First Foundations III-Acute and Chronic Inflammation PowerPoint Presentation

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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

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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.

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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

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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 =

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

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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

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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

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

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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:

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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

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

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

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

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

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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

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

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

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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

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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.

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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

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Leukocyte-induced injury

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Genetic defects in leukocyte function

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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?

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

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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

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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

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

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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.

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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.

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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.

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Nitric Oxide: synthesized in endothelial cells & macrophages Two types of nitric oxide synthase (NOS): endothelial NOS 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.

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

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Summary: important mediators Tissue damage mechanism used by which leukocytes? Produced by all leukocytes

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

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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

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

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

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Activation of Macrophages Activated CD4 Th1cell RESULT: RESULT:

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

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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.

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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

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

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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

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

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

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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

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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:

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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.

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

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Other anatomic sites seeded in bacteremia Fluid aspirated from swollen knee, 1000x oil immersion

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Morphologic patterns of inflammation Outpouring of watery fluid from blood plasma or secretions of watery fluid by mesothelial cells Fibrinogen leaks into tissues from permeable vessels and is converted to fibrin in tissues Pleural fluid cytology from effusion in patient with heart failure; mesothelial cells and lymphocytes Heart, pericarditis in chronic renal failure

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Morphologic patterns inflammation (2) Aggregates of neutrophils, necrotic cells, and fibrinous exudate, characteristic of pyogenic bacteria: Focal skin or mucosal defect produced by sloughing of necrotic inflammatory tissue: Localized, demarcated area of such inflammation with central liquefied necrosis: Small intestine, Crohn’s disease Heart, acute pericarditis

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Systemic effects of inflammation: acute phase reaction Metabolic: secretion of by liver Autonomic: redirection blood flow between cutaneous & deep vascular beds to control heat loss Behavioral: rigors (shivering), chills, anorexia, somnolence, malaise FEVER

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Mechanism of Fever Prostaglandin E Fig. 3-34, Pathologic Basis of Disease, 6th ed, WB Saunders, 1999.

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Lab evidence of inflammation Increased serum acute phase proteins Leukocytosis Absolute Neutrophilia—suggests bacterial; acute infl. Absolute Lymphocytosis—suggests viral; chronic infl. Absolute Eosinophilia—suggests hypersensitivity or parasitic infection