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1

Describe the biosynthetic pathways for production of prostaglandins, prostacyclin, thromboxane, and leukotrienes, including the source of the precursor arachidonic acid and the specific enzymes involved.

5-Lipoxygenase. Critical enzyme in pathway for production of leukotrienes from arachidonic acid.COX-1 & 2 are critical for prostaglandin formation.

2

List the effects of prostaglandins on vascular smooth muscle, platelets, GI tract smooth muscle and secretory cells, kidney cells, uterus, and inflammatory cells and be able to relate these actions to side effects that occur from use of drugs that block their synthesis.

Vascular smooth muscle: PGE2/I2 causes vasodilation. TXA2 causes vasoconstriction.Platelets: TXA2: Pro-aggregatory effectGI tract smooth muscle/secretory cells: PGE2/PGI2 inhibit HCl secretion, increase mucous secretion, increase smooth muscle contractionsKidney cells: PGE2/PGI2 increase renal blood flow, promotion of diuresisUterine cells: PGF2a/E2: induces contractionsInflammatory cells: PGE2/PGI2 potentiate pain, edema, and fever.One would then predict that NSAIDs that inhibit COX-2 would possess therapeutic actions that include relief of pain, reduction of fever, and reduction of inflammation, while potential side effects would include acute renal failure, thrombotic events (COX-2 selective agents), and prolonged gestation.Inhibition of COX-1 by NSAIDs produces potential side effects of GI ulceration and prolonged bleeding time, and acute renal failure.

3

Describe the effects of leukotrienes on inflammatory cell function and pulmonary / vascular smooth muscle.

LTB4: Neutrophil chemotaxis, aggregation, and transmigration through endotheliumLTC4 / LTD4 / LTE4: Increased vascular permeability, bronchoconstriction, vasoconstriction. Important role in pathophysiology of asthma, psoriasis, and various arthritic / allergic / hypersensitivity processes.

4

Describe the functional interaction of prostacyclin and thromboxane A2 with relation to physiologic effects on vascular smooth muscle and platelets.

Thromboxane effects: Vascular smooth muscle: vasoconstriction (mainly in platelets). Platelets: aggregation.Prostacyclin effects (exactly opposite to thromboxane): Vascular smooth muscle: vasodilation (mainly in endothelial cells). Platelets: disaggregation.

5

Describe the mechanism whereby low-dose, but not high-dose, aspirin is able to exert an anti-thrombotic / cardioprotective effect. Relate this effect to potential cardiovascular toxicity associated with use of COX-2 selective agents.

A small amount of COX-1 inhibitors (low dose aspirin) inhibits aggregation of platelets through decreasing TXA2 and slightly decreases the chances of having a cardiovascular event. Cox 1 selectivity is better achieved at low doses.  Moderate to high doses promote bleeding.High doses of COX-2 causes endothelial cells to increase platelet aggregation, increasing the chance of a cardiovascular event. This is a side effect. 

6

Aspirin:1) Therapeutic uses2)Metabolism and excretion3)Common side effects at therapeutic doses4)Overdose toxicities and their treatment5)Contraindications to use6)Drug-drug interactions

Analgesic, antipyretic, anti-inflammatory, antithrombotic activities.Phase 2, renalGI irr, bleed, allergiesSevere acidosisavoid when flu, preggers, renal insufficiencyPhenytoin, Warfarin, EtOH, Lithium

7

Acetominophen1) Therapeutic uses2)Metabolism and excretion3)Common side effects at therapeutic doses4)Overdose toxicities and their treatment5)Contraindications to use6)Drug-drug interactions

Analgesic, antipyretic, less anti-inflammatoryPhase 2 (liver)Increases hepatic enzymes, CNS madnessLiver damageCan take when preggers!Alcohol induces formation of hepatotoxic metabolite

8

Ibuprofin1) Therapeutic uses2)Metabolism and excretion3)Common side effects at therapeutic doses4)Overdose toxicities and their treatment5)Contraindications to use6)Drug-drug interactions

Analgesic, antipyretic, anti-inflammatory, activities.Hepatic, RenalGI (less than aspirin), reversible platelet effectsDon't take when preggers

9

Celicoxib1) Therapeutic uses2)Metabolism and excretion3)Common side effects at therapeutic doses4)Overdose toxicities and their treatment5)Contraindications to use6)Drug-drug interactions

Analgesic, antipyretic, anti-inflammatory, reversibile inhibition Cox-2 activities.Hepatic, RenalRenal, cardiovascular events, better for GI and platelets (less bleeding)Overdose toxicities unknownPreggersWarfarin- Increase chances for bleeding

10

Define regeneration, indicate the two requirements for it.

Regeneration is the process by which the lost tissue is replaced by cells/tissue identical to the original cells/tissue.This process requires: A viable population of stem cells capable of dividing and differentiating into cells identical to those which were lost. Labile or stable cells. A viable and intact stroma, including basement membrane.

11

What are some examples of regeneration?

Examples of regeneration:Replacement of hepatocytes after exposure to hepatotoxic chemicals or viral hepatitis.Replacement of renal tubular epithelium after acute tubular necrosis or exposure to a nephrotoxic chemical.Replacement of the mucosal epithelium in gastric erosionReplacement of the epidermis in a first degree burn

12

Define stem, labile, stable and permanent cells, give examples, and indicate their role in healing and regeneration.

Stem cells are characterized by their prolonged self-renewal capacity and by their asymmetric replication. Asymmetric replication describes a special property of stem cells; that is, in every cell division, one of the cells retains its self-renewing capacity while the other enters a differentiation pathway and is converted to a mature, nondividing population.Labile cells. These are continuously and rapidly replaced. Examples: Surface epithelium of skin, G.I. tract, G.U tract, hematopoietic cells.Stable cells. These are continuously but slowly replaced. Their proliferation can be markedly accelerated during regeneration. Also called quiescent cells. Examples: Hepatocytes, renal tubular epithelial cells, endothelium, smooth musclePermanent cells: Although portions of these cells may be restored (e.g. neuron), the cells themselves are not replaced. Regeneration does not occur. Examples: Skeletal and cardiac muscle, CNS neurons.

13

What is fibrosis?

Fibrosis: The lost tissue is replaced by fibrous connective tissue. Ultimately the fibrous connective tissue may become collagenized, i.e. converted to mature (Type I) collagen - a scar. Scar is virtually all dense collagen with few cells and vessels.

14

describe the three types of situation in which repair occurs by fibrosis rather than by regeneration.

Loss of permanent parenchymal cells. Example: Myocardial infarcts heal by fibrosis and scar formation. This is due to the permanent nature of myocardial myocytes as well as the loss of stroma which occurs in an infarct regardless of location.Loss of underlying stroma. Example: Infarcts result in the loss of both parenchyma and stroma. Although the parenchymal cells of the kidney, lung and spleen are capable of regeneration, the loss of stroma precludes healing by regeneration.Ongoing loss/destruction of parenchyma/stroma: Example: The ongoing loss/destruction of parenchyma and stroma in alcoholic hepatitis cirrhosis, i.e. massive scarring of the liver.

15

Define organization and indicate the situations in which it occurs and give examples. Describe a recanalized thrombus.

Organization, i.e. fibrosis leading to scar formation Peritoneal pyogenic exudate secondary to a ruptured appendix, which undergoes organization into fibrous adhesions.Organization of an exudate in pneumonia results in scar formation in the affected portion of lung (organized pneumonia).A coronary artery thrombus which undergoes organization and scar. When vascular channels form in the organizing thrombus, the tissue which had been perfused by the obstructed artery may be reperfused. This is the process of recanalization.A subdural hematoma which organizes and forms a scar.

16

Describe the sequence of events involved in the healing of a skin wound and an infarct.

Before fibrosis can occur dead tissue and any exudate or blood must be removed. Phagocytic cells play a major role - neutrophils and macrophages ingest and lyse these materials.Ingrowth and proliferation of fibroblasts and endothelial (vascular) buds. The fibroblasts produce “ground substance” - glycosaminoglycans and other extracellular matrix components, and then Type III collagen - the pliable collagen which is present in embryonic and fetal tissues. Macrophages continue to be present. This process occurs between 3 - 5 days.By 10 - 14 days the removal of dead tissue is complete. Granulation tissue has replaced it and more collagen is being synthesized and secreted.Increased amounts of intercellular collagen are laid down and immature collagen (Type III) is being replaced by dense, mature, high tensile strength collagen (Type I). This is accompanied by the replacement of fibroblasts and vessels. This occurs during the subsequent 6 weeks.At the end of 2 months repair is complete and the area has been converted to dense collagen - a scar - virtually devoid of cells and vessels. Scar achieves a maximal tensile strength of about 70% - 80% that of the original tissue.

17

Define debridement, granulation tissue, collagen Types I and III, tensile strength, scar and keloid.

Debridement: The manual removal of dead tissueGranulation tissue: Ground substance + Type III collagenType III Collagen: immature collagenType I Collagen: Dense, mature, high tensile strength collagenTensile strength: resistance to stretching.Scar: Areas of fibrous tissue that replace skin after injuryKeloid: the scar exceeds the area of the original tissue

18

Indicate the difference between healing by primary vs. secondary union.

Primary union (healing by “first intention”) involves fibrosis within a wound the edges of which are apposed, e.g. by sutures.Secondary union (healing by “secondary intention”). The defect is large. Wound contraction, accomplished by myofibroblasts, is necessary for repair to occur. If the defect is too large grafts may be necessary

19

Discuss some systemic and local factors which may impede wound healing.

Systemic - poor nutritional status (e.g. vitamin C deficiency, zinc deficiency), underlying disease (e.g. diabetes mellitus), certain medications (e.g. corticosteroids).Localized - retention of dead tissue, foreign body, infection, reduced blood supply

20

Define repair and compare the concepts of parenchyma and stroma.

Repair (healing) refers to the replacement of lost tissue. The loss of tissue can occur through such processes as surgical resection, infarction, chemical toxicity and infection. The tissue can be replaced by either one of two processes, regeneration or fibrosis.Parenchyma-the key functional cell type(s) of a tissue or organ.Examples: Muscle cells in myocardium; hepatocytes in liver; neurons in brain.Stroma - the supporting framework or interstitium of a tissue or organ.

21

Describe the two major responses to tissue injury (regeneration and repair).

Regeneration is the process by which the lost tissue is replaced by cells/tissue identical to the original cells/tissue.Repair is regeneration or scarring.

22

Define the different pathologic aspects of repair and understand why they occur. Give examples of each.

Deficient scar formation: inadequate granulation tissue leads to ulceration and dehiscience: foot ulcersExcessive formation of repair components: excessive collagen deposition: keloid scarsContraction: contractures often form after burns, affects joint movement.

23

Who is at risk for chronic renal insufficiency?

Elderly

24

Aspirin: why avoid in children <12yo w/ viral infections?

Linked to Reye's syndrome (liver damage and encephalopathy).