LAMP 4177 Lecture Notes PDF

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LAMP 4177 Notes - Unit 3...

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LAMP 4177 Lecture 1 Notes: Introduction to Pathology  Disease: any structural or function issue with the body  Symptoms of disease are things that the patient experiences  Signs of a disease: aspects of disease witnessed by outside observer – found during physical exam  Laboratory findings – blood work, etc.  Findings are the diagnosis  Etiology: studies the causes of disease  Pathogenesis: branch of pathology that looks at the mechanism involved in the development of a disease state o Where most of the research in pathology occur  Morphologic changes: the branch of pathology where people look at the differences of morphology to define a disease process  Clinical significance: looks at the expression of the disease states  Experimental pathology: research  Academic pathology: research and teaching responsibilities (sometimes have clinical responsibilities)  Anatomic pathology: study tissues, biopsies, perform autopsies  Clinical pathology: oversee various labs in the hospital  Cells are the basic functional units of life (when we are talking about the disease state we are talking about sick cells)  Normal cell, adapted cell (reversible – will revert to normal)  irreversible cell injury, cell death  Hypoxia: cellular lack of oxygen o Loss of blood supply to an organ (atherosclerosis and thrombi) o Inadequate oxygenation of blood (cardio respiratory failure) o Loss of oxygen-carrying capacity of blood (anemia or carbon monoxide poisoning)  Physical agents: o Trauma o Temperature extremes o Radiation o Changes in atmospheric pressure o Electric shock  Chemical agents and drugs: a huge amount can cause disease states o Glucose (high concentrations) o Cyanide (trace amounts) o Cytoxan (anticancer drug)  Infectious agents: o Bacteria o Fungi

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o Viruses o Parasites Immunologic reactions: o Hypersensitivity reaction to a foreign substance (ex. Bee sting) o Hypersensitivity reaction to the body’s own components (autoimmune diseases) Genetic derangements: o Chromosomal aberrations (down’s) o Gene mutations (sickle cell) o Multifactorial (diabetes) Nutritional imbalances: o Excess: lipids-atherosclerosis and obesity o Deficiency: protein-calorie and vitamin Mechanisms of Cellular Adaptation: o Atrophy: decrease in cell size  Can occur in normal life (physiological atrophy)  Pathological/abnormal atrophy  Inadequate nutrition  Disuse  Pressure  Denervation  Lack of endocrine stimulation o Hypertrophy: increase in size  Ex: increase in heart muscle size with untreated hypertension o Hyperplasia: increased growth  Capacity for hyperplastic growth  High o Epidermis o GI epithelium o Hepatocytes o Fibroblasts o BM cells  Intermediate o Bone o Cartilage o Smooth muscles  Nil o Nerve o Skeletal muscle o Cardiac muscle  (normal) physiological hyperplasia

o hormonal: breast at puberty and pregnancy o compensatory: liver after partial hepatectomy, skin following abrasion, endometrium following menses  (abnormal) pathological hyperplasia o endometrium: excess estrogen leads to abnormal bleeding o Metaplasia: one adult cell type of replaced by another  The metaplastic tissue is more protective, but often loses the function of the issue it has replaced Cell Injury  Intracellular Systems Vulnerable to Injury o Maintenance of cell membranes o Aerobic respiration o Synthesis of enzymatic & structural proteins o Preservation of the integrity of the genetic apparatus  Mechanisms of injury o Ischemic and hypoxic o Free radicals: molecules that have an unpaired electron in their outer radius o Chemical injury Pathology/Cellular Injury, Adaptation and Necrosis  Necrosis: the sum of the morphologic changes that follow cell death in a living tissue or organ o Coagulation of proteins o Autolysis: dead cell releases own digestive enzymes o Heterolysis: white blood cells recruited into dead tissues and release digestive enzymes o Phagocytosis: white blood cells digesting and engulfing material o Calcification: deposits of calcium salts

o Types of Necrosis o Apoptosis: distinctive form of cell death resulting from activated enzymes that degrade the cell’s own nuclear DNA and nuclear cytoplasmic proteins  Cell death in tumors  Tissues that lose hormone stimulation  Pancreas after duct obstruction  Cell injury in certain viral diseases  Cell death by a variety of injurious stimuli (ex. Anti-cancer drugs) LAMP 4177 Lecture 2 Notes: Circulatory Diseases  Circulation basics o Delivers oxygen and nutrients to cells and tissues o Maintains fluid homeostasis o Disorders are abnormalities in blood supply or fluid balance o 60% of lean body mass is water  2/3 of that is within (inside) cells  5% is blood plasma  the rest is interstitial fluid bathing the cells  intermediary between vascular compartment and intracellular compartment (outside of circulatory system and cells) o hydrostatic pressure=blood pressure  pumping of left ventricle at the arterial end of the capillary  blood pressure increase  blood pressure = cardiac output times vascular resistance  cardiac output determined by blood volume and heart rate

 vascular resistance governed primarily by the size of the peripheral arterioles o arterioles dilate = lowered resistance, lowered blood pressure o arterioles constrict = higher resistance, higher blood pressure o osmotic pressure=oncotic pressure  the pressure exerted by the tendency of water to move to a compartment of higher dissolved solutes  dissolved proteins  dissolved ions (Na+, K+)  most important is plasma albumin  venous end of the capillary  pressure exerted by dissolved solutes in the plasma  drives solutes and waste back into the compartment  blood pressure decrease o fluid exchange happens at the capillary level  imbalances in this process leads to disease states  Circulatory disorders o Edema: (non-inflammatory)  Abnormal shift of water from the vascular space into another compartment  Interstitial space o Local or generalized  Body cavities  Decreased plasma osmotic pressure OR increased intravascular hydrostatic pressure (elevated BP) can cause water to escape from the interstitial space or into a body compartment causing edema formation  Overwhelmed lymphatic system leads to edema  Can be a sign of congestive heart failure

 Can also be a sign of venous obstruction or compression  Anasarca: full body edema  Other causes of edema:  Sodium/water retention o Increased osmotic pressure leads to fluid retention in the vascular space and increased hydrostatic pressure o Renal insufficiency/failure o Increased renin-angiotensin-aldosterone activity  Blocking lymphatic channels (lymphedema) o Hyperemia: localized increase in blood volume to a specific area  Active process that results from dilation of arterioles (body does this process on purpose)  Serves some physiological purpose o Congestion: blood volume increased to an organ or region due to impaired venous flow  Passive process, pathological state  Clinical sign that something has gone wrong in the circulatory system o Hemorrhage: extravasation of blood due to vessel rupture  Can be tiny and insignificant, or large and life threatening  Depends on volume and rate of blood loss  Exsanguination  Trauma  Surgical complications  Rapid loss of 1/3 of blood volume results in shock  Rapid loss of more than ½ of blood volume results in death  Accumulations of blood in a body cavity  Hemothorax (plural cavity), hemoperitoneum (abdominal cavity), hemopericardium (heart), hemoarthrosis (joint)  Hematoma: space-occupying collection of blood in the tissue  Consequences range from ugly/annoying to death depending on location (under skin-inconsequential, brain-fatal)  Contusion: local traumatic rupture of skin vessels  Petechiae (tiny hemorrhages 1-2mm) and purpura (larger than 2mm): from clotting disorder, severe infection, diffuse capillary reaction from trauma o Can be a sign of underlying disease

 Thrombosis: inappropriate activation or over-reaction of normal hemostatic processes, coagulation in normal vessel, thrombotic occlusion of vessel in response to minor injury o Hemostasis vs. thrombosis:  Hemostasis: maintains blood in a fluid, clot-free state in normal vessels  Produces a rapid response to vascular injury by forming a hemostatic plug  Not pathologic – thrombosis is o Normal hemostasis  Initiated by injury to the vascular endothelium (innermost vascular wall)  Platelet plug  Exposure of tissue factor  Initiation of coagulation cascade  Permanent plug of cross-linked fibers (polymer that aggregates to form a solid hemostatic plug at the site of injury to stop further blood loss)  Coagulation cascade because each enzyme activates the next enzyme in the chain ending in fibrin cross-linked clot at the end (which forms the clot)  Counter-regulation: antithrombotic pathways (anti-coagulation)  Antithrombin  Protein C and protein S  Plasminogen o Thrombus forms when anticoagulation methods fail (thrombus formation):  Dysregulation of normal hemostasis  Virchow’s triad required to form a thrombus  Endothelial injury (direct trauma to vessel, inflammation, cigarette smoking, high cholesterol)  Abnormal local blood flow (stasis or turbulence) o Blood floor is normally laminar with fluid plasma & platelets in the outer flow with fluid and cells in the center o Stasis: prolonged immobility, permanent immobility  Hypercoagulability o Inherited causes:  Factor V Leiden mutation  Mutations of anti-coagulants  Antithrombin III

 Protein C or Protein S o Acquired conditions:  High estrogen states – oral contraceptives, pregnancy  Liver disease  Anti-phospholipid antibody syndrome in lupus  Cancer (pancreatic most common)  Fate of a thrombus  Resolve completely  Grow and occlude the vessel o Completely organize and form new channels through it  Embolization o Thrombus breaks off and travels through the venous system and lodges in the next smallest place  Smaller thrombus may organize and be incorporated into the wall  Embolism: intravascular object that travels in the bloodstream from one location to another – may occlude circulation to the area where it eventually lodges o May cause infarction – death of tissue due to lack of blood flow o Thromboemboli: thrombi within veins or arteries that may break off and travel through the circulation until they lodge somewhere  Pulmonary thromboemboli: thrombus from extremity (usually lower extremity or pelvis) and travels to lungs and lodges in the main pulmonary artery  Results in sudden death  Infarction: area of ischemic necrosis, death of tissue o Major complication of thrombi and emboli o Caused by arterial occlusion or lack of venous flow o 50% of infarcts are in brain or heart o development is infarct is influenced by organ’s vascular supply, rate at which the vascular occlusion develops, and vulnerability of organ to hypoxia o heart muscle and neurons are more vulnerable to infarcts than other organs o infarcts over time cause the organ to function differently/at a lower level  Shock: circulatory collapse with systemic hypoperfusion o Low blood pressure (below 70 systolic)

o Caused by decreased cardiac output or dramatically decreased effective circulating blood volume o Three main categories of shock:  Cardiogenic: heart failure (pump failure)  Hypovolemic: hemorrhage, dehydration, severe burns  Results in low blood volume  Septic: overwhelming infection, toxin-mediated  Loss of effective blood volume caused by widespread hypotension o Other categories of shock  neurogenic shock: loss of vascular tone from central nervous system injury  anaphylactic shock from severe allergic reactions  hemorrhagic shock: subcategory of hypovolemic shock  results specifically from rapid, large-volume blood loss (internal or external) o usually caused by injury or rupture of a blood vessel like trauma, aneurysm rupture, surgical complication OR due to clotting defects like hemophilia, platelet disorders or medications o progressive disorder that will lead to death if left unchecked o there are “stages” of shock  non-progressive stage: the body is still able to compensate for the changes that are going on  tachycardia (increased heart rate)  vasoconstriction to increase vascular resistance and restore BP  compensatory mechanisms are activated and working  progressive stage: consequences of hypoperfusion and hypoxia start to take hold  compensatory mechanisms start to fail  tissue hypoxia begins  vital organs begin to fail  metabolism shifts to anaerobic cycle because oxygen is not being delivered to the tissues (producing lactic acidosis to vasodilation to blood pooling to further hypoxia – vicious cycle)  irreversible stage  compounded metabolic pathology due to cycles of progressive stage  multi-organ failure  death

o mortality rate of cardiogenic and septic shock: 75% o survival rate of hypovolemic shock: 80-90% LAMP 4177 Lecture 3: Inflammation I  Inflammation: reaction of vascularized living tissue to local injury o Reaction of tissues to injury, characterized clinically by heat, swelling , redness, pain, and loss of function; pathologically by vasoconstriction followed by vasodilation, stasis, hyperemia, accumulation of leukocytes, exudation of fluid, and deposition of fibrin; and according to some authorities, the processes of repair, the production of new capillaries and fibroblasts, organization, and cicatrization o Response to injury  Acute inflammatory process followed by a chronic inflammatory process which ends in one of two ways  Resolution: the body of the tissue that has been damaged goes back to normal (more frequent)  Repair: scarring  Exceptions – skip chronic inflammation: o Resolution after acute inflammatory response o Repair after acute inflammatory response o Stereotypical  There are many different injuries but the response is almost always the same o Exquisitely balanced  Pro- and anti- inflammatory forces in our body  Balance between the two that will also your body to go back to normal or scarring after injury o –itis is going to refer to an inflammatory process  Appendicitis, cellulitis, meningitis, pneumonitis, nephritis, myocarditis o There are varied etiologies for inflammatory response (microbial infections: pneumonia, skin infections, etc., physical agents: burns, trauma-like cuts, radiation., chemicals: toxins and caustic substances., others: immunologic acid) or injuries but all lead to the stereotypical response of an acute inflammatory response o Four signs of inflammation (described by Celsus – 1AD):  Rubor – redness  Tumor – swelling  Calor – heat  Dolor – pain

 Virchow (19th century) added a 5th – loss of function o Distinguish between acute and chronic inflammation two ways  Time course  Acute: less than 48 hours  Chronic: greater than 48 hours (weeks, months, years)  Cell type  Acute: polymorphonuclear leukocyte (PMN) – these cells get to the site of injury quicker  Chronic: mononuclear cells (macrophages, lymphocytes, plasma cells) – these cells are slower in moving to the site of injury o Acute inflammation:  Defined by PMNs on the microscope (serving as mediators)  Defined in the clinic as changes which take place usually within the first few minutes to several hours to days after an injury (48 hours)  Can be defined by three key physiological events (what is happening in the body when the tissue has incurred some sort of damage) and the stereotypical processes that bring the body back to normal (or to repair):  Changes in vascular flow and caliber (hemodynamic changes) o Vasoconstriction  Transient and inconstant event o Vasodilatation  First the arterioles (lined by smooth muscle, which allows them to dilate), then the capillaries (passive conduit through which blood flows)  Get peripheral blood that is outside the vasculature system to the point of injury (makes sense to increase the amount of blood that’s flowing) o Slowing of circulation  Outpouring of albumin rich fluid into the extravascular tissues results in the concentration of RBCs in small vessels and increased viscosity of blood o Leukocyte marginalization  PMNs become oriented at the periphery (inside margins) of blood vessels and start to stick

 Changes in vascular permeability (vascular leakage) o Starling’s hypothesis  Intravascular hydrostatic pressure is about the same as colloid osmotic pressure (in normal tissue)  Hydrostatic pressure: pressure being exerted from one end to another (closed) end  Osmotic pressure: pressure moving from where there is less solute (albumin) to more solute  Excess fluid is picked up by lymphatics  Responsible for draining of edema (excess of fluid in the interstitial tissue or serous cavities – either a transudate or an exudate) o Transudate: an ultrafiltrate of blood plasma  Permeability of endothelium is usually normal  Low protein content (mostly albumin)  Specific gravity less than 1.012 o Exudate: a filtrate of blood plasma mixed with inflammatory and cellular debris  Permeability of endothelium is usually altered  High protein content  Specific gravity greater than 1.020  In inflamed tissue the hydrostatic pressure on both the venule and arteriole side significantly increases and the colloid osmotic pressure decreases on both sides  Efflux of fluid from inside vessel to outside the vessel o loss of albumin-rich fluid

 packed red blood cells

 Leukocyte exudation o Four steps  Margination, rolling, adhesion  Diapedesis (transmigration (of PMNs) across/through the endothelium)  Migration toward a chemotactic stimulus  Phagocytosis (bacteria eaten by PMN or microphages) – three steps  Recognition and attachment o Fc and C3 antibodies allow the cells to attach to any bacteria  Engulfment o Using pseudopods  Killing or degradation o Lysosomes filled with lysozymes (deadly)  Lysosome combines with phagosome (body which has taken in bacteria) to create phagolysosome which then releases lysozymes o 2 mechanisms  oxygen dependent: (myeloperoxidase dependent – the most important, myeloperoxidase independent) – myeloperoxidase is the most common lysozyme

 oxygen independent  defects in leukocyte function o margination and adhesion  etoh (alcohol), steroids, autosomal recessive (AR) leukocyte adhesion deficiency o emigration toward a chemotactic stimulus  drugs  chemotaxis inhibitors o phagocytosis  chronic granulomatous disease (CGD) o Abnormality in PMN leads to pathology/disease  Major players are PMNs and microphages (allow the body to go down one of the two phases)  Bring chemical mediators that are embedded within cells  Want to bring cells of interest to point of injury (stereotypical response)  How does white blood cell (PMN in acute inflammation) get from where it normally resides to the point of injury o How are the PMNs mobilized? LAMP 4177 Lecture 4 Notes: Inflammation II

 Chemical mediators of inflammations o Vasoactive amines (histamine and serotonin)  Plasma proteases  Kinin system  Complement system  Coagulation-fibrinolytic o Arachidonic acid metabolites  Via cyclooxygenase  Via lipoxygenase o Platelet activating factor (PAF) o Cytokines (IL-1, TNF, IL-8, IL-12) o Nitric oxide (vasodilator, cytotoxin) o Lysosomal constituents of leukocytes o Oxygen derived free radicals o Vasodilation (vascular flow/caliber; hemodynamic changes)  Prostaglandins, nitric oxide o Increased vascular permeability (vascular leakage)  Vasoactive amines (histamine, serotonin)  C3a and C5a (through liberating amines)  Bradykinin  Leukotrienes C4, D4, E4 o Fever  IL-1, IL-6, TNF  Prostaglandins o Pain  Prostaglandins  Bradykinin o These systems are all interrelated o There seems to be a very good system of checks and balances  Abscess formation  Stedman’s dictionary: a circumscribed collection of pus appearing in an acute or chronic localized infection, and associated with tissue destruction, and frequently swelling o Usually the result of a pyogenic organism – pus forming organism (ex. Staph) o Abscesses are usually chronic but always have PMN presence  Chronic inflammation: o Time course greater than 48 hours o Mononuclear cel...