Inflammation Acute Inflammation – Vascular Changes, Cellular Events – Outcomes of Acute Inflammation – Morphologic Patterns of Acute Inflammation – Chemical Mediators and Regulators of Inflammation – Cell-Derived Mediators – Plasma Protein-Derived Mediators – Anti-inflammatory Mechanisms Chronic Inflammation – Chronic Inflammatory Cells and Mediators – Granulomatous Inflammation Systemic Effects of Inflammation

Inflammation Inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the subsequent repair process can themselves cause considerable harm

Sequence of events in an inflammatory reaction

The components of acute and chronic inflammation and their principal functions

Acute or Chronic ACUTE INFLAMMATION is rapid in onset, of short duration – Few minutes to as long as a few days – Fluid and plasma protein exudation – Neutrophil accumulation CHRONIC INFLAMMATION is insidious, of longer duration – Days to years – Lymphocytes and macrophages – Vascular proliferation – Fibrosis (scarring)

Features of Acute and Chronic Inflammation Weeks, months

Cardinal signs of Inflammation 1.Heat (calor) 2.Redness (rubor) 3.Swelling (tumor) 4.Pain (dolor) Cornelius celsus 5.Loss of function (functio laesa) Rudolf Virchow Rubor, Calor, Tumor are mediated by Histamine Dolor (pain): mediated by PGE 2 and bradykinin

Steps of the inflammatory response 5 “R”s 1.Recognition of the injurious agent 2.Recruitment of leukocytes 3.Removal of the agent 4.Regulation (control) of the response 5.Resolution (repair)

Acute Inflammation Vascular changes – VASODILATION – INCREASED VASCULAR PERMEABILITY Cellular events – Emigration of leukocytes (mainly neutrophils) from circulation and accumulation in the focus of injury, followed by activation

Stimuli for Acute Inflammation Infections (bacterial, viral, fungal, parasitic) Trauma (blunt and penetrating) Physical and chemical agents (Burns, frostbite, irradiation, toxic chemicals) Tissue necrosis (from any cause), including ischemia Foreign bodies (splinters, dirt, sutures, crystal deposits) Immune reactions (hypersensitivity reactions)

Recognition of Microbes, Necrotic Cells, and Foreign Substances Phagocytes, dendritic cells and other cells express “pattern recognition receptors” – Toll-like receptors (TLRs) – Inflammasome

Vascular Changes Changes in Vascular Caliber and Flow – “Arteriolar vasodilation” – cause of redness (erythema) and warmth – caused by histamine and other vasodilators (NO) Increased Vascular Permeability – “Increased permeability of post-capillary venules” – caused by histamine and other mediators – leads to the movement of protein-rich fluid and even blood cells into the extravascular tissues (EXUDATE)

Vascular dilation and increased blood flow (causing erythema and warmth)

Mechanisms of Increased Vascular Permeability Endothelial cell contraction leading to intercellular gaps in post-capillary venules Endothelial injury Increased transcytosis Leakage from new blood vessels

Mechanisms of increased vascular permeability in inflammation

Cellular Events Leukocyte Recruitment 1.Margination and rolling along the vessel wall 2.Firm adhesion to the endothelium 3.Transmigration between endothelial cells 4.Migration in interstitial tissues toward a chemotactic stimulus

Mechanisms of leukocyte migration through blood vessels

Margination and Rolling Selectins – E-selectin (CD62E) on endothelial cells – P-selectin (CD62P) on platelets and Weibel – Palade bodies on endothelium – L-selectin (CD62L) on leukocytes

Acute inflammatory response showing vasodilation with margination of neutrophils

Adhesion Integrins ICAM-1 (immunoglobulin family) CD11/CD18 integrins (LFA-1, Mac-1) VCAM-1 (immunoglobulin family) VLA-4 integrin

β2-integrins Located on neutrophils and interact with corresponding ligands on venular endothelial cells Activated by C5a and leukotriene B4 (LTB4) Inhibited by catecholamines and corticosteroids

Activation of endothelial cell integrin adhesion molecules (ligands) IL-1 and TNF activate intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM) on venular endothelial cells Activated ICAM ligands bind to activated β2-integrins on neutrophils causing them to firmly adhere to venular endothelium Activated VCAM ligands firmly bind to activated β1-integrins on eosinophils, monocytes, and lymphocytes

Leukocyte Adhesion Deficiency (LAD) disorders Autosomal recessive inheritance pattern LAD type 1 - deficiency of β2-integrin (CD11a:CD18) LAD type 2 - deficiency of endothelial cell selectin that binds neutrophils First manifestation in either type is delayed separation of the umbilical cord Severe gingivitis, poor wound healing, and peripheral blood neutrophilic leukocytosis (loss of the marginating pool)

Transmigration Diapedesis Platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31) Collagenases (released by neutrophils moving along the venular endothelium dissolve the venular basement membrane)

Chemotaxis Bacterial products, particularly peptides with N- formylmethionine termini Cytokines, especially those of the chemokine family Components of complement system, particularly C5a Products of the lipoxygenase pathway of arachidonic acid (AA) metabolism, particularly leukotriene B4 (LTB4)

Leukocyte Activation Phagocytosis of particles Intracellular destruction of phagocytosed microbes and dead cells Liberation of substances that destroy extracellular microbes and dead tissues Production of mediators

Phagocytosis Recognition and attachment of the particle to the ingesting leukocyte – Opsonization ( IgG, C3b, collectins) Engulfment, with subsequent formation of a phagocytic vacuole Killing and degradation of the ingested material

Bruton agammaglobulinemia Recurrent bacterial infections after 6 months due to Opsonization defect (↓ IgG) Pre–B cells cannot mature to B cells; therefore plasma cells, which are derived from B cells, cannot synthesize immunoglobulins (IgG)

Leukocyte activation

Killing and Degradation of Phagocytosed Microbes Oxidative burst (respiratory burst) NADPH oxidase (phagocyte oxidase) oxidizes NADPH and converts oxygen to superoxide ion (O2 ) Superoxide is converted by spontaneous dismutation into hydrogen peroxide (O2 + 2H+ → H2O2) Lysosomes of neutrophils (azurophilic granules) contain myeloperoxidase (MPO), and in the presence of a halide such as Cl−, MPO converts H2O2 to HOCl (hypochlorous radical)

Phagocytosis

Chédiak-Higashi syndrome A form of phagocyte bactericidal dysfunction characterized by unusual oculo-cutaneous albinism, high incidence of lymphoreticular neoplasms, and recurrent pyogenic infections A defect in microtubule function prevents lysosomes from fusing with phagosomes to produce a phagolysosome

O 2 -dependent myeloperoxidase system

Neutrophil killing of bacteria/fungi by the O 2 - dependent myeloperoxidase (MPO) system O 2 -dependent MPO system – most potent microbicidal system – only present in neutrophils and monocytes (not macrophages) NADPH oxidase enzyme complex converts molecular O 2 to superoxide FRs, releases energy (respiratory/oxidative burst) Superoxide dismutase (SOD) converts O 2 – to H 2 O 2, some peroxide is converted to hydroxyl FRs by iron via Fenton reaction Production of bleach (HOCl): MPO in the phagolysosome combines H 2 O 2 with chloride (Cl–) to form hypochlorous FRs (HOCl), which kill bacteria and some fungi

Chronic granulomatous disease (CGD) X-linked recessive (65%) or autosomal recessive (30%) X-linked type - mutation in CYBB gene that codes for a component in the NADPH oxidase enzyme complex ↓production of O 2 – (absent respiratory/oxidative burst) Catalase-positive organisms that produce H 2 O 2 (e.g., Staph aureus, Nocardia asteroides, Serratia marcescens, Aspergillus and Candida) are ingested but not killed, because the catalase degrades the H 2 O 2 produced by these pathogens Myeloperoxidase is present, but HOCl is not synthesized because of the absence of H 2 O 2

Chronic granulomatous disease (CGD) Catalase-negative organisms (e.g., Streptococcus species) that produce H 2 O 2 are ingested and can be killed when myeloperoxidase combines H 2 O 2 (derived from the bacteria) with Cl– to form HOCl Granulomatous inflammation occurs because neutrophils, can phagocytose bacteria but not kill them and so are replaced by lymphocytes and macrophages. Macrophages fuse to form multinucleated giant cells (a characteristic feature of granulomatous inflammation) Severe infections involving the lungs (pneumonia most common), skin, visceral organs, and bones

Chronic granulomatous disease (CGD) NITROBLUE TETRAZOLIUM (NBT) DYE TEST Leukocytes in a test tube are incubated with the NBT dye, which turns blue if superoxide FRs are present, indicating that the respiratory (oxidative) burst is intact The NBT dye test is negative in the X- linked type of CGD (NBT dye is not converted to a blue dye), because the NADPH oxidase enzyme complex is dysfunctional

Chronic granulomatous disease (CGD) Severe infections involving the lungs (pneumonia most common), skin, visceral organs, and bones Treatment of CGD involves prophylaxis and treatment of infections and bone marrow transplantation

Myeloperoxidase (MPO) deficiency Differs from CGD in that both O 2 – and H 2 O 2 are produced (normal respiratory burst) Absence of MPO prevents synthesis of HOCl

Neutrophil killing of bacteria by O 2 -independent microbial systems Lactoferrin (present in neutrophil granules), which binds iron that is necessary for normal bacterial growth and reproduction Major basic protein (MBP), an eosinophil product that is cytotoxic to helminths

Extravascular fluid collections EXUDATE : fluid rich in protein and/or cells, appears grossly cloudy – Dilutes bacterial toxins, if they are present – Provides opsonins (IgG, C3b) to assist in phagocytosis TRANSUDATE : basically an ultrafiltrate of plasma with little protein and few or no cells, appears grossly clear

Effusions into body cavities SEROUS : a transudate with mainly edema fluid and few cells SEROSANGUINOUS : an effusion with red blood cells FIBRINOUS (SEROFIBRINOUS) : fibrin strands derived from a protein-rich exudate PURULENT : numerous PMN's are present, also called "empyema" in the pleural space

Outcomes of Acute Inflammation