Path Inflammation (4)

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  1. Inflammation
    • the response of a living tissue & its microcirculation to injury
    • for inflammation to occur, tissue must be LIVING & VASCULARIZED
    • it functions to localize & eliminate a cause of the injury (microorganisms, damaged cells, foreign particles etc.), & to then initiate the repair process, returning a tissue to normal structure & function
  2. Cardinal Signs of Inflammation
    • redness, heat, swelling, pain, loss of function
    • 1. Rubor: redness caused by vasodilation & increased blood flow
    • 2. Calor: as vessels dilate, more warm core blood from inside can move to the periphery → increased temperature at the site
    • 3. Tumor: swelling caused by increased vascular (BV) permeability at the site of inflammation
    • 4. Dolor: pain from substance P released at the injury site by nerve endings
    • 5. Functio laesa: loss of function
  3. What are the 3 main components of inflammation?
    • 1. Vascular: reaction of vessels & movement of fluids from blood to extravascular tissue
    • 2. Cellular: movements of leukocytes & other cells from blood vessels into tissues
    • 3. Chemical: production of inflammatory mediators from inflammatory cells
  4. Phases of Inflammation
    • 1. Initiation: an immediate response to injury (eg. acute inflammation)
    • 2. Amplification: depending of injury severity/nature (eg. further recruitment of WBCs to a site)
    • 3. Elimination: destruction of the causative agent + removal of damage tissues
    • 4. Termination: intrinsic & anti-inflammatory mechanisms stop the process, limit tissue damage with either a return to normal structure/function or scar development
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  5. Resolution
    removal of exudate, restoration of normal tissue architecture & physiological function
  6. Scar
    • replacement of injured tissue by connective tissue
    • normal architecture & function NOT restored
  7. Persistent Inflammation
    prolonged acute response or chronic inflammation
  8. Differences Between Acute & Chronic Inflammation
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    • Acute Inflam Cells: neutrophils (appear early on)
    • Chronic Inflam Cells: monocytes → macrophages, lymphocytes (mononuclear cells, appear in later stages)
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  9. Sequence of Events in Acute Inflammation
    • 1. Injury to tissue (infections, trauma, tissue necrosis, foreign bodies, immune reactions etc.)
    • 2. Vasodilation
    • 3. Increased blood flow
    • 4. Increased vascular permeability
    • 5. Hemoconcentration → slowing of flow or stasis
    • 6. Elaboration of mediators (eg. ↑ NO, cytokines)
    • 7. Leukocyte margination (rolling & sticking)
    • 8. Leukocyte firm adhesion & extravascular emigration
    • 9. Homing, chemotaxis - follow molecules bringing them to the site of injury
    • 10.Elimination of offending agent
    • 11.Termination
    • 12. Outcome: scar, resolution, or chronic
  10. Vascular & Cellular Reactions of Acute Inflammation
    • arterioles & venules dilate (vasodilation)
    • capillary beds expand
    • as a result there is increased blood flow to damaged tissue, neutrophils are able to emigrate into vessels to move to the site of inflammation, & *PLASMA PROTEINS LEAK OUT OF VESSELS → edema*
  11. Hyperemia
    • increased blood flow to the tissue that results from vasodilation of pre-capillary arterioles
    • it accounts for redness (erythema) & warmth at the site of tissue injury
    • this vasodilation & subsequent ↑ blood supply to tissues is caused by specific mediators: histamine, prostacyclin, & nitric oxide
  12. By increasing endothelial permeability, what effect do mediators like histamine have on blood vessel endothelial cells?
    • increased permeability leads to leakage of fluid into extravascular space → Edema (loss of fluid from vessels into tissue)
    • categorized as severe injury if leakage persists for hours or days
  13. Edema
    accumulation of fluid within the extravascular compartment & interstitial tissue
  14. Oncotic Pressure (Colloid Osmotic Pressure)
    • a form of osmotic pressure exerted by proteins in a blood vessel's plasma
    • usually tends to pull water INTO the circulatory system
    • it opposes hydrostatic pressure
  15. Hydrostatic Pressure
    • the force exerted by a fluid against a vessel wall
    • (in the capillary bed, it's the same as capillary blood pressure)
  16. Transudate
    • edema fluid w/ a LOW protein content (SG < 1.015)
    • caused mainly by increased hydrostatic pressure or decreased colloid osmotic pressure
    • appears clear (mainly just fluid leakage)
  17. What are some pathologies that can lead to transudate production?
    • venous outflow obstruction, like in congestive heart failure, causes ↑ hydrostatic pressure
    • liver disease can cause low protein synthesis & kidney disease can cause protein loss, both leading to ↓ colloid osmotic pressure
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  18. Exudate
    • edema fluid w/ a HIGH protein content (SG > 1.015)
    • caused mainly by inflammation*
    • appears cloudy (fluid & protein leakage)
    • Fibrinous Exudate contains lots of fibrin
    • Purulent Exudate contains pus & has a lots of cells (eg. neutrophils)
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  19. How is edema managed?
    lymphatic vessels drain edema fluids, leukocytes, & cell debris from the extravascular space
  20. Endothelial Cell Retraction
    • occurs mainly in venules
    • induced by histamine, NO, other mediators
    • is rapid & short-lived (minutes long)
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  21. Endothelial Cell Injury
    • occurs in arterioles, capillaries, & venules
    • caused by things like burns, microbial toxins
    • is rapid & may be long-lived (hours → days)
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  22. Leukocyte-mediated Vascular Injury
    • can occur in endothelial walls of venules & pulmonary capillaries
    • associated w/ late stages of inflammation
    • is long-lived (hours)
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  23. Increase Endothelial Transcytosis
    • occurs in venules & is induced by VEGF
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  24. Granulocytes
    • include neutrophils, basophils, & eosinophils
    • named for their conspicuous cytoplasmic granules
  25. Neutrophils
    • phagocytic leukocytes that play an important role in engulfing and destroying extracellular pathogens, primarily bacteria; often referred to as polymorphonuclear leukocytes (PMN), or “polys”, due to their multi-lobed nucleus
    • they make H2O2 to damage bacterial DNA
  26. Monocytes
    • phagocytic leukocytes found in the blood
    • when they move into tissue they differentiate into macrophages (monocytes = macrophage precursors)
  27. Macrophages
    • phagocytic leukocytes found in tissues
    • are derived from blood monocytes
  28. Mast cells
    • congregate in tissue & release various soluble mediators such as histamine when activated
    • they play a major role in allergic responses
  29. Basophils
    • circulate in the blood & are thought to have a function similar to mast cells
    • (Basophils in the Blood; mast cells in the tissue)
  30. Eosinophils
    • leukocytes important in the defense against parasitic infections
    • also related to IgE mediated functions, fighting off parasites, & the allergic reaction response
  31. Platelets
    • small, disk shaped, clear cell fragments (no nucleus) derived from fragmentation of precursor megakaryocytes
    • are a natural source of growth factors, are involved in hemostasis, & lead to the formation of blood clots
  32. Lymphocytes
    • includes BOTH B lymphocytes (B cells) & T lymphocytes (T cells)
    • express antigen-specific receptors & mediate the adaptive/acquired immune response
    • histology: small cells composed mostly of nucleus with only a thin rim of cytoplasm
  33. Leukocyte Recruitment Overview
    • In acute inflammation, leukocytes, particularly PMNs, accumulate in the affected tissues
    • leukocytes in the blood 1st adhere to the endothelium & become activated (margination, rolling, adhesion)
    • they then migrate through the endothelial cell layer into the surrounding tissue (transmigration, chemotaxis)
    • PMNs ingest foreign materials, microbes, & debris in the extravascular tissue
  34. Molecules that mediate Rolling
    endothelial P-selectin & later E-selectin bind to carbohydrates on leukocyte transmembrane glycoproteins (Sialyl-Lewis X-modified glycoprotein)
  35. E-selectin
    • expressed on activated endothelial cells
    • synthesis of E-selectin follows shortly after P-selectin synthesis, induced by cytokines such as IL-1 & TNFα
    • E-selectins bind PSGL-1 & ESL-1
  36. P-selectin
    • a cell adhesion molecule (CAM) found normally in Weibel-Palade bodies inside BV endothelial cells
    • upon activation by mediators (histamine & thrombin), P-selectin moves to the inner surface of blood vessels
  37. What purpose does activated P-selectin serve when on the inner surface of blood vessels?
    it's able to bind to Sialyl-Lewis X-modified glycoprotein found on the surface of 'rolling' leukocytes
  38. Integrin
    • a surface protein on leukocytes that normally exists in a low affinity state
    • in the presence of CHEMOKINES integrin avidity is increased → bind to integrin ligand (ICAM-1) on epithelial BV cells, slowing the roll of leukocytes
  39. What molecules are involved in the stable adhesion of migratory leukocytes to blood vessel endothelium?
    activated (high-affinity) integrin + ICAM1
  40. ICAM1
    • surface glycoprotein expressed on endothelial cells
    • it binds to integrins to stably adhere leukocytes to the blood vessel endothelium
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  41. PECAM-1
    • protein found on both leukocytes & endothelial cell surfaces
    • as leukocytes migrate through the endothelium, PECAMs interact & function to pull the cell through the vessel wall
    • *responsible for leukocyte migration through the endothelium*
  42. Rolling Leukocytes Have on Their Surface:
    • Sialyl-Lewis X-modified glycoprotein
    • Integrin
    • PECAM-1 (CD31)
  43. Activated Endothelial Cells
    • P-selectin
    • E-selectin
    • ICAM-1 (integrin ligand)
    • PECAM-1 (CD31)
  44. What are some of the ways leukocytes can be activated?
    • 1. chemokines
    • 2. lipid mediators
    • 3. N-formyl-methionyl peptides
    • 4. microbe itself
    • 5. cytokines (eg. INF-gamma)
    • 6. phagocytic receptors
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  45. Opsonization
    • Fc-gamma receptors exist on some cell membranes (eg. macrophages)
    • they won't recognize free antibodies, however antibodies that bind to bacterial surfaces & CLUSTER may activate Fc-gamma receptors & PROMOTE macrophages to engulf the bound bacteria
    • the bacteria is brought into the cell inside a Phagosome
    • the phagosome fuses w/ a lysosome → phagolysosome
    • this fusion exposes the bacteria to lysosomal enzymes, which degrade it
  46. What are the 3 types of destruction reactions can occur in a phagolysosome after a microbe has been phagocytosed?
    • Oxygen dependent reactions
    • Non-oxygen dependent reactions
    • ‘Collateral damage’ (neutrophil generated ROSs)
  47. Oxidative Mechanisms of Bactericide
    • NADPH oxidase
    • Superoxide anion
    • Hydrogen Peroxide
    • Hypochlorous Acid
    • Hydroxyl radicals
    • Nitric oxide
  48. Non-Oxidative Mechanisms of Bactericide
    • Lysosomal hydrolases
    • Bactericidal permeability-increasing proteins
    • Defensins
    • Lactoferrin
    • Lysozyme
    • Bactericidal proteins of eosinophils
  49. Which of the following is involved in oxygen-dependent mode of antimicrobial action?
    • Lysozyme
    • Cathepsin G
    • Lactoferrin
    • NADPH
    • NADPH & NADPH oxidase are involved in oxygen-dependent mode of bacteria killing
  50. What do neutrophils generate in the process of phagocytizing bacteria or general cellular debris?
    • Reactive Oxygen Species - if/when these leak out they can cause "collateral damage" to tissue
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  51. pathologic consequences of inflammation
    • acute respiratory distress syndrome
    • acute transplant rejection
    • asthma
    • arthritis
    • pulmonary fibrosis
  52. In contrast, what can defects in leukocyte function lead to?
    • severe & frequent infections
    • can involve inadequate number of leukocytes (eg. in chemotherapy/radiation which cause bone marrow suppression)
    • can involve any step in the sequence of adherence, emigration, chemotaxis, phagocytosis, or killing mechanisms
    • may be congenital or acquired
  53. Congenital Defects in Leukocyte Functioning
    • Chediak-Higashi Syndrome
    • Chronic Granulomatous Disease
    • Myeloperoxidase deficiency
    • LAD (Leukocyte Adhesion Deficiency)
  54. Acquired Defects in Leukocyte Functioning
    • Bone Marrow Suppression (chemo/radiation)
    • Diabetes (adhesion/chemotaxis issues)
    • Leukemia
    • Malnutrition
    • Sepsis
    • Viral Infection
  55. Serous Inflammation
    • characterized by the outpouring of non-viscous (protein-poor) serous fluid, commonly produced by mesothelial cells of serous membranes, but may be derived from blood plasma
    • (accumulation of fluid in these cavities is called effusion)
    • eg. skin blister
  56. Fibrinous Inflammation
    • inflammation resulting in vascular permeability so large that fibrin can pass through the blood vessels
    • fibrinous exudate is characteristic of inflammation of body cavity lining (eg. meninges, pericardium, pleura)
  57. Suppurative (Purulent) Inflammation
    • production of large amount of purulent exudate (pus) containing neutrophils, necrotic cells, & edema fluid
    • eg. infection by pyogenic bacteria (staphylococci)
  58. Ulcers
    a local defect, or excavation, of the surface of an organ or tissue produced by sloughing off of inflamed necrotic tissue
  59. How can mediators activate cells?
    • 1. binding to specific receptors
    • 2. recruiting cells to the site of inflammation
    • 3. stimulating the release of additional soluble mediators
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  60. Chronic Inflammation
    • a long-lasting or permanent form of inflammation in which an organ or tissue is infiltrated by characteristic inflammatory cells, as well as frequently w/ elements of regeneration and repair, in response to persistent injury
    • denotes the presence of an adaptive immune response (cellular and/or humoral) against foreign or self antigens
    • the pathology - “immunopathology” - resulting from an ongoing immune response
  61. Primary Mediators of Acute v. Chronic Inflammation
    • Acute: vasoactive amines, arachidonic acid metabolites
    • Chronic: interferons + other cytokines, growth factors, reactive oxygen species, hydrolytic enzymes
  62. Cells of Chronic Inflammation
    • Monocyte/Macrophages
    • Epithelioid cells (activated macrophages)
    • Multinucleated giant cells (fused macrophages)
    • Lymphocytes
    • Plasma cells (terminally differentiated B cells)
    • Fibroblasts
  63. What is an example of a granuloma that has necrosis in its center?
    • caseous granuloma, like in TB infection
    • center: amorphous (eosinophilic) cellular debris (necrosis, cheese-like)
    • multinucleated giant & epitheliod cells surround the necrotic center
    • 3rd layer: lymphocytes
    • outer layer: fibroblasts (in an effort to wall it off)
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  64. Acute SYSTEMIC Effects of Inflammation
    • Fever (IL-1, TNF, prostaglandins)
    • Elevated Plasma Levels of Acute-phase Proteins
    • Leukocytosis (↑ number of immune cells brought about by TNF, IL-1, chemokines, C3a, C5a, LTB4)
    • Increased heart rate & blood pressure, chills, anorexia etc.
    • Septic shock
Card Set:
Path Inflammation (4)
2014-01-25 03:13:35
MBS Pathology
Exam 1
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