Pathophysiology I: Acute and Chronic Inflammation PDF

PATHOPHYSIOLOGY I Acute and Chronic Inflammation Granulomatous Inflammation Ruben Mora, MD 1 LEARNING OBJECTIVES Differentiate between acute and chronic inflammation Name various causes of inflammation Recognize and describe the rol...

PATHOPHYSIOLOGY I Acute and Chronic Inflammation Granulomatous Inflammation Ruben Mora, MD 1 LEARNING OBJECTIVES Differentiate between acute and chronic inflammation Name various causes of inflammation Recognize and describe the role of various meditators of inflammation Describe the role of various cells in acute inflammation Describe the the various cells involved in chronic inflammation Identify caseous vs non-caseous necrosis 2  ROADMAP Chronic Inflammation Mediators Granulomatous inflammation 03 Acute Inflammation Inflammation 02 Mediators Complement 01 Mediators of inflammation Cardinal signs of inflammation 3 INTRODUCTION TO INFLAMMATION Appropriate inflammation Infections Trauma Surgery Inappropriate inflammation Excess (sepsis) Prolonged (unresolved infection) Inappropriate (autoimmune disease) 4 INFLAMMATION – CHRONICITY Acute inflammation Rapid onset (minutes to hours) Quick resolution (usually days) Chronic inflammation Lasting weeks, months, years 5 INFLAMMATION – CARDINAL SIGNS Cardinal Signs Rubor Calor Tumor Dolor Loss of function 6 INFLAMMATION – CARDINAL SIGNS Rubor and Calor – due to arteriolar vasodilation → increased blood flow Histamine Mast cells, basophils, platelets Preformed → released quickly Prostaglandins Mast cells, leukocytes Synthesized via arachidonic acid Bradykinin 7 8 INFLAMMATION – MEDIATORS Arachidonic Acid and Metabolites PGI2 Mediate vasodilation Arachidonic acid released from phospholipid PGD2 Increase vascular PGE2 permeability (smooth cell membrane by phospholipase A2 → muscle contraction) then broken down by cyclooxygenase or PGE2 Mediates pain 5-lipoxygenase Cyclooxygenase produces prostaglandin (PG) LTB4 Attracts neutrophils 5-lipoxygenase produces leukotrienes (LT) LTC4 Mediate LTD4 vasoconstriction LTE4 Bronchoconstriction Increased vascular permeability 9 10 INFLAMMATION – MEDIATORS Bradykinin How is it created? Produced through kinin system involving factor XII (Hagemann factor) Role Vasodilator Increases vascular permeability Pain sensitivity Degradation Angiotensin converting enzyme (ACE) ACE-I ↑ bradykinin levels → angioedema C1 inhibitor (complement system) C1 inhibitor deficiency → hereditary angioedema 11 12 INFLAMMATION – CARDINAL SIGNS Tumor Fluid leaves vasculature into tissue Increase in vascular permeability Direct vessel injury Mediators – Leukotrienes (LTC4, LTD4, LTE4), Histamine, Bradykinin Changes in pressure gradient Hydrostatic pressure gradient Oncotic pressure gradient 13 INFLAMMATION – CARDINAL SIGNS Tumor Factors affecting pressure gradient Hydrostatic pressure Oncotic pressure 14 INFLAMMATION Transudate Causes: increased hydrostatic pressure, decreased oncotic pressure Fluid leak NOT due to inflammation Low protein content (albumin remains in plasma) Low specific gravity (dilute, not concentrated) 15 INFLAMMATION Exudate Inflammatory edema from high vascular permeability Seen in infection, malignancy (leaky vessels) High protein content (similar to plasma) High specific gravity (concentrated) 16 INFLAMMATION – CARDINAL SIGNS Dolor (pain) Key mediator – PGE2 Increases skin sensitivity to pain Causes fever 17 INFLAMMATION – SYSTEMIC INFLAMMATION Systemic Inflammation Fever Leukocytosis Acute Phase Reactants 18 INFLAMMATION – SYSTEMIC INFLAMMATION Pyrogens ↑ cyclooxygenase activity in hypothalamus ↑ prostaglandins in hypothalamus Lipopolysaccharide – exogenous pyrogen IL-1, TNF – endogenous pyrogens Prostaglandins Alter temperature set point (i.e. PGE2) 19 INFLAMMATION – SYSTEMIC INFLAMMATION Leukocytosis Normal WBC: 2 days) Longer life Replicate in tissues 41 STUDY CHECK Which cardinal sign of inflammation is characterized by increased sensitivity to pain, and which mediator is primarily responsible for it? A. Calor, mediated by Prostaglandins B. Tumor, mediated by Leukotrienes C. Rubor, mediated by Histamine D. Dolor, mediated by PGE2 42 STUDY CHECK Which of the following best describes the mechanism behind the cardinal signs of rubor (redness) and calor (heat)? A. Increased vascular permeability due to leukotrienes B. Arteriolar vasodilation resulting in increased blood flow, mediated by histamine, prostaglandins, and bradykinin C. Activation of complement proteins leading to membrane attack complex formation D. Phagocytosis by neutrophils and macrophages at the site of inflammation 43 ACUTE INFLAMMATION Typical Timeline – Exceptions Viral infections Lymphocytes predominant early on Hypersensitivity reactions Eosinophils predominate 44 ACUTE INFLAMMATION Complement Proinflammatory serum proteins that "complement" inflammation Circulate as inactive proteins and activated by three pathways: Classical pathway C1 binds IgG or IgM that is bound to antigen Mannose-binding lectin pathway MBL binds to mannose on microorganisms and activates complement Alternative pathway Microbial products directly activate complement 45 ACUTE INFLAMMATION Complement All pathways result in production of C3 convertase (mediates C3 → C3a and C3b) C3b produces C5 convertase (mediates C5 —> C5a and C5b) C5b complexes with C6-C9 to form membrane attack complex (MAC) Trigger mast cell degranulation, resulting in C3a and C5a histamine-mediated vasodilation, increased (anaphylatoxins) vascular permeability C5a Chemotactic for neutrophils C3b Opsonin for phagocytosis Lyses microbes by creating a hole in cell MAC membrane 46 47 ACUTE INFLAMMATION Mast cells Distributed throughout connective tissue Activated by tissue trauma (cold, trauma, heat) complement proteins C3a and C5a cross-linking of cell surface IgE by antigen Types of Response Release of preformed histamine granules (which binds H1 receptors of Immediate endothelial cells) response Mediate vasodilation of arterioles Increase vascular permeability of venules Delayed Production of arachidonic acid metabolites (particularly LT) response 48 ACUTE INFLAMMATION Three Outcomes Resolution of inflammation Removal of microbes/debris Healing/Scar Tissue damage surpasses regeneration Connective tissue growth Chronic inflammation 49 STUDY CHECK What is the role of leukotrienes in the inflammatory process? A. Vasodilation and fever B. Chemotaxis, leukocyte adhesion, and increased vascular permeability C. Increased sensitivity to pain D. Opsonization and membrane attack complex formation E. Chemotaxis, leukocyte adhesion, and increased vascular 50 CHRONIC INFLAMMATION Prolonged inflammation (weeks or months) Characterized by Active inflammation — mononuclear cell infiltration (macrophages, leukocytes, plasma cells) Tissue destruction Attempts at healing (via angiogenesis and fibrosis) Caused by Persistent infections — i.e. mycobacteria, viruses, fungi, parasites Hypersensitivity diseases — immune reactions against ones own tissue Prolonged exposure to toxic agents — exogenous (i.e. silica) or endogenous agents (i.e. xol) 51 CHRONIC INFLAMMATION Mononuclear cells Lymphocytes (T and B cells) Plasma cells Macrophages Secrete cytokines Activate T-cell response 52 CHRONIC INFLAMMATION T Lymphocytes Produced by bone marrow as progenitor T- cells Sent to thymus to mature into CD4+ helper or CD8+ cytotoxic T cells TCR complex recognize antigen on MHC molecules CD4+ T cells — MHC class II CD8+ T cells — MHC class I 53 CHRONIC INFLAMMATION CD4+ helper T cell Activation requires two steps 1) Antigen presented on MHC class II by APC 2) B7 on APC binds CD28 on CD4+ helper T cell Activated CD4+ helper T cell secrete cytokines INF-𝛾 : macrophage activator TH1 IL-2 : T-cell growth factor and CD8+ T cell activator IL-4 : B-cell class switching to IgG and IgE IL-5 : eosinophil chemotaxis and activation, TH2 B class switching to IgA IL-10 : inhibits TH1 phenotype 54 CHRONIC INFLAMMATION CD8+ cytotoxic T cell Activation requires two steps 1) Antigen presented on MHC class I by nucleated cells and platelets 2) IL-2 from CD4+ TH1 cell provides 2nd activation signal CD8+ cytotoxic T cell are activated for killing Secretion of perforin (perforate) and granzymes (activate apoptosis) 55 CHRONIC INFLAMMATION Naive B cells produced in bone marrow express surface IgM and IgD B-cell activation occurs via Antigen binding of IgM or IgD → produces IgM or IgD secreting plasma cells B-cell antigen presentation to CD4+ helper T cells via MHC class II CD40 receptor on B cell binds CD40L on helper T cell Helper T cell secretes IL-4 and IL-5 (isotype switching and maturation of plasma cells) 56 GRANULOMATOUS INFLAMMATION Characterized by granuloma Collection of epithelioid histiocytes (macrophages with abundant pink cytoplasm) surrounded by giant cells and lymphocytes 57 58 GRANULOMATOUS INFLAMMATION Granulomas divided into 2 types Noncaseating Lack central necrosis Common with foreign material, sarcoidosis, beryllium exposure, Crohn disease, cat scratch disease Caseating Have central necrosis Common in tuberculosis and fungal infections 59 (Left) Non caseating granuloma: center of pink aggregates which are the macrophages. Lack central necrosis. Histology shows giant cells (with multiple nuclei) and a rim lymphocytes. (Right) Caseating granuloma shows a necrotic dead center — “central necrosis” (due to dead and dying macrophages). 60 Macrophage–lymphocyte interactions in chronic inflammation. Activated T cells produce cytokines that recruit macrophages (tumor necrosis factor [TNF], interleukin-17 [IL-17], chemokines) and others that activate macrophages (interferon-γ [IFN-γ]). Activated macrophages stimulate T cells by presenting antigens and via cytokines such as IL- 12. Prolonged reactions involving T cells and macrophages may result in granuloma formation. 61 Type Nucleus Color (granules) Function Granulocytes Neutrophils First to arrive at an infection 2-5 lobes Faint/light pink (40-60%) Kill & phagocytose bacteria Eosinophils Kill helminths & other parasites (1-4%) bilobed Red Regulate inflammatory response in allergic reactions Basophils Release histamine, heparin during allergy (+mast cells) bilobed Dark blue (