Cell injury and death
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| Pathology | Study of disease, focusing on physiological, gorss and microscopic changes reacting to injury
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| Categories of disease | Inflammation, neoplasia, hemodynamic/vascualar, environmental /nutritional, genetic/developmental, infectious and immunologic (both often categorized as susets of inflammation), and endocrine/metabolic
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| Idiopathic | unknown ideology
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| iatrogenic | provider induced (a result of medical treatment)
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| pathogenesis | the mechanism by which diseases develop
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| sign | objective evidence, something that you can measure as opposed to subjective experience (symptoms)
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| pathognomonic | a sign, symptom or characteristic of a disease that leads to accurate diagnosis.
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| prognosis | reasonable predictions about the course of a disease or process taking into account the natural history, and the expected effects of therapy and particualr factors specific for the individual case
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| parenchyma | the functional elements of an organ
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| stroma | the framework or support element of an organ
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| What does disease result from? | cumulative effects of injury to individual cells
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| different cells... | -respond differently to stress-have different consequences of cell injury
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| Are cells static? | no. they msut be able to adapt to their environment
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| Deficiency | lack of necesary substance. -nutritional-inability to absorb nutrients-genetic defect leading to inadequate production or regulation
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| Intoxication | Presence of substance that interferes with cell function that can be endogenous or exogenous
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| Endogenous intoxication | due to genetic defect or accumulation of metabolite due to poor circulation.
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| Exogenous intoxication | due to infectious agents, chemcials or drugs
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| Trauma | loss of structural integrity-hypothermia-hyperthermia (causes denaturation of proteins)-mechanical pressure-infections (cause cell rupture or lysis)
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| Oxygen deprivation | This is an example of deficiency and occurs by two different processes-Hypoxia= the state of tissue or cell oxygen deficiency-Ischemia= oxygen deprivation due to lack of blood flow
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| Are all hypoxic cells ischemic? | No, but all ischemic cells are hypoxic.
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| Anaerobic glycolysis | The process by which cells generate 2ATP and 2 lactate without oxygen.
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| Oxidative Phosphorylation | The process by which (when combined with glycolysis) cells generate 36 ATP, 6 CO2 and 6 H2O from glucose and 6 O2. Makes much more energy that glycolysis alone due to presence of oxygen!
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| What happens if there is not enough O2? | -metabolism switches to anaerobic glycolysis-if due to ischemia, toxic buildup of waste products-consume energy reserves-Lactic acid and inorganic phosphates build up, decreasing pH
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| What cellular processes are affected first due to hypoxia | When there is no oxygen, we are not generating as much ATP, without which cells cannot generate concentration gradients. -Na+ increases inside the cell and water follows, causing swelling.
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| Why cells swell during ischemia | Na+/K+ ATPase is needed to prevent Na+ levels from rising inside the cell. Without ATP, pump is off and Na+ come in. Tissue osmolality increases due to catabolism within ischemic cells and water flows in passively.
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| Hydropic change | Tubules swell, lumen diameter decreases.
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| Fatty Change | lipids accumulate, especially in hepatocytes.Causes:-impaired lipoprotein synthesis -decreased fatty acid oxidation due to hypoxia-increased liberation of fat from peripheral stores due to starvation
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| Hepatocytes and fatty change | Normal: Liver recieves free fatty acids, packages them in the cytoplasm and sends them to the rest of the body. If damaged, we can't make liver proteins and thus can't package and export fats out of the liver, so they build up there.
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| Changes that occur with cell injury | -Chromatin Clumps in the nucleus-mitochondria swell-lysosomes eat cellular components (autophagy)-Intrmembranous particles aggregate-Endoplasmic reticulum swells and ribosomes disperse-Cell membrane develops blebs-generalized swelling occurs
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| What are the manifestations of cells injury | 1. Acute cessation of specialized function2. Impairment of function even after removal of noxious stimulus3. loss of ability to replicate (can be irreversible)
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| What happens during radiation | generates free radicals that damage cell membranes and DNA.Low doses affect RBC and WBC production. Medium doses prevent cell repilcation in the intestine. Large doses kill neurons in the brain, usually causing death within 24 hours.
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| Morphological resonse to non-lethal cell injury | atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia, intracellular storage
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| Atrophy | decrease in size and often function of cells. Generally associated with decrease in size and/or function of a tissue or organ
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| Causes of atrophy | -disuse (voluntary or due to nerve damage)-decreased blood supply-inadequate nutrition-loss of endocrine stimultion-loss of growth factors
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| Hypertrophy | Increase in size of cells due to an increase in the amount of protein and organelles. Resutls in an increase in the size of the tissue or organ.
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| Causes of hypertrophy | -mechanical stimulus (cardiac and skeletal mucle)-growth factor stimulation (pregnancy: uterus, puberty)-INcreased functional demand (ie increased kidney size after donating the other)
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| Hyperplasia | increase in the number of cells in an organ or tissue. This often results in an increase in the size of the tissue or organ.
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| causes of hyperplasia | -Growth factor stimulation, either due to stress or changes in endocrine function. -Viral-induced (warts)
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| Examples of hyperplasia due to growth factor stimulation | -endometrial proliferation during the menstrual cycle-callus formation during bone healing-erythroid hyperplasia due to chronic hypoxia (ie high altitude)
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| Metaplasia | Replacement of one differentiated cell type with another. Usually caused by chronic irritation
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| Examples of metaplasia | -respiratory tract metaplasia in smokers-cervical metaplasia in sexually active women-esophageal metaplasia in people with acid reflux, GERD
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| dysplasia | abnormal or diorderly growth recognized by a change in size, shape and/or organization of cells within a tissue. Can be a precursor to cancer
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| Intracellular storage | Lipid acumulation in hepatocytes, anthracotic pigment in alveolar macrophages, and lipofuscin in highly active cells
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| hemochromatosis | most comon genetic disease in the US, caused by increased absorption of iron which builds up in the tissues and damages the liver.
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| Can cells be permanently injured without affecting their viability? | Yes. Foe example, radiation can prevent cells from dividing without killing them. This results in a lag between cell injury and organ dysfunction.
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| necrosis | a morphological expression of cell death that is generally initiated by overwhleming stress. Characterized by progressive disintegration of cellular structure. Generally elicits acute inflammatory cell response.
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| Apoptosis | Programmed cell death that is controlled by specific genes causing fragmentation of DNA and thus the nucleus. Also causes bleb formation and release of apoptotic bodies, which are phagocytized. NO INFLAMMATION.
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| COnsequences of necrosis | loss of functional tissue, imparied organ function which can be transient or permanent
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| consequences of apoptosis | not neccesarily any. Result is removal of damaged or uneccesary cells.
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| Apoptotic remodeling of tissue | Dead cell releases connection with neighbors, shrivels and remnants are eaten by surrounding cells. These cells grow bigger
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| Physiological states where apoptosis may be important | Embryogenesis and withdrawl of trophic hormones
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| Examples of withdrawl of tropiv hormones affecting apoptosis | Prostate glandualr epithelium after castration. regression of lactating breast after weaning. Withdrawl of interleukin-2 results in apoptosis of T lympohcytes to remove unecesary T cells.
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| Pathological state where apoptosis may be important | ionizing radiation, free radical presence, miold thermal injury, glucocorticoids (in lympohcytes), viral infection, cell-mediated immunity, automimmune diseases, neoplasia and degenrative CNS diseases.
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| Neoplasia | Apoptosis may be an important mechanism for elimnating cells with genetic defects. Inhibition of apoptosis may contribute to a prolonged life span of malignant cells
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| N vs. A: cells affected | A: scattered individual cells. N: large contiguous areas of cells
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| N vs. A: control of intracellular environment | A: maintained in early stges. N: Lost early
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| N vs. A: cell morphology | A: cells contract. N: cells and their organelles swell
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| N vs. A: chromatin | A: marginates and condenses, becoming very compact. N: marginates early while injury is reversible.
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| N vs. A: DNA | A: fragmentation occurs with chromatin condensation and results in 200bp units (ladder pattern in gels). N: cleavage occurs later and fragments are of random size (smear pattern in gels)
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| N vs. A: cell membrane | A: Blebs form and apoptotic bodis containing nuclear fragments are shed. N: CM ruptures as terminal even and cell contents are released (chemotactic)
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| N vs. A: neutrophils and chemotactic factors | A: Phagocytosis of intact apoptotic bodies occurs and there NO chemotactic factors generated. N: When cell contents are released, chemotactic factors lead to neutrophil infiltration to degrade dead cells
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| Regulation of apoptosis | Stimulating and preventing factors balance. P53 upregulates baxm which is a stimulting factor for apoptosis. Bcl-2 is a regulating factor, so when there is more, cells acumulate.
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| Fate of a cell under attack | 1. Noxious agent damages cell. 2. A still viable cell has an influx of sodium and water: Swelling 3. Cell undergoes necrosis=death. 4. Calcification OR autolysis->replacement->regeneration or fibrosis
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| Different types of necrosis | Coagulative, liquefactive, fat, caseous or fibrinoid
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| Coagulative necrosis | -progressive loss of structure, cell constituents coagulate and persist until inflammatory cells degrade them. Similar to autolysis=self-digestion, which happens with blood or Oxygen deprivation. This doens't recquire inflammatory cells
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| What happens in the cell during coagulative necrosis? | cytoplasm becomes more eosinophilic (more red), and nuclear change (pyknosis, karyorrhexis or karyolysis) occurs.
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| pyknosis | nucleus shrinks and chromatin condenses. Nucleus becomes basophilic (very dark blue with H&E stain)
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| karyorrhexis | nucleus breaks into small peices
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| karyolysis | nucleus becomes progressively paler staining and eventually disappears
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| Liquefactive necrosis | characterized by dissolution of necrotic cells. Seen in abcess lots of neutrophils that release enzymes to break down dead cells). Forms Pus=liquefied remnants of dead cells and neutrophils
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| Fat necrosis | Results from the release of lipases into adipose tissue, often in pancreatic injury Triglycerides are cleaved into fatty acids, which bind and precipitate calcium ions and form insoluble salts. Look chalky white grossly, basophilic when stained blue w/H&E
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| Casseous necrosis | Occurs w/granulomatous inflammation in response to microorganisms like TB. Host response=chronic inflammation, formation of a granuloma w/a cheesy center.
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| Fibrinoid necrosis | Occurs in the walls of arteries in cases of vasculitis. Inflammation of blood vessels causes damage to the endothelium and necrosis of smooth muscle cells: deposition of plasma proteins (fibrin) occurs in the area.
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| Infarction | cell death and coagulative necrosis due to prolonged ischemia. Renal and splenic infarcts are wedge-shaped, liver infarcts have centrilobular necrosis around the central vein.
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| Early Histologic changes in infarcts | Cytoplasm is hyper-eosinophilic, karyolysis is complete around 2 days, and acute inflammatory cell infiltration begins aroudn 12 hours after coronary occlusion and peaks at 2-3 days.
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| Late Histological changes in infarcts | Karyorrhectic debris from neutrophils becomes prominent @3-4 dyas, neutrophil infiltration abates by day 5. New capillary sprouting occurs around day 5 and phagocytosis of dead myocytes begins at teh periphery at day 5.
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| Healing phase of infarction | New capillaries sprout, fibroblasts proliferate and make collagen and dead myocytes are replaced with mature scar tissue.
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| What are the earliest changes in cardiac infarction | contraction bands
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| Other manifestations of ischemic injury | Release of creatine kinase, LDH, transaminases and other enzymes. Releae of special proteins by the heart. Arrhythmias. Permanent ECG changes. Heart failure related to infarct size. Tissue rupture, aneurism and mural thrombi.
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| How do we identify and monitor cell injury? | Oxygen, mobility and bilirubin (functional loss). Release of cell consituents such as K+ from RBC's, troponin or CPK from the heart. Change in electrical activty (EKG, EEG, EMG). Direct examination of the tissue
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