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First Foundations in Pathology, Part 2: Acute and Chronic Inflammation

First Foundations in Pathology, Part 2: Acute and Chronic Inflammation. Paul G. Koles, MD Asst. Prof. Pathology and Surgery Director of Pathology Education Boonshoft School of Medicine at Wright State University. Overview of Inflammation.

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First Foundations in Pathology, Part 2: Acute and Chronic Inflammation

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  1. First Foundations in Pathology, Part 2: Acute and Chronic Inflammation Paul G. Koles, MD Asst. Prof. Pathology and Surgery Director of Pathology Education Boonshoft School of Medicine at Wright State University

  2. Overview of Inflammation • Definition: a protective response to injury in which blood vessels facilitate accumulation of fluid and leukocytes in extravascular tissue Fig. 3-1, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  3. Patterns of Inflammation • Acute • Short duration (minutes-days) with emigration of fluid, plasma proteins, and into tissue. • Chronic • Longer duration (days-months) with tissue accumulation of lymphocytes, plasma cells, & macrophages plus variable proliferation of and

  4. Historical Milestones • Celsus, 1st century A.D., described four cardinal signs of inflammation accurately: • Metchnikoff, 1882, observed ingestion of bacteria by mammalian leukocytes called Rubor = Tumor = Calor = Dolor =

  5. 3 processes involved in acute inflammation Fig. 3-2, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999. 1 = Leading to increased blood flow 2 = Of non-cellular components 3 = Of cellular components

  6. Inflammation: essential definitions • = escape of fluid, proteins, and blood cells from vessels into tissues • = inflammatory fluid, high protein concentration and sp.gr. > 1.020 • = watery fluid, low protein concentration and sp. gr. < 1.012 • = excess fluid in tissues • = excess fluid in serous cavities lined by mesothelium (pleural, pericardial, peritoneal) • = inflammatory exudate rich in neutrophils and cell debris

  7. Vascular changes in inflammation • Altered blood vessel caliber and flow • Vasodilation  slowing of flow  stasis of blood cells  leukocyte margination • Increased vascular permeability (leakage) • Escape of protein-rich fluid into interstitium  altered osmotic pressure gradient  further outflow of fluid

  8. Five proposals, Fig. 3-4, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999. Mechanisms vascular permeability

  9. Extravasation of Leukocytes • Sequence of 3 events • In lumen of blood vessel (3 phases): • Diapedesis through endothelium of venules: • Migration into interstitium toward injury site by locomotion along a chemical gradient:

  10. Mechanisms of adhesion • Complementary binding of adhesion molecules on leukocytes and endothelium • 4 families of adhesion molecules: • : on endothelial cells, platelets, and leukocytes • : ICAM-1 and VCAM-1 on endothelial cells • : transmembrane heterodimeric glycoproteins on leukocytes • : on endothelial cells and leukocytes, enabling diapedesis through endothelium

  11. Leukocyte emigration: overview Fig. 2-6, Pathologic Basis of Disease, 2006.

  12. How are leukocytes induced to adhere? Redistribution of Fig. 2-7, Pathologic Basis of Disease, 7th edition, Elsevier Saunders, 2005 Cytokine induction of Increased avidity of

  13. Steps in neutrophil extravasation, 1 Fig. 3-9, Pathologic Basis of Disease, 6th ed., WB Saunders, 1999.

  14. Steps neutrophil extravasation, 2 Fig. 3-9, Pathologic Basis of Disease, 6th ed., WB Saunders, 1999.

  15. Chemotaxis • Definition: locomotion of leukocytes toward site of injury along chemical gradient • Chemical attractants, exogenous: bacterial products (proteins, lipids) • Chemical attractants, endogenous: • Complement components, esp. • (LTB4) • Cytokines, esp. chemokines like IL-8

  16. Time-related cellular response to MI Later response: (48 hrs-2 weeks) Early response (12-48 hrs.)

  17. Leukocyte Locomotion An extension of cytoplasm which pulls cell in direction of the extension: Pseudopod motion mediated by assembly & disassembly of which contractile proteins?

  18. Phagocytosis by neutrophils and macrophages: three steps • Recognition and attachment to particle • Microbes coated by which promote binding to leukocyte receptors: • Engulfment & formation phagocytic vacuole • Membrane phagocytic vacuole merges with limiting membrane of: • Killing/degradation of ingested material • Mainly by oxygen-dependent mechanisms with release of from azurophilic granules in neutrophils Fc fragment of IgG; C3b; plasma lectins

  19. Phagocytosis: mechanism Activation NADPH-oxidase generates H2O2, which converts to HOCl in presence of Cl- and myeloperoxidase; H2O2-MPO-halide system is bactericidal in which leukocyte ? Fig. 3-13, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  20. Leukocyte-mediated injury: too much of a good thing can be bad • Amplified inflammatory response releases neutrophil products into extracellular space: • Lysosomal enzymes • O2-derived active metabolites • Products of arachidonic acid metabolism

  21. Leukocyte-induced injury

  22. Genetic defects in leukocyte function

  23. Neutropenia: decreased concentration of neutrophils in peripheral blood (absolute neutrophil count < 1600/ul) What is most frequent pathophysiologic mechanism of neutropenia? What are two most common specific etiologies of neutropenia caused by this mechanism?

  24. Chemical mediators of inflammation Lysosomal enzymes cytokines Fig. 2-12, Pathologic Basis of Disease, 7th ed, Elsevier Saunders, 2005

  25. Histamine: in granules of mast cells, basophils, and platelets • Triggers for degranulation/release histamine • Physical injury • Immune reactions • Anaphylatoxins: • Neuropeptides, eg. Substance P • Cytokines IL-1, IL-8 • Function histamine: dilation arterioles and creation of gaps in for increased vascular permeability

  26. Plasma-derived mediators of inflammation (synthesized by liver) • system of 20 component proteins and cleavage products • system, generating vasoactive peptides from plasma proteins by specific proteases called kallikreins. • system, divided into two pathways that converge, culminating in activation of thrombin & formation of fibrin

  27. Complement activation pathways C3b: Functions of complement in inflammation: C5-9 MAC: C3a and C5a

  28. Plasma mediators: summary Initiates four systems involved in inflammation Powerful mediators of increased vascular permeability Fig. 3-17, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  29. Role of arachidonic acid metabolites Inhibited by: Selective Cox-2 inhibitor: Cox 1&2 inhibitors: Fig. 3-18, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  30. 2 Major cytokines of inflammation Cytokine effects may be: 1) On the same cell that produces them: 2) On cells in nearby vicinity: 3) systemic: Fig. 3-21, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  31. Nitric Oxide: synthesized in endothelial cells & macrophages Two types of nitric oxide synthase (NOS): endothelialNOS expressed at low levels in endothelial cells; is induced when macrophage activated by cytokines (TNF-a or IFN-y) Fig. 3-22, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  32. Neutrophil: lysosomal granules Smaller, dump into phagocytic vacuoles within cell but also easily release contents extracellularly Larger, dump granule contents primarily into phagocytic vacuoles within cell Fig. 3-23, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  33. Summary: important mediators Produced by all leukocytes Tissue damagemechanism used by which leukocytes?

  34. Outcomes of acute inflammation Fig. 3-24, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

  35. Chronic Inflammation • Definition: inflammation of prolonged duration (weeks-months-years) in which active inflammation, tissue destruction, and tissue repair are simultaneously present. • Clinical settings of chronic inflammation: • Persistent infections (eg, M. tuberculosis) • Prolonged exposure to toxins (silicosis) • Autoimmunity (rheumatoid arthritis) • Neoplasia

  36. Histopathology of chronic inflammation Mononuclear cell infiltration (3 cell types): Tissue destruction with replacement of damaged tissue by well-vascularized young fibrous tissue Biopsy temporal artery, H&E Diagnosis?

  37. Origin & Distribution of Macrophages Anatomic sites: Microglia: Kupffer cells: Sinus histiocytes: Osteoclasts:

  38. Activation of Macrophages Activated CD4 Th1cell RESULT: RESULT:

  39. Macrophage arsenal: friend & foe Friend: potent destroyer of unwanted substances: bacteria, fungi, foreign particles Foe: significant tissue destruction accompanies the chronic inflammatory response

  40. Cells of chronic inflammation (1) • : mobilized by Ab-mediated and cell-mediated immune reactions; use adhesion molecule pairs and chemokines to migrate into sites of inflammation • : mature, fully differentiated B-cells, manufacture and secrete specific immunoglobulin directed against persistent antigen or altered tissue components.

  41. Cells of chronic inflammation (2) • : have surface receptors for Fc portion of IgE antibody. Binding of antigen-specific IgE causes degranulation and release of histamine. • : seen in immune reactions mediated by IgE and parasitic infections. Chemotaxis mediated by eotaxin. Large cytoplasmic granules contain which is toxic to parasites and epithelial cells. Activated by cytokine

  42. Reciprocal activation of lymphocytes and macrophages MØ Activates T cells by secreting CD4+ Th1 INF-gamma and which autocrine cytokine ? TNF and TNF, IL-1 and Fig. 2-31, Pathologic Basis of Disease, 7th ed, Elsevier, 2005.

  43. Granulomatous inflammation • Definition: distinctive pattern of chronic inflammation mediated by • Why important to recognize in tissue? • Limited number of causes (narrows the differential diagnosis) • Identification of specific cause (by various methods) allows specific treatment for potentially serious disease

  44. Name this structure: Definition: microscopic aggregate of macrophages with epithelioid features, usually encircled by peripheral collar of lymphocytes and plasma cells

  45. Disease Tuberculosis Leprosy Sarcoidosis Syphilis Histoplasmosis (& other fungi) Cat scratch disease Brucellosis undulant fever Berylliosis Cause Diseases with granulomatous inflammation

  46. Variant forms of granuloma : incited by inert foreign materials that can’t be destroyed by single macrophages and do not incite much inflammation or immune response : formed by fusion of activated macrophages; contains haphazardly arranged multiple nuclei Lung biopsy, H&E and polarized light

  47. Morphologic type of granuloma 2 Immune granulomas: :incited by poorly soluble particles which induce cell-mediated immune response involving activated macrophages processing and presenting Ag to T-lymphocytes : formed by fusion of activated macrophages; showing peripheral wreath-like arrangement of multiple nuclei + central necrosis: No central necrosis:

  48. Role of lymphatics in inflammation • Function: lymphatics and lymph nodes are secondary defense to contain inflammation when local reaction fails to neutralize injury • = inflammation of lymphatics • = inflammation of lymph nodes draining a focus of injury • may result when local infection is not contained by lymphatics and regional lymph nodes.

  49. Which anatomic sites may be commonly seeded by organisms in bacteremia?

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