Chapter 8 FLUID AND ELECTROLYTES What are the Functional Fluid components of the Body? 1. Intracellular fluid: - Fluid contained within all cells of the body 2. Extracellular fluid: - Contains fluid outside the cells (interstitial fluid, plasma, transcellular) How does water move through the ICF and ECF? 1. Hydrostatic Pressure: - Arterial end of blood vessel pushes nutrient rich fluid (oxygen and minerals) out of vessel into interstitial space so it can absorbed by the cells 2. Colloidal Osmotic Pressure: - Venous end of the blood vessel pulls nutrient poor fluid (deoxy blood) back into capillaries to be sent back to lungs to be re-oxygenated. - Albumin helps maintain fluid balance on venous end → Not enough albumin in venous end can lead to fluid imbalance and edema ● Paracentesis: needle pulls out excess fluid build up due to ascites (fluid buildup in abdomen) → albumin may be administered thru IV 3. Filtration: - Endothelial cells are porous and permeable to small molecules → not usually permeable to albumin unless something is damaged or an infection is present What is edema and how is edema caused? Edema is the buildup of fluid in the interstitial space, leading to swelling. Fluid that is filtered out at the arterial end is reabsorbed at the venous end, if this doesn’t take place, edema can occur. 1. Increased capillary hydrostatic pressure: - Capillary hydrostatic pressure rises due to 1. Increased vascular volume, (heart failure, kidney disease, pregnancy) 2. Venous obstruction (venous thrombosis, liver disease with portal vein obstruction) 3. Decreased arteriolar resistance (calcium channel blocking drugs) → can lead to dependent edema (edema at ankles and feet) due to gravity 2. Decreased capillary osmotic pressure: - Capillary osmotic pressure decreases due to 1. Increased loss of plasma proteins (extensive burns, protein losing kidney diseases) 2. Decreased production of plasma proteins (liver disease, starvation/malnutrition) → low levels of albumin in venous end can prevent fluids (water) from being absorbed from interstitial space, leading to edema. 3. Increase capillary permeability: - Capillary walls become enlarged due to damage or infection leading to excessive permeability. → Plasma proteins leak into interstitial space, followed by fluids, leading to edema. 4. Lymphatic obstruction: - Leftover fluids not absorbed from interstitial space by venous end of blood vessels are absorbed by lymphatic vessels. → Obstruction of lymph nodes, or removal of lymph nodes can prevent that leftover fluid from being absorbed, leading to lymphedema. What are the Clinical Manifestations of Edema? - Weight gain, swelling and puffiness, tight fitting clothes and shoes, limited movement of affected joints. What is Osmolality? What are the three solution types? Describes concentration of electrolytes in fluid 1. Isotonic solutions: contain the same osmolality as the intracellular fluid. → Do not shrink or swell the cell. 2. Hypotonic solutions: ICF has higher concentration of solutes than the solution does. → Leads to swelling of the cell as fluid flows into the cell. 3. Hypertonic solutions: ICF has lower concentration of solutes than the solution does → Leads to shrinking of the cell as fluid flows out of the cell. What is Fluid Volume Excess? What can it lead to? Excessive fluid in the extracellular space. → Overhydration (too much fluid going in with failure to eliminate) - Clinical manifestations: rapid weight gain, bounding peripheral pulses, warm extremities, peripheral pitting edema, pulmonary edema, high central venous pressure, tachycardia, changes in LOC, confusion, headache. What is Fluid Volume Deficit? What can it lead to? (SCCPLHB) Fluid intake is less than output, leading to fluid deficit → Dehydration - Clinical manifestations: 1. Moderate: flushed dry skin, dry mucous membranes, skin tenting, concentrated urine, thirst 2. Severe: cold, clammy skin, sunken eyeballs, postural hypotension (standing up from laying down and BP drops), dry cracked tongue, lethargy, increased HR/decreased BP What are acids and bases? What is pH? Acids: molecules that can release an H+ ion when dissolved in water Bases: molecules that bind to H+ ions when dissolved in water pH: concentration of H+ ions in a solution What is Acidosis? Excess of H+ ions as a result of: (pH <7.35) - Overproduction of acids that release H+ ions - Under elimination of acids leading to retention of H+ ions → Can lead to imbalance of K+, Ca++ and Na+, these imbalance can result in dysfunctions of 1. 2. 3. 4. Cardiac system Central nervous system Neuromuscular system Respiratory system What is Alkalosis? Excess of base (especially bicarbonate) resulting from: (pH <7.45) - Overproduction of bases that combine with H+ ions - Under elimination of bases, leading to loss of H+ ions as bases combine with them to form new molecules → Can effect K+, Ca++, 1. Central nervous system 2. Cardiovascular system 3. Musculoskeletal system Many symptoms related to hypocalcemia and hypokalemia Serum potassium is decreased as body tries to regain electroneutrality What are the Arterial Blood Gas Ranges (ABGs)? - pH: 7.35 - 7.45 - HCO3: 22-26 - CO2: 35-45 ABG Issues and how is it compensated for? Metabolic acidosis: pH decreases cause HCO3 decreases (EQUAL) → Respiratory system compensates by hyperventilating to breathe off CO2 and decrease acidity of blood Metabolic alkalosis: pH increase cause HCO3 increases (EQUAL) → Respiratory system compensates by slowing breathing to retain CO2 and increase acidity of blood Respiratory acidosis: pH decreases because CO2 increases (OPPOSITE) → Kidneys compensate by conserving HCO3 and releasing H+ ions in urine. Respiratory alkalosis: pH increases because CO2 decreases (OPPOSITE) → Kidneys compensate by releasing H+ Electrolyte Imbalances: HYPOCALCEMIA and HYPERCALCEMIA TABLE HYPERKALEMIA - What leads to it? What does it cause? - Usually caused in acidosis due to the body’s attempt to increase pH by pulling in H+ ions into the cell from extracellular space and pushing out potassium into extracellular space, increasing concentration of K → leads to hyperkalemia. - Other causes: too much intake of potassium, no excretion of K in the urine or feces Hyperkalemia causes: bradycardia and weak pulses, prolongation/widening of QRS complex, tall/peaked T waves, and life-threatening ventricular tachycardia if not corrected. HYPOKALEMIA - What leads to it? What does it cause? (DITCH) - Usually caused in alkalosis due to body’s attempt to decrease pH by pulling in potassium from extracellular fluid into the cell and pushing out H+ ions into extracellular fluid, decreasing concentration of K outside of the cell → leads to hypokalemia - Other causes of Hypokalemia: drugs (laxatives, diuretics → lead to loss of K in urine and stool), Inadequate K intake from food (NPO, anorexia), Too much water intake (dilutes K in blood), Cushing’s syndrome (increases secretion of aldosterone, aldosterone controls - K released in urine), Heavy fluid loss (NJ suction, vomiting, diarrhea) and hypoglycemia due to overactive insulin, insulin also pulls K into the cell. Hypokalemia causes: cardiac arrhythmias (tachycardia, V-Fib, V-tach), lethargy, EKG changes - flattening or inversion of t-waves, increased U wave, prolonged QU interval, ST depression, weak irregular pulse, low BP and HR. Chapter 8 NEOPLASMS What are the characteristics of cancer cells? 1. Anaplasia: loss/lack of cellular differentiation 2. Autonomy: act dependently/OUTSIDE of normal cellular control mechanisms 3. Immortality: cancer cells/mutated DNA, they can survive when they normally should die What are the common cancers in each age group? Young children: Hematopoietic system, nervous system, soft tissues, bone, kidneys - Leukemia, lymphoma, wilms tumor (kidney), gliomas Adolescents: Soft tissues, bones, hematopoietic - Hodgkin lymphoma, gonadal germ cell tumors (testicular and ovarian carcinomas) Adults: Epithelial cells - Lung cancer, breast cancer, colorectal cancers What are the risk factors associated with cancer? 1. Age 2. Obesity - chronic inflammation and hormonal changes 3. Genetics - individual's genetic makeup 4. Heredity - a single gene inherited by family 5. Carcinogens - environmental (radiation), ingested (food, tobacco, pathogens) 6. Oncogenic viruses - HIV (karposis sarcoma), Hep B&C, HPV, EBV Benign vs. Malignant Benign: well differentiated - Will not invade other areas - Tumor is well encapsulated - Still have rapid and quick growth - Growth – can push on other organs, blood vessels cause ischemic blood flow, can press on nerve causing pain and impaired function - Slower division rate than malignant cells but still fast than normal Typically easier to remove surgically Malignant: less differentiated. - Cancer � disorder of cell growth and differentiation - Cells often do not mature normally (differentiate) to do the “job” the tissue is supposed to do. - Cancer cells can avoid apoptosis due to genetic and DNA characteristics leading to an immortal cancer cells Uncontrolled proliferation – very fast mitotic rate What are the Characteristics of Malignant Tumors? 1. Contain cells that do not look like normal adult cells - Do not perform normal functions of the tissue → may secrete signals, enzymes, toxins 2. 3. 4. 5. 6. Grow rapidly - high mitotic rate Lack capsules - sends “legs” into surrounding tissue to infect surrounding tissue Infiltrate, invade, and metastasize (to distant site) using enzymes Can compress and/or destroy the surrounding Angiogenesis - caused by growth factors secreted by abnormal cancer cells, new vessels can supply tumors with oxygen What are the growth properties of Cancer cells versus Normal cells? - Secrete growth factors and/or have receptors - Grow new vessels to supply tumor with blood and oxygen - Lack cell density - dependent or contact inhibition, don't stop growing, invades space of other tissues - Anchorage independence - Decreased anoikis: apoptosis of cells that detach from tissue of origin does not occur - Faulty cell to cell communication - Do not respond to cell signals - Immortal → higher telomerase leads to longer telomeres, telomerase maintains length of telomeres What is the normal cell cycle and how does cancer change that? - Number of cells produced = number of cells that die - Total number of cells in the body remains constant → In cancer, the growth fraction (dividing:resting cells) increases and doubling time decreases - Tumor growth becomes exponential What is Metastasis? What contributes to metastasis? Cells in a primary tumor develop the ability to escape, travel, and survive in the blood/lymph, exit the blood/lymph, and develop a secondary tumor. → Contributing factors: - Cancer cells can attach to platelets to avoid detection, allowing for easier metastasis - Immune system not functioning properly Common sites of metastasis: liver, lungs, bones, brain What are the Cancer Associated Genes? Proto-oncogenes: code for normal cell division proteins - Growth factors, growth factor receptors, transcription factors, cell cycle proteins, apoptosis inhibitors Oncogenes: mutated proto-oncogenes - Insertions, deletions, translocations → increased or activated leading to mutations. Protooncogenes become oncogenes. Tumor suppressor genes: inhibit cell division and induce apoptosis - Mutations inhibit or decrease tumor suppressor genes, causing cancer cells not to undergo apoptosis - P53 tumor suppressor gene: Once activated and mutated, can contribute to the development of cancer What is Oncogenesis? What is the pathway to cancerous cells? Pathogenesis, or the development of cancer. Carcinogen agent → Normal Cell → DNA damage (if cell is unable to repair itself after exposure to carcinogenic agent) → Activation of growth-promoting oncogenes , Inactivation of tumorsuppressor genes (normally stop cell division), Alterations in genes (p53) that control apoptosis (Cancer cells become immortal)→ Unregulated cell differentiation and growth → Malignant neoplasm What are the major mechanisms that take place in oncogenesis? - Defects in DNA repair mechanisms - Disorders in growth factor signaling pathways - Evasion of apoptosis - Development of sustained angiogenesis (new vessel growth) What are the stages of Carcinogenesis? 1. Initiation: Initial mutation occurs (triggered by chemical, physical, biological, viral, environmental, genetic factor) 2. Promotion: Mutated cells are stimulated to divide (grow and proliferate more rapidly) 3. Progression: Tumor cells compete with one another and develop more mutations, which more them more aggressive (lose differentiation (specified role of the body), become autonomous (do not listen to cell signals), can invade other parts of the body (metastasize), become immortal (do not undergo apoptosis due to increase size in telomeres and telomerase enzyme that keeps them from shortening)) What are host and environmental factors that contribute to Oncogenesis? 1. Mendelian inheritance of genes - increases the risk of someone developing cancer - Ex: BRCA-1, BRCA-2, Retinoblastoma genes → Autosomal dominant gene single gene of inheritance 2. Reproductive hormones - Tumors that are endocrine in nature survive off of reproductive hormones - Ex: estrogen (breast and ovarian cancer) and testosterone/androgen (testicular cancer) hormones → Overproduction of these hormones are linked to obesity, thus obesity can increase the risk of cancer 3. Obesity - linked to multiple types of cancer, can induce hormonal changes and chronic inflammation (chronic inflammation is also linked to the development of cancer) - Ex: breast cancer, endometrial cancer, prostate cancer 4. Immune surveillance and tumor antigens - Immunosuppressed hosts (AIDs patients), or immunocompromised hosts may not have an immune system strong enough to detect tumor antigens and attack tumor antigens - Ex: Karposi sarcoma in AIDs patients. T-Cells cannot help recognize the antigens due to their lack in number and suppression 5. Chemical carcinogens (cigarettes, alcohol, diet, occupational hazards) - free radicals form and attack DNA leading to mutations 6. Radiation - ionizing radiation can lead to chromosomal breakage and DNA damage, can lead to translocations, point mutations in chromosomes. 7. Viruses, bacteria → HPV, Hep-B, Epstein-Barr (EBV), HHV-8 Karposi sarcoma What are the Local Effects of Tumor Growth? 1. Compression of adjacent structures - Hollow organs → Ischemia, pain due to tumor growth, may affect their ability to function - Blood vessels → bleeding, hemorrhage - Nerves 2. Effusions → Collection of fluid in a body cavity where it is not supposed to be (third spacing, transcellular space) - Pleural effusion: build up of fluid in the pleural cavity of the lungs, can impair ability of lungs to expand fully Peritoneal effusion: build up of fluid in the peritoneal cavity that surrounds lower abdominal organs, can lead to swelling in the belly. (usually in ovarian cancer and abdominal cancers) What are the Systemic Manifestations of Cancer? Group of manifestations that affect the entire body 1. Anemia - hemoglobin (Normal F: 12, M: 13, Anemia 9-8) and hematocrit (F: levels used to determine severity of anemia → Cancer cells divert oxygen and deprive healthy cells of oxygen which can lead to hypoxia and is accompanied with fatigue - Can be tested by CBC lab. 2. Anorexia and cachexia - Anorexia (loss of appetite), cachexia (wasting syndrome patient loses weight in a small period of time, unintentional weight loss. Involves loss of fat and proteins → tumor cells take a lot of nutrients from normal/healthy cells) 3. Fatigue and sleep disturbances: low energy, sleep disturbances can be caused by metabolic imbalances, pain, anxiety 4. Ectopic hormones and factors secreted by tumor cells (paraneoplastic disorders) - Disorders that occur alongside cancer, not caused directly by cancer. What is Paraneoplastic Syndrome? → Caused specifically because patient has cancer** Cancer cells produce hormones or hormone-like proteins, inappropriate release of hormones - ADH (antidiuretic hormone) SIADH → imbalance of ADH, ADH is in excess. Can lead to effusions (pleural and peritoneal) due to retention of fluid - ACTH (adrenocorticotropic hormone) Cushing’s syndrome → ACTH stimulating hormone for corticosteroids. Cushings leads to metabolic imbalances (hyperglycemia, hypernatremia, hypokalemia), causes body to retain fluid leading to edema and high BP, also suppresses inflammation which can cause delayed wound healing and susceptibility to infections - PTH-related protein (parathyroid hormone) Hypercalcemia → PTH is responsible for balancing blood calcium levels. PTH stimulates bones to release their calcium, when bones release CA, it gets into the serum. - Serum CA+ normal: 9-11 How do cancer cells affect clotting? Cancer cell imbalance causes an excess of procoagulation factors and not enough anticoagulation factors. Risk → Blood clots/DVTs (deep vein thrombosis) → dangerous because they can travel to heart, brain, lungs which can cause heart attacks, ischemic strokes. How is Cancer Diagnosed? 1. Tumor Markers - enzymes or hormones secreted when a patient has abnormality like cancer in the associated organs or glands. Help oncologists decide what treatment to use, stage cancer, evaluate how successful the treatment was→ Cannot be used as a diagnostic by themselves. Why? - Nonspecific for one tissue type (prostate specific antigen) 2. Cytologic studies - view abnormal cells on microscope to see if dysplasia or other abnormalities have occured (pap smear) 3. Tissue biopsy - sample of actual tumor allows for examination under microscope, how quickly cells are dividing, can look at antigens → can confirm cancer (fine needle aspiration) 4. Immunohistochemistry - looking at hormonal receptors on cells for cancer → Cannot be used as diagnostic by themselves. (Estrogen receptor) - Helps determine cancer type (etiology of the cancer) and what type of treatment to use 5. Microarray technology - looks at gene expression. → Not used for diagnosis of cancer but can help. (gene chips) What are the different cancer treatment types? 1. Surgery - Can be used to assist in the effectiveness of other therapies (ex: tumor surgically shrank, may respond better to chemo or radiation) - Sometimes used for complete removal 2. Radiation - Ionizing radiation - Supposed to break the mitochondrial or dna chromosomal bonds to kill the cancer cells - Different routes - Beam therapy – be is concentrated on the solid tissue tumor - Oral types of radiation - Brachytherapy – person has a radiated capsule put into their body cavity (good for abdominal cancers and certain types of brain cancers) - Tons of risks 1. Chemotherapy - Chemical substance/ pharmaceutical agents that interrupts the cell cycle (interferes with cell division at some point) - Usually put in through a port in the chest (central line) (extremely high risk for infection) - Highly toxic to the body – kills normal cells along with cancer cells - Tons of side effects (nausea, vomiting, inflammation, bone marrow suppression which increases the risk for infection, can decrease RBCs and platelets) - Infection due to bone marrow suppression is the most serious and dangerous side effect 2. Hormone and antihormone therapy - Used in adjunct with other therapies - Can assist in the effectiveness of chemo for certain hormone bound cancers - Usually oral - Can increase the production of a hormone or block the production of a hormone 3. Biotherapy - enhances the immune system to fight cancer - Focus on certain biological pathways and function of the cancer cells - Can inhibit angiogenesis making tumors lose blood supply and die - Can help to boost up the immune system to help eradicate cancer that way - Doesn’t target a cancer cell, rather targets the mutation responsible for targeting the immortal cell 4. Targeted therapy - deals with genetic causes of cancer - Ex: philadelphia chromosome → allows telomere caps to remain intact, allowing cancer cells to continue to divide. Drugs turn off genes that allow telomere caps to remain intact, allowing for apoptosis of cancer cells. Side notes: Combination therapy: multiple treatment types used to treat cancer. Helps reduce damage to normal healthy cells, more efficient → increases chance of remission Palliative treatment: treatment may be used as palliative treatment instead of curable treatment, cancer will not go into remission but can prolong life. Comfort care (Hospice): pain control → delivered with understanding treatment is to help with pain levels, nothing done is going to cure cancer. Goes hand in hand with hospice. Curative treatment: treatment with the intention to cure the cancer, go into remission Chapter Nine ACUTE INFLAMMATORY RESPONSE What are the four stages of Acute Inflammation: 1. Recognition: mast cells and macrophages are the first to alert immune system and initiate inflammatory response. —> Bind to pamps and damps, stimulating the release of chemical mediators that induce inflammation (histamines, bradykinin) - Histamines: stimulate vasodilation and permeability of endothelial cells —> Vasodilation: enlargement of blood vessels for increased blood flow to the area (causes redness in tissues and can decrease BP) —> Vascular permeability: allows exudate to seep into interstitial tissues (causes swelling in tissues) - Nitric oxide is released by endothelial cells and histamines that enhances vasodilation and vascular permeability —> allows albumin to extravasate from circulation, causing water to follow which leads to swelling. 2. Recruitment: cytokines are released that attract leukocytes (usually neutrophils) to the area of tissue damage —> this attraction and migration is called chemotaxis - Neutrophils attach to adhesion proteins on endothelial cells and transmigrate (move from circulation to the injured tissue) where they follow a chemical gradient to the direct site of tissue injury - Neutrophils phagocytose pathogens and commit cell suicide once they’ve had their fill. 3. Removal: neutrophils and macrophages phagocytize pathogens and dead/dying cells, making room for new cells. - Complement system is activated due to antibodies that are bound to pathogens. —> Opsonization: mark pathogens for phagocytosis, MAC complex punctures holes in pathogens, leading to cell death, release of cytokines, causing chemotaxis of more leukocytes to area of injured tissue. 4. Repair: WBCs (macrophages) degranulate, releasing growth factors that stimulate angiogenesis (growth of new blood vessels), also attracts fibroblasts, platelets, and other clotting factors that repair tissue using collagen What are the cardinal signs of inflammation? 1. Redness (Caused by vasodilation and increase blood flow to the area of injury) 2. Pain - (Caused by swelling due to vascular permeability of blood vessels. Permeability allows for albumin to escape circulation, water follows albumin, leading to swelling/edema) 3. Swelling (see above) 4. Heat - (cause by increased blood flow to area of injury, blood is warm) 5. Loss of function (combination of swelling and pain, lead to temporary loss of function) What are causes of inflammation: 1. Surgery 2. Trauma 3. Toxic chemicals 4. Pathogens 5. Ischemic (low oxygen) damage to body tissues 6. Extremes of heat and cold What are the two stages of acute inflammation: Vascular: 1. Vascular permeability: allows exudate (WBCs, fluid) to escape to tissues. → Albumin enters tissues, followed by water, leading to swelling - Mediators include: histamines, leukotrienes and bradykinin - Results: swelling/edema, pain, and impaired function 2. Vasodilation: allows for increased blood flow to the area. - Mediator: nitric oxide (released by endothelial cells), histamine - Results: redness and warmth Cellular: movement of phagocytic WBCs into area of injury WBCs enter injured tissue site through transmigration → attracted to injured area by chemokines and complement C3a proteins (known as chemotaxis) - WBCs (leukocytes) phagocytize infective organisms Complements - C3b (activated by antibodies bound to pathogens) opsonize pathogens, marking them for phagocytosis More chemical mediators are released to control further inflammation and stimulate the repair process What does complement C3b do? - Opsonization of pathogens, marking them for phagocytosis What does complement C3a do? - Release chemokines that attract neutrophils to site of injury Extravasation vs. Transmigration Transmigration: movement of WBCs into injured tissue Extravasation: movement of fluid (other than WBCs) into injured tissue What WBCs cells are involved in inflammation? 1. Granulocytes - respond the fastest, attack pathogens - Neutrophils***: most numerous WBC, first responder in acute inflammation, ability to complete phagocytosis - Eosinophils: more involved in allergic reactions and chronic inflammation, important in parasitic infections - Basophils: Mast cells are derived from same line of basophils, more prominent in allergic reactions, release histamine → Mast cells are sentinel cells (keep watch and alert in pathogens are present) 2. Agranulocytes - Monocytes → Macrophages and/or Dendritic cells (both are APCs) - Mature in macrophage at the site of injury, “garbage truck of the body” - Lymphocytes - identify antigens - T cells - (adaptive immune response) are presented antigens by macrophages or dendritic cells, and can trigger humoral response (B cell production of antibodies), and cytotoxic T cells - B cells - (humoral immune response) produce antibodies at the direction of CD4 T helper cells. What are the inflammatory mediators? (What do they do, and where do they originate?) Inflammatory Mediators – Plasma Derived → synthesized in liver and present in plasma in precursor form Kinins Increase capillary permeability and cause pain during acute Ex) bradykinins phase inflammation Coagulation system Formation of fibrin mesh during clotting process Ex) fibrinolysis proteins Complement system A group of complement proteins that are inactive in the plasma and then activated when a microbe is recognized Results in: → Chemotaxis (C3a) → Opsonization (C3b) → Phagocytosis/Pathogen lysis (MAC complex – C5-C6789) Inflammatory Mediators – Cell Derived → produced by cells Vasoactive amines Mast cells, platelets Ex) histamine, Vasodilation, increased vascular permeability, endothelial activation serotonin Vasoconstriction (lasts a few seconds b4 vasodilation) Eicosanoid family Leukocytes Ex) prostaglandins, Vasodilation, pain ,fever Leukotrienes (slower Increased vascular permeability, chemotaxis, leukocyte produced than histamine) adhesion and activation, Platelet-activating factor Leukocytes Degranulation, oxidative burst Cytokines Macrophages, lymphocytes(leukocytes), endothelial cells chemokines Chemotaxis, leukocyte activation Omega 3 May contribute to inflammation if too many are present Tumor Necrosis Factor Macrophages - fever, hypotension, increased HR Alpha Release cytokines, chemokines, ROS, adhesion molecules by endothelial cells, lethargy, SKM down Nitrous oxide Leukocytes, macrophages, endothelial cells Vascular smooth muscle relaxation, platelet adhesion, degranulation, leukocyte recruiter Reactive oxygen species Leukocytes and Endothelial cells (ROS) Killing of microbes, tissue damage IL-12 Macrophages**, endothelial cells, neutrophils Adhesion molecules, release cytokines, chemokines, ROS Induce fever, hypotension, increased HR, lethargy Growth Factors Helps tissue heal Definitions: What is CBC, Exudate, Purulent, Hemorrhagic? Complete Blood Count (CBC) = erythrocytes, leukocytes, thrombocytes “with differential” - Normal WBC: 4000-10,500 - Leukocytosis: High WBC count ex: 18,000 - Leukopenia: Low WBC count ex: 1,500 Exudate: contains WBC that help fight infection/injury and albumin - Serous exudate: watery fluids low in protein content - Other exudate types: Hemorrhagic: occurs when there is severe tissue injury that causes damage to blood vessels or when there is significant leakage of red blood cells from capillaries Purulent: contains pus, composed of degraded WBCs, proteins and tissue debris What does elevated CRP level (C-reactive protein) mean?: Nonspecific, systemic inflammation Chapter 12 HYPERSENSITIVITY Excessive or inappropriate activation of the immune response What are the 4 types of hypersensitivity? 1. Type 1 (IgE mediated) 2. Type 2 (Antibody and complement mediated) 3. Type 3 (Immune complex mediated) 4. Type 4 (T-cell mediated/delayed) Type 1 Hypersensitivity: Allergic reactions - Any antigen that elicits an IgE response Can lead to: 1. Systemic or anaphylactic reactions 2. Local reactions - What are they? - Urticaria (hives) → caused by vascular permeability and exudate leaking into the interstitial tissues - Rhinitis (hay fever) → inflammation of the nose - Atopic dermatitis - Bronchial asthma → cause by histamines binding to H1 receptors, causing bronchoconstriction and difficulty breathing 3. Food allergies What is anaphylaxis? Anaphylaxis → systemic response to the inflammatory mediators released in type 1 hypersensitivity - - Vasodilation: caused by histamine, acetylcholine, kinins, leukotrienes and prostaglandins - Arteriole vasodilation can cause the BP to decrease due to expanded blood vessels and increased blood flow to the area. However, fluid leaks into the interstitial tissues and may not get to vital organs, contributing to anaphylaxis Bronchoconstriction: caused by acetylcholine, kinins, leukotrienes, and prostaglandins - Bronchoconstriction can cause respiratory difficulty What can trigger these reactions: Shellfish, Bee venom, Peanuts, Antibiotics, Latex ** If BP drops, fight or flight response may be triggered to get the heart pumping and blood flowing to vital organs, increasing BP. → Epinephrine is released What is the role that T helper cells play? What are the 2 types? - Two Subtypes of T helper cells 1. T helper 1 (Th1) cells: Macrophages and dendritic cells direct CD4 T-helper towards Th1 cells. - Stimulate differentiation of B cells into IgM or IgG producing plasma cells 2. ***T helper 2 (Th2) cells: Mast cells and T cells direct CD4 T-helper cells towards Th2 cells. - Stimulate B helper cells to switch to producing IgE antibodies necessary for an allergic response and hypersensitivity response. - Responsible for activation of mast cells, basophils, and eosinophils. What do Mast cells, Eosinophils and Basophils do in Type 1 allergic responses? - Mast cells: located in mucous membranes of respiratory, GU, GI tract, beneath the skin, and next to blood and lymph vessels. → Allows them to be readily available when allergens are present. - Eosinophils: Th2 cell releases IL4 and IL5, causing eosinophil to degranulate, releasing toxic substances that can damage nearby tissues Basophils: release histamines. First and Second Exposure: First exposure to allergen - Mast cell (APC) presents the allergen to a naive T helper cell, and after binding the allergen and co-stimulatory molecule, the naive T helper cell becomes a primed T helper cell. - Interleukins 4,5,and 10 induce primed T helper cell to become Th2 cell. Th2 cell releases interleukin 5 that attracts and induces production of eosinophils. - Th2 also releases IL-4, causing B cells to undergo antibody class switching and start producing IgE antibodies. - IgE antibodies produced have high affinity for the FCe (FC epsilon) receptors on mast cells, → mast cell is now ready to respond to second exposure Second exposure to allergen - Mast cell with IgE antibodies binds to two antigens on the allergen (forming a crossbridge), causing mast cell to degranulate - Degranulation releases chemical mediators such as: 1. Histamine: increases nitric oxide production, relaxes smooth muscles of endothelial cells of blood vessels, causes smooth muscle contraction and bronchial construction, permeability of capillaries and venules 2. Acetylcholine: similar to histamine (uses parasympathetic nervous system) 3. Kinins: smooth muscle contraction, vasodilation, pain 4. Chemotactic mediators: amplify inflammatory response by attracting eosinophils - 2-8 hours after allergic reaction initiated, late phase reactions begin due to release of leukotrienes (actions similar to histamines but stronger and longer duration) and prostaglandins, prolonging type 1 hypersensitivity reactions Type 2 Hypersensitivity: Antibody and Complement Mediated - Mediated by IgG and IgM antibodies → directed against target antigens on specific host cell surfaces or specific tissues/organs - Cytotoxic hypersensitivity 3 Diseases associated with Type 2? 1. Myasthenia disease: IgG antibodies bound to ach receptors, preventing ach from binding and muscles from being stimulated → leads to progressive weakness 2. Grave’s Disease: overstimulation of hormone throxine by thyroid due to IgM antibody bound to thyroid receptor, leads to hyperthyroidism 3. Good pasture’s syndrome: destruction of collagen on basement membranes of kidneys and lungs → can lead to kidney failure What is Central Tolerance? Central Tolerance: Self-reactive immune cells are destroyed, immune cells that are not selfreactive are allowed to survive - Sometimes self-reactive cells escape, leading to B cells that produce IgM and IgG (with help of CD4 t helper cells) antibodies that attack self antigens. What are the two antigen types? Extrinsic Antigens: antigens introduced to the body after exposure to a foreign substance. (ex: penicillin binds to receptor on cell surface creating an extrinsic antigen Intrinsic Antigens: antigens that are inherently a part of the host cell Four Types: 1. Complement Activated Cell Destruction - Activation of C5-C9 complements leads to formation of Membrane attack complex (MAC), which punctures cell membranes, causing lysis after influx of ions, small molecules and water into the cell. - Opsonization: IgG and complement C3b act as opsonins by binding to cell surfaces of macrophages, which destroy target cell by phagocytosis - Rh or RBC incompatibility → blood transfusions can initiate this response 2. Antibody-Dependent Cell Cytotoxicity (ADCC) - Antigen-antibody complex is recognized by NK cells (innate immune system), by binding to FC fragment on the antibody, causing degranulation of NK cells (perforins that poke holes in the cell and allow enzymes in and cause apoptosis) 3. Complement and Antibody Mediated Inflammation - IgG or IgM (rarely) antibody binds to antigen on host cell surface, activating complement system. - - Complement C1 binds to the FC portion of the antibody, activating complements C2-C9. Specifically C3a and C5a release chemotactic factors that attract neutrophils to the area. Neutrophils bind to C3b or FC portion of the antibody and degranulate, releasing chemical mediators involved in the inflammatory response and toxic substances that harm the cells (peroxidase, myeloperoxidase, proteinase 3 which generate oxygen radicals), leading to cell death → can lead to glomerulonephritis, acute renal failure, hemorrhagic lung disease. - Goodpasture's syndrome: antibodies bind to antigens on collagen IV, an essential protein in the basement membranes of kidneys and lungs. → can lead to kidney failure 4. Antibody Mediated Cellular Dysfunction - Antibody binds to cell reception, preventing binding of ligands to cell surface receptors, causing cellular dysfunction. - Graves disease: thyrotropin-binding inhibitory Ig antibodies bind to and activate thyroid stimulating hormone receptors on thyroid cells, stimulating thyroxine production and leading to development of hyperthyroidism - Myasthenia gravis: antibodies specific to aCH receptors in the muscle bind to them, preventing aCH from binding to them, preventing stimulation of muscles and causing progressive muscle weakness. Type 3 Hypersensitivity: Immune Complex Mediated Disorders - Mediated by immune complexes → IgG antibodies bind to free-floating, soluble antigens that are NOT attached to any tissues or cells (such as in Type 2). - Complexes are deposited in the tissues, eliciting an inflammatory response by activating the complement system (C3a, C4a, C4a → Anaphylatoxins). - Activation of complement system stimulates vascular permeability, and recruitment of phagocytic cells due to release of chemokines. → Edema, redness etc. - Neutrophils attempt to phagocytize immune complex but are unable to and degranulate, releasing ROS and lysosomal enzymes that induce inflammation and damage tissues → can lead to vasculitis - Commonly takes place in kidneys (blood filtered)→ glomerulonephritis, joints (plasma filtered) → arthritis - Serum sickness: begins with receiving a foreign serum to treat an illness or toxin, the body makes antigens against the toxin/microbe and foreign serum complex, activating the inflammatory response. - Arthus reaction: localized immune complex reaction with tissue necrosis, caused by repeated local exposure to an antigen → can lead to ulcers, lesions, vasculitis. Type 4 Hypersensitivity: T Cell Mediated Hypersensitivity - Reactions are caused by T cells (CD8 - Cytotoxic T cells, and CD4 - Helper T cells) 4 Subtypes of Type 4 Reactions 1. Type 4A: CD4 TH1 cells activate macrophages and monocytes through secretion of IFNgamma, - Macrophages release pro-inflammatory cytokines (TNF, and IL-12), allowing permeability of endothelial cells and more immune cells into area→ leads to edema, fever (TNF stimulates hypothalamus to induce fever) and redness (contact dermatitis) - Takes 24-72 hours to develop 2. Type 4B and D: TH2 cells secrete IL-4 and IL-5 which activate mast cells and eosinophilic responses. 3. Type 4C: cytotoxic responses mediated by CD4 (T helper cells) and CD8 (cytotoxic T cells) - Antigens bound by CD8 cells on MHC 1 (usually bound to viral antigens) APCs trigger CD8 cells to kill the cell presenting the antigen - Antigens bound by CD4 cells on MHC 2 (usually bound to bacterial antigens) APCs trigger CD4 cells to activate CD8 cells, macrophages and B lymphocytes. - Contact dermatitis: activation of TH1 helper cells and T-helper lymphocytes that recruit and activate memory specific T cells to initiate an inflammatory response → takes 12-2 hours to experience symptoms. → treatment corticosteroids and removal of offending agent - Hypersensitivity Pneumonitis: TH1 cells stimulate release of TNF, IFN-gamma, IL-12, and IL-18 in lung tissue. → treatment corticosteroids and removal of offending agent HIV AND AIDS How is HIV transmitted and who are in high risk groups? HIV: - Transmission: - Sexual fluids - Blood (childbirth, transfusions, needles) - Breast milk - High Risk Groups: drug users, gay men, prison settings or other close quarters, transgender people, sex workers and their clients - Pre-exposure prophylaxis - usually gay men who have high risk sexual encounters - Post exposure prophylaxis - healthcare worker who is stuck with a needle (must be started within 72 hours of exposure) How much is transmission reduced by adhering to antiretroviral regimen? If an infected person with HIV adheres to effective antiretroviral regimen, the risk of transferring the virus to their non-infected partner is reduced by 96% What type of virus is the HIV virus?: Retrovirus: HIV is a retrovirus that specifically attacks the CD4+ T lymphocytes (response for coordinating immune response to certain infections, and some cancers) → Those with HIV infections have a deteriorating immune system. - Deteriorating immune systems puts them at high risk of infections that are usually harmless (opportunistic infections) - Without treatment the HIV virus can gradually destroy the immune system and progress to AIDs → acquired immunodeficiency virus What does reverse transcriptase do? Reverse Transcriptase: HIV is a retrovirus that infects cells using reverse transcriptase. - In regular transcriptase, DNA is transcripted into RNA which can move out of the nucleus into the rest of the cell. - Reverse transcriptase viral RNA is transcribed into DNA and enters the DNA of the cell, infecting the cell. → Can remain latent in the cell for many years, so an infected person doesn't appear ill. → When the virus becomes active, the infected person gets very sick from opportunistic infections and by that time their CD4 t-cell count is below 200 and has progressed to AIDS. What do CD4 T lymphocytes do? CD4 T Lymphocytes: - Help the body fight infections and certain cancers. - Important in recognition of certain foreign antigens. - Helps activate B cells to produce antibodies. Help cytotoxic CD8 t cells and NK cells directly destroy viral infected cells, TB infections and other foreign antigens CD4 T cells assist in enhancing the phagocytic function of macrophages → When CD4 t cell count drops, acquired immunity functionality decreases, innate immunity functionality decreases and the infected individual becomes immunocompromised Clinical Course of HIV: 3 stages Primary Infection Phase (Acute phase): When the infection is first contracted - Newly infected person becomes pretty sick with flu-like symptoms, fever, fatigue, night sweats, swollen lymph nodes, muscle aches. - During the acute phase the retrovirus is rapidly replicating, leading to an extremely high viral load → last for 7-10 days. - First 3-6 months of infection, antibody screenings will show up negative for HIV in the bloodstream→ called the window period (first 1-6 months of HIV infection, virus can still be transmitted to others) - After window period, seroconversion takes place allowing for the detection of HIV antibodies. Latency Phase: Immune system responds and reduces viral load to a manageable level. - No signs or symptoms of the HIV infection - CD4 T cell count will gradually continue to decrease from normal 800-1000 down to 200 due to the cytopathic effect of the HIV virus. - Latency phase can last about 10 years in the normal clinical course of infection - Until CD4 T cell count drops to a low level, an HIV infected person can remain asymptomatic although viral replication is still occurring. AIDS phase: - CD4 count drops below 200 and/or infected person develops AIDS-related opportunistic infections → AIDS. - If left untreated, can lead to death with 2-3 years. → **TB is the leading cause of death for infected HIV persons worldwide. (can be the first manifestation of an HIV infection) - Treatment: antiretroviral drug therapy AIDS Associated Illnesses Opportunistic infections - Respiratory (bacterial pneumonia, P.jiroveci pneumonia, TB) - Gastrointestinal (oral candida, stomatitis, diarrhea) Nervous system (HIV-related dementia, toxoplasmosis - usually latent until the AIDS stage of HIV) Malignancies - kaposi sarcoma - associated with human herpes virus strain 8, occurs in other immunocompromised patients. Lesions are found on skin, mucosal surfaces (GI tract, oral cavity, lungs), lesions are purple, violent spot. - non-hodgkin's lymphoma - numbers of patients with this lymphoma has increased drastically due to the extended life expectancy of those with AIDS. Wasting syndrome: involuntary weight loss of at least 10% of baseline body weight, diarrhea (more than two stools per day), chronic weakness, and fever. Metabolism syndrome ART Therapy - AntiRetroviral Therapy Combination of at least three antiretroviral drugs from two of the 5 classes that exist → meds taken on a daily basis for a lifetime Does not cure HIV - Allows people with HIV live longer and healthier lives - ART prevents HIV virus from replicating - Reduces the amount of HIV in the body Goals of ART Therapy: 1. Sustain suppression of HIV replication (which may result in an undetectable viral load) 2. Increase CD4 T cell count Slows down the progression of HIV to AIDS, and improve the overall quality of life and survival time of those who are infected CHAPTER 3 - CELL DEATH, ADAPTATION, AND INJURY Chapter Three: Cell Adaptation, Injury, and Death Cellular Adaptations Cells will always adapt to changes in the internal environment. Cells can adapt to increased work demand by changing: 1. Size - Atrophy: reduction in cell size due to disuse, denervation, loss of endocrine stimulation, ischemia (decreased blood flow), and inadequate nutrition. → shrucken leg muscle due to ALS - Hypertrophy: increase in cell size and mass due to increased workload in skeletal and cardiac muscle. → (physiologic) Marathan runner with enlarged calf muscles, (pathologic) Left ventricular hypertrophy 2. Number - Hyperplasia: increase in the number of cells in an organ or tissue. Takes place in cells that can complete mitosis (not skeletal or muscle cells), like the epidermis, glandular cells, and intestinal epithelium. → Endometriosis 3. Form - Metaplasia: one adult cell type is replaced by another adult cell type that is better suited to current internal environment (i.e. smokers replacing cells that have cilia for those that don’t) → Stratified squamous cells in the bronchi of a smoker from ciliated epithelium - Dysplasia: deranged cell growth that results in cells of different shapes, sizes, and arrangements. Can become pre-cancerous → Cervical changes associated with HPV Intracellular Accumulations Three sources of intracellular accumulations: 1. Normal body substances (i.e. fatty liver disease) - Lipids - Proteins - Carbs 2. Abnormal endogenous products (i.e. jaundice and von gierke disease) - Results from errors in metabolism 3. Exogenous products (coal in lungs, lead, etc) - Environmental agents that cannot be broken down by the cell Pathologic Calcifications Abnormal deposits of calcium salts with smaller amounts of iron, magnesium and other minerals into tissues. Two types: 1. Dystrophic calcification: deposit of calcium salts occurs in tissue that is dying or dead 2. Metastatic calcification: deposit of calcium salts occurs in normal tissue. (worse then dystrophic calcification) - Hypercalcemia: increase levels of calcium - can be caused by metastatic bone lesions, vitamin D intoxication, hyperparathyroidism. (Greater than 11 mg) Causes of Cellular Injury What are the causes of cellular injury? Physical Agents: - mechanical forces, - electrical forces, - extremes of temperature Chemical: drugs, lead, mercury Radiation: - Ionizing radiation: release free radicals that can cause damage and destroy cells SIDE NOTE: Free Radicals Ions that are missing an electron and become extremely unstable. Free radicals have the potential to steal electrons from other molecules, resulting in cellular function malfunctions, genetic mutations, and potentially cell death. - Antioxidants: provide the missing electron the free radical needs to become stable - UV radiation: causes sunburn, increases cancer risk - Non-ionizing radiation: radiation from microwaves, TVs, industrial operations. Biological Agents: viruses, parasites, bacteria Nutritional Imbalances: excesses and deficiencies Reversible Cell Injury What are the cell injuries that impair function but do not result in cell death? Two patterns: 1. Cellular Swelling: results from the malfunction of energy-dependent sodium potassium pumps due to hypoxia. Leads to excessive sodium in the cell and resulting cellular swelling due to influx of water, following sodium. 2. Fatty Change: Intracellular accumulation of fat, may indicate the body cannot metabolize fat properly. Mechanisms of Cell Injury Free Radicals and Reactive Oxygen Species (ROS) Formation - What are free radicals? - Free radicals are highly unstable and reactive chemical species due to an unpaired electron in their outer valence shell. - Types of Free Radical Injuries: 1. Lipid peroxidation: disruption of cell membrane by free radicals due to removal of electrons in lipids of the cell membrane, causing a chain reaction of lipids to steal electrons from other lipids in the cell membrane. 2. DNA effects (mutations) 3. Oxidative stress: occurs when generation of ROS exceeds the body’s ability to neutralize ROS. - Antioxidants neutralize free radicals by providing their missing electron. Hypoxic Cell Injury Deprives cells of oxygen, disrupting the ETC system and generation of ATP. - Acute cellular swelling: caused by the disruption of ATP dependent K+/NA+ pumps, leading to the influx of NA+ to the cytoplasm, followed by water, leading to edema. - Anaerobic metabolism: leads to depletion of glycogen stores and accumulation of lactic acid which can cause acidosis. Causes of Hypoxia: 1. Inadequate amount of oxygen in the air 2. 3. 4. 5. Respiratory disease Inability of cell to use oxygen Edema Ischemia (decreased blood flow to cells) Impaired Calcium Homeostasis Calcium is an important second messenger and cytosolic signal for many cell responses. Impaired calcium homeostasis which can be caused by ischemia can lead to: the improper activation of enzymes that can lead to damaging effects Programmed Cell Death Apoptosis: elimination of damaged (genetic, improper development), or old cells. Also called cell suicide. Necrosis: cell death in an organ or tissue that is part of a living person - Can interfere with cell replacement and tissue regeneration Dry gangrene: tissue becomes dry, skin wrinkles, changes to dark brown or black color, spread to other tissues is slow. Wet gangrene: tissue is cold, swollen, and pulseless. Skin is moist, black and under tension. Foul odor from bacterial infection, liquefaction occurs, spread to other tissues is rapid. Chapter One: Introduction to Patho What is pathophysiology? - Study of the body’s response to dysfunction and disease What is disease? - Interruption, cessation, disorder of a body system or organ structure What are the aspects of the disease process? 1. Etiology - Cause of disease 2. Pathogenisis - Manner in which a disease develops; from etiology to presentation 3. Morphological changes - How cells and tissues change due to the disease 4. Clinical manifestations - Objective signs and subjective symptoms, complications, and lasting morbidity due to disease 5. Diagnosis - Identification of disease using medical history, lab test, physical exams 6. Clinical course - Evolution/progression of the disease What are Risk Factors? - Conditions suspected of contributing to the development of a disease What is Primary Prevention? - Keeping diseases from occuring by removing risk factors
