENTS IN ACUTE INFLAMMATION:]/b]1- Initial transient vasoconstriction 2- Vasodilation- Histamine dep. Event that increases blood flow/hydrostatic pressure 3- Increased vessel permeability histamine dep. Receptors on endothelial cells in venules contract leaving a bare basement mb transudate initially moves into the interstitium lymphatics take up excess fluid SEQUENCE OF CELLULAR EVENTS IN ACUTE INFLAMMATION:1. Neutrophil margination: * Due to adhesion molecule synthesis in Neutrophils /Endothelial cells * Neutrophils are pushed to the periphery of the vessel 2. Neutrophil Adhesion to endothelial cells (pavementing) A. Adhesion molecules are CD11/CD18 complexes of glycoprotein and B1 and B2 Integrins B. Endothelial cell derived adhesion molecules: Synthesis is stimulated by IL-1 and Tumor Necrosis factor TNF Leukocyte adhesion molecules (ELAM) Intercellular adhesion molecules (ICAM) C. Neutrophil adhesion molecule synthesis: Stimulated by C5 and LTB4 3. Emigration of Neutrophils in venules Neutrophils emit Collagenase and destroy type IV collagen leading to the accumulation of a protein/ cell rich fluid in the interstitium called an EXUDATE (tumor of inflammation). 4. RECEPTORmediated Chemotaxis (directed migration)- chemical mediators enhance Chemotaxis: C5a LTB4 Bacterial products 5. Phagocytosis: A. Receptor-mediated Opsonization of bacteria by IgG and C3b enhances Neutrophil / Monocyte / M= Macrophage phagocytosis, all of which have Fc receptors for IgG and C3b: Nonspecific opsonizing agents include C-reactive protein, fibrinogen, and Fibronectin B. Bacteria are internalized by leukocytes into vacuoles (phagosomes), which become filled with Lysosomal enzymes (phagolysosomes). 6. Bactericidal mechanism in Leukocytes- A. Neutrophils and Monocytes have three systems: O2 dependent myeloperoxidase MPO system; most potent system. Macrophages only have the latter two systems. RESPIRATORY BURST MECHANISM INNEUTROPHILS/MONOCYTES 1. Part of the O2-depndent myeloperoxidase (MPO) bactericidal system 2. NADPH oxidase located in the leukocyte membrane and using NADPH derived from the Hexose Monophosphate shunt as a cofactor, it converts molecular oxygen into superoxide free radicals: energy given off in this reaction is called the Respiratory Burst. 3. Superoxide FPs converted by superoxide dismutase into peroxide 4. Myeloperoxidase (MPO) combines peroxide with chloride anions to form bleach, which destroys bacteria. 5. NBT (Nitroblue tetrazolium test) dye test : - Evaluate the integrity of the respiratory burst - Neutrophils convert a colorless dye into a colored dye if the respiratory burst system is intact. CHRONIC GRANULOMATOUS DISEASE OF CHILDHOOD:1. SXR Disease microbicidal defect 2. Absent NADPH Oxidase- A. Absent respiratory burst: negative NBT dye test B. Absence of peroxide in the phagolysosome: MPO and chloride anions are present in phagolysosomes 3. Leukocytes cannot kill Catalase positive S. aureus- b/c it releases its own peroxide (missing in CGD), However, catalase is released, which neutralizes the peroxide. 4. Leukocytes can kill catalase negative Streptococci peroxide released by streptococci is used by MPO to synthesize bleach and kill the bacteria. Myeloperoxidase Deficiency: Acquired or genetic Absent azurophilic granules in neutrophils in peripheral blood Respiratory burst is normal can generate superoxide FRs Can not kill bacteria * Microbicidal defect * No MPO to produce bleach. Congenital adhesion molecule (B2-integrins) defect: Failure of the umbilical cord to separate in newborns No adhesion of neutrophils to the endothelial cells No inflammatory cells in the umbilical stump Summary of Chemical mediators in acute inflammation:1) HISTAMINE Overall most important mediator Released/synthesized by Basophils/mast cells Vasodilator/increases vessel permeability Important in anaphylactic shock Produces the wheal and flare reaction in type I Produces the wheal and flare reaction in type I hypersensitivity reactions. 2) SEROTONIN Rel/sx by basophils/mast cells/platelets Sx from Triptophan Vasodilator (can also be a vasoconstrictor) Increases vessel permeability Neurotransmitter Cause of flushing in carcinoid syndrome 3) C3a/C5a Anaphylatoxins that directly stimulate histamine release from basophils/mast cells Important in tissue swelling and shock 4) C3b Opsonizing agent 5) C5a Adhesion molecule synthesis on Neutrophils Chemotactic agent Anaphylatoxin 6) Bradykinin Vasodilator/increases vessel permeability Bronchoconstrictor Pain (dolor) of acute inflammation Cough and angioedema with ACE inhibitors 7) Important PG H2 products - a) THROMBOXANE A2 (TX A2) PG H2 is converted by platelet-derived thromboxane synthase into TXA2: dipyramidole inhibits the enzyme, Platelet aggregator Vasoconstrictor Bronchoconstrictor b)PROSTACYCLIN (PGI2) PGH2 is converted by endothelial cell-derived prostacylcin synthase into PGI2 Prostacyclin synthase is not inhibited to any significant degree by aspirin and NSAIDs Inhibits platelet aggregations Vasodilator c) Prostaglandin E (PGE) Dolor of acute inflammation Vasodilator in kidneys: blocked by NSAIDs but not acetaminophen Increases renal blood flow: vasodilates afferent arteriole Increases gastric mucosal blood flow: important in generation of the mucosal barrier Activates osteoclasts: important in producing hypercalcemia in malignancy Important in FEVER PRODUCTION: IL-1 stimulates its sx in the anterior hypothalamus D) PGF2 : Constricts uterine muscles: cause of primary dysmenorrheal Vasoconstricts, bronchoconstricts. 8. LTB4 Adhesion molecule synthesis on neutrophils Chemotactic agent 9. LTC D E4 Bronchoconstrictor / vasoconstrictor Very important in asthma 10. Nitric Oxide Endothelial cell and macrophage-derived vasodilator/increase vessel permeability Important in shock 11. Interleukin (IL-1) Generation of fever : stimulates prostaglandin E synthesis in anterior hypothalamus B cell stimulation to synthesize immunoglobulins Activates osteoclasts: called osteoclasts activating factor Increases adhesion molecule synthesis by endothelial cells Increases liver synthesis of acute phase reactants Coagulation factors: fibrinogen, V, VIII C reactive protein RACHIDONIC ACID METABOLISMCyclooxygenase.- a) Aspirin irreversible acetylates Cyclooxygenase (COX) while others NSAIDs reversible acetylate the enzyme. b) COX-1 : Present in non-inflammatory cells Cytoprotective prostaglandins (e.g. PG E in gastric tissue TX A2 in platelet aggregation c) COX-2 : Inducible enzyme: Upregulated in inflammatory processes Present in inflammatory cells d) Salicylates and other NSAIDs inhibit COX1>COX2 e) Selective COX-2 inhibitors (e.g. Celecoxib) have less chance of producing peptic ulcer disease, since cytoprotective prostaglandins are not inhibited. f) Acetaminophen is a weak Cyclooxygenase inhibitor in peripheral tissue: Stronger Cyclooxygenase inhibitor in CNS: prevents synthesis of PG in hypothalamus and lowers fever. Antipyretic and analgesic but not anti-inflammatory g) USMLE Scenario: in a volume depleted patient with fever, acetaminophen should be used as an antipyretic rather than NSAIDs, since the latter block PGE2 synthesis (sx) in the kidneys (normally a vasodilator) leaving the vasoconstrictive effects of AT II unopposed danger of acute tubular necrosis. 2. LIPOXYGENASE a) Leukotrienes are produced in this pathway b) Enzyme is specifically blocked by Zileuton useful in treatment (Rx) of bronchial asthma by preventing formation of LTC- D- E4 c) Other drugs block receptors for the leukotrienes, hence inhibiting their function: e.g. Zafirlukast, Montelukast. CORTICOSTEROID EFFECTS IN ACUTE INFLAMMATION Block Phospholipase A2 decreased synthesis of PG and LT Decreases leukocyte adhesion synthesis marginating pool (normally 50% of the peripheral blood leukocyte pool) is now circulating absolute neutrophilic leukocytosis Decreases peripheral blood lymphocytes Lymphopenia decreases synthesis of Antibodies Decreases peripheral blood eosinophils eosinopenia Stabilizes the basophil/mast cell membrane prevents release reaction of preformed mediators: important in Rx of asthma NEUTROPHILS1. Key cell in : Acute inflammation Immunocomplex reactions: activation of complement by immunocomplexes increases C5a c5a is chemotactic to neutrophils neutrophils damage the tissue wherever immunocomplexes are deposited 2. Contains Receptors for IgG/C3b 3. Bone marrow mitotic pool (can divide) myeloblasts, progranulocytes, myelocytes. 4. Bone marrow post-mitotic pool (can no longer divide) metamyelocytes, band neutrophils, segmented neutrophil 5. Peripheral blood pools a) marginating pool: adherent to endothelium account for 50% of peripheral blood pool account for >50% in African Americans: reason for neutropenia in Africa-americans becomes part of circulating pool when adhesion molecule synthesis is decreased: e.g. *corticosteroids, *Lithium, *catecholamine release b) Circulating pool: Measured in CBC Decreases if adhesion molecule synthesis is increased: e.g. endotoxemia. MONOCYTES / MACROPHAGES: 1. Key cell in chronic inflammation 2. Receptors for IgG/C3b: Important in extravascular removal of RBCs, leukocytes, platelets 3. Monocytes become macrophages A. Fixed macrophages: Kupffer cells Macrophages in Splenic Red pulp M outside sinusoids in the bone marrow B. wandering: alveolar microglial cells in CNS 4. Functions: Process antigen Scavenger cells Enhance host immunologic response: Secrete Cytokines like IL-1, IL-2, TNF LYMPHOCYTES Primary inflammatory cell in viral infections. B cells, T cells, Plasma cells, Chemokines, Lymphotoxin. PLASMA CELLS 1. Derived from activated B Lymphocytes 2. Functions: a) Antibody production b) IgM produced on first Antigen exposure in acute inflammation: IgM is more potent than IgG in activation of the classical complement pathway, hence ensuring complement components for acute inflammatory process - IgG is synthesized after 10-14 days by Isotype switching: heavy chain is spliced out and heavy chain is spliced in - IgG is the main immunoglobulin of chronic inflammation 3. Morphology - Well developed rough endoplasmic reticulum - Bright blue cytoplasmic staining with Wright Giemsa - Cartwheel appearing nuclear chromatin pattern ENDOTHELIAL CELLS: Synthesis of: Prostacyclin Von Willebrand factor: platelet adhesion factor Nitric Oxide Tissue Thromboplastin: activates factor VII in the Extrinsic system. MAST CELLS/BASOPHILS 1. Main effector cell for type I hypersensitivity reactions 2. Activated by: - Histamine - Specific allergens interacting with IgE antibodies on their surface - C3a/C5a (anaphylotoxins) 3. Preformed mediators are initially released- - Histamine - Serotonin - heparin Eosinophil Chemotactic factor 4. Late Phase Reaction- synthesis and release of prostaglandins and leukotrienes, which enhance and prolong the acute inflammatory process 5. Early and late phase release reaction is prevented by Chromelin Sodium and corticosteroids. EOSINOPHILS1. Destruction of invasive helminths Type II (not type I) hypersensitivity reaction Eosinophils have Fc receptors for IgE Receptors interact with IgE coating the surface of invasive helminthes -->antibody dependent cytotoxicity reaction causes the release of major basic protein --> kills helminth 2. Granules contain crystalline material become Charcot-Leyden crystals in sputum of asthmatics. 3. Chemical Mediators- Major basic protein: kills invasive helminthes Histaminase: neutralize Histamine Arylsulfatase; neutralize Leukotrienes 4. EOSINOPHILIA- A. Type I Hypersensitivity reactions: Allergic rhinitis Bronchial asthma Drug allergies: Penicillin MCC Response to invasive Helminthic infections excluding pinworms, which are not invasive B. Miscellaneous: Hodkings disease B. Miscellaneous: Hodkings disease Polyarteritis Nodosa Hypercortisolism 5. Eosinopenia: Corticosteroids Cushing Syndrome IMPORTANT CLUSTER DESIGNATION (CD) TYPES FOR USMLE1. CD1 Histiocytes (Langerhans cells), dendritic cells 2. CD3 T cell antigen recognition site, OKT3 monoclonal antibody is an immunosuppressive agent that blocks this site. 3. CD4- helper T cell marker, gp 120 antigens in HIV-1 and 2 bind to this molecule 4. CD8 marker for cytotoxic and suppressor T cells 5. CD10 common acute lymphoblastic leukemia (CALLA) marker 6. CD11/CD18 - B1 and B2 Integrins 7. CD15 and CD30 markers for Reed-Sternberg cell in Hodgkins disease. 8. CD21- receptor for EBV on Bcells 9. CD45 Leukocyte marker * very useful in surgical pathology in separating leukocyte from epithelial malignancies. ROLE OF FEVER IN INFLAMMATION Right shifts oxygen dissociation curve (ODC) more O2 available for O2 dependent MPO system. Provides a hostile environment for bacterial/viral reproduction TYPES OF ACUTE INFLAMMATION1. Suppurative e.g., abscess due to Staphylococcus aureus contains Coagulase, which cleaves Fibrinogen into Fibrin and traps bacteria/neutrophils. 2. Cellulitis Commonly (not exclusively) due to Streptococcus: bacteria contain Hyaluronidase, which allows bacteria to spread through subcutaneous tissue. Examples: erysipelas and Impetigo due to group A Streptococcus 3. Pseudomembranous - Toxin- induced damage of tissue: not an invasive infection Examples: * Diphteria * Clostridium difficile in pseudomembranous colitis 4. Fibrinous - Protein-rich fluid that has a bread and butter appearance on serosal membranes E.g. pericarditis TYPES OF WOUND HEALING Primary intention wound edges are apposed Secondary intention - * wound is left open *Myofibroblasts are important in closing wound. SEQUENCE IN PRIMARY INTENTION HEALING OF WOUND1. First day : Clot develops in wound and neutrophils infiltrate the wound 2. Second day: Squamous cells from basal cell layers of apposing skin margins seal off the wound after 48h and macrophages emigrate into wound. 3. Third day: A. Beginning of granulation tissue formation: Angiogenesis is due to basic fibroblast growth factor Fibroblasts lay down type III collagen B. Fibronectin is key chemical mediator: Derived from Macrophages / Fibroblasts / Endothelial cells Chemotactic to fibroblasts/macrophages Opsonizing and adhesion agent 4. Fourth to Sixth day: 4th 6th days Granulation tissue formation peaks 5. 7th to 10th days: Tensile strength 10% of normal 6. Weeks months: A. Collagenization: Type III Collagen replaced by type I to increase tensile strength Collagenases important in remodeling: Zinc is a cofactor B. Maximum tensile strength of 80% after 3 months. IMPORTANT COLLAGEN TYPES ASKED ON USMLE:Type I: Highest tensile strength Tissues: Bone 90% Skin 80%, Tendons. Type II: Cartilage Type III: Initial type in wound repair Type IV Basement membrane Type X Epiphyseal plate KEY FACTOR INTERFERING WITH WOUND HEALING Infection most important and Staphylococcus aureus MC pathogen. Zinc deficiency cofactor in Collagenase involved in wound remodeling Vit C deficiency - * No hydroxylation of Proline and Lysine * hydroxylation sites are where cross-bridges attach to form strong collagen bundles *Structurally weak (low tensile strength) collagen in scurvy Genetic disorders: - Marfans: defect in Fibrillin - Ehlers-Danlos: defect in collagen - Osteogenesis imperfecta: defect in synthesis of type I collagen - Congenital adhesion molecule defects KELOID- Hypertrophic scar tissue - Resembles a tumor and contains type III collagen - Predisposition to squamous cancer, particularly if due to third degree burns. CHARACTERISTICS OF CHRONIC INFLAMMATION1. Pathogenesis - Previous acute inflammation - De novo: e.g. granulomatous inflammation, autoimmune disease 2. Cell types - - Monocytes / Macrophages : primary cells - Lymphocytes/plasma cells * Fibroblasts / endothelial cells 3. IgG is the predominant immunoglobulin polyclonal peak in Gamma Globulin region in a protein electrophoresis. RECOGNITION/PATHOGENESIS OF A GRANULOMA:1. Histology - Well circumscribed Red Contain multinucleated giant cells 2. Usually a type IV hypersensitivity reaction Cell mediated immunity primarily involving CD4 T helper cells and macrophages. 3. Pathogenesis of a TB granuloma and a positive PPD A. Phagocytosis of TB by alveolar macrophages B. Systemic lymphohematogenous spread of macrophages with bacteria: macrophages begin processing TB antigen without eliciting a systemic infection--> C. Macrophage interacts with CD4 T helper cell via class II antigen sites--> Macrophage release of IL-12, which causes some of the CD4 Tcells to differentiate into TH1 class cells TH1 class cells retain memory of encounter and are important in PPD reaction and reactivation TB D. Macrophages also secrete IL-1, which augments T cell proliferation by causing IL-2 release from CD4 T helper cells and produces fever E. CD4 T helper cells secrete cytokines--> 1. Gamma Interferon: Activates Macrophages to kill TB PPD becomes positive Lipid from killed bacteria is responsible for caseous necrosis Activated macrophages are called epithelioid cells. 2. Macrophage inhibitory factor keeps macrophages together to form discreet granulomas. F. Macrophages fuse into multinucleated giant cells, the best markers for granulomas G. PPD reaction: 1- Injection of purified protein derivative (PPD) into skin 2- Langerhans cells (CD1 positive histiocytes of the skin) phagocytose and process the PPD antigen -> present antigen to previously sensitized TH1 CD4 cells -> reactivated TH1 CD4 cells locally release cytokines into tissue leading to redness and duration. LIVER REACTION TO INJURY1- Stable tissue in Go phase enters cell cycle - Regeneration of hepatocytes Persistent injury causes regenerative nodules to form cirrhosis 2- Scar tissue formation in alcoholics, an acetaldehyde-protein complex stimulates Ito cells (normally stores retinoic acid) to synthesize collagen. CARDIAC MUSCLE REACTION TO INJURYPermanent tissue, hence it is replaced by non-contractile scar tissue KIDNEY REACTION TO INJURY1. Stable tissue enters cell cycle A. Renal cortex responds better to injury than medulla: receives 90% of the blood versus only 10% in the medulla B. Renal tubular cells regenerate only if the basement membrane is intact: Reason why nephrotoxic damage is more likely to recover than ischemic damage In ischemic damage there is disruption of the basement membrane 2. Thick ascending limb - Most susceptible part of nephron for hypoxia, where the Na/K/2Cl cotransport pump is located. LUNG REACTION TO INJURY 1. Replaces damaged type I pneumocytes 2. Synthesizes Surfactant- Lowers surface tension to keep airways open on expiration Surfactant is present in lamellar bodies 3. Other names for surfactant- Lecithin Phosphatidyl choline Phosphatidyl glycerol CENTRAL NERVOUS SYSTEM REACTION TO INJURY1. ASTROCYTE is analogous to the fibroblasts except it does not produce collagen 2. CNS Astrocyte response to injury is called Gliosis Gliosis is primarily a proliferation of Astrocytes Protoplasmic processes offer some structural support Microglial cells (macrophage) are scavenger cells in the repair process PERIPHERAL NERVE REACTION TO INJURY:Undergoes WALLERIAN DEGENERATION Distal degeneration of axon and myelin sheath and proximal degeneration up to the nearest internode Macrophages/SCHAWNN cells phagocytose axonal/myelin debris Muscle undergoes Atrophy in aprox 15 days Nerve cell body undergoes central chromatolysis- * swells * Nissl substance disappears centrally * nucleus peripheralized Schawnn cells proliferate and enlarge in distal stump Axonal sprouts develop in proximal stump and extend distally using Schawnn cells for guidance Regenerated axon grows 2-3 mm/day Axon becomes remyelinated Muscle eventually reinnervated ERYTHROCYTE SEDIMENTATION RATE:1. Measure of rate of settling of RBCs in a vertical tube in mm/hr 2. RBC and plasma factors are responsible for ESR A. Aggregation of RBCs increases settling: Agglutination (clumping) of RBCs is due to increased IgM (e.g., cold agglutinins) or cold reacting globulins called cryoglobulins. Rouleaux (stack of coins) is due to increase in Fibrinogen and/or gamma Globulins. B. Abnormally shaped RBCs (e.g., sickle cells) do not settle or too many RBCs (e.g., polycythemia) interferes with settling. C. Anemia enhances settling 3. ESR Increased Acute/chronic inflammation Monoclonal gammapathies: - e.g. multiple myeloma - Waldenstroms macroglobulinemia Anemia 4. Low ESR - Sickle cell anemia Polycythemia LAB FINDINGS IN ACUTE BACTERIAL INFECTIONS:1. Absolute Neutrophilic leukocytosis 2. left shift > 10% band neutrophils presence of any neutrophil less mature than a band (e.g. metamyelocyte or myelocyte) 3. Toxic granulation prominence of azurophilic granules containing myeloperoxidase (MPO) End of chapter
|
hope u will put more