1 Innate Immunity: Inflammation Chapter 6

Mosby items and derived items © 2006 by Mosby, Inc. 2 Immunity  First line of defense Innate resistance  Second line of defense Inflammation  Third line of defense Adaptive (acquired) immunity

Mosby items and derived items © 2006 by Mosby, Inc. 3 First Line of Defense  Physical and mechanical barriers Skin Linings of the gastrointestinal, genitourinary, and respiratory tracts  Sloughing off of cells  Coughing and sneezing  Flushing  Vomiting  Mucus and cilia

Mosby items and derived items © 2006 by Mosby, Inc. 4 First Line of Defense  Biochemical barriers Synthesized and secreted saliva, tears, earwax, sweat, and sebum Antimicrobial peptides  Cathelicidins, defensins, and collectins Normal bacterial flora

Mosby items and derived items © 2006 by Mosby, Inc. 5 Second Line of Defense  Inflammatory response Caused by a variety of materials  Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc. Local manifestations Vascular response  Blood vessel dilation, increased vascular permeability and leakage, white blood cell adherence to the inner walls of the vessels and migration through the vessels

Mosby items and derived items © 2006 by Mosby, Inc. 6 Inflammation  Goals Limit and control the inflammatory process Prevent and limit infection and further damage Interact with components of the adaptive immune system Prepare the area of injury for healing

Mosby items and derived items © 2006 by Mosby, Inc. 7 Plasma Protein Systems  Protein systems Complement system Coagulation system Kinin system  All contain inactive enzymes (proenzymes) Sequentially activated  First proenzyme is converted to an active enzyme  Substrate of the activated enzyme becomes the next component in the series

Mosby items and derived items © 2006 by Mosby, Inc. 8 Plasma Protein Systems  Complement system Can destroy pathogens directly Activates or collaborates with every other component of the inflammatory response Pathways  Classical  Lectin  Alternative

Mosby items and derived items © 2006 by Mosby, Inc. 9 Plasma Protein Systems  Coagulation (clotting) system Forms a fibrinous meshwork at an injured or inflamed site  Prevents the spread of infection  Keeps microorganisms and foreign bodies at the site of greatest inflammatory cell activity  Forms a clot that stops bleeding  Provides a framework for repair and healing Main substance is an insoluble protein called fibrin

Mosby items and derived items © 2006 by Mosby, Inc. 10 Plasma Protein Systems  Kinin system Functions to activate and assist inflammatory cells Primary kinin is bradykinin Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis

Mosby items and derived items © 2006 by Mosby, Inc. 11 Plasma Protein Systems

Mosby items and derived items © 2006 by Mosby, Inc. 12 Plasma Protein Systems

Mosby items and derived items © 2006 by Mosby, Inc. 13 Cellular Mediators of Inflammation  Cellular components Granulocytes, platelets, monocytes, and lymphocytes  Cell surface receptors Pattern recognition receptors (PRRs) Pathogen-associated molecular patterns (PAMPs) Toll-like receptors Complement receptors Scavenger receptors

Mosby items and derived items © 2006 by Mosby, Inc. 14 Mast Cells  Cellular bags of granules located in the loose connective tissues close to blood vessels Skin, digestive lining, and respiratory tract  Activation Physical injury, chemical agents, immunologic processes, and toll-like receptors Chemical release in two ways  Degranulation and synthesis of lipid-derived chemical mediators

Mosby items and derived items © 2006 by Mosby, Inc. 15 Mast Cell Degranulation  Histamine Vasoactive amine that causes temporary, rapid constriction of the large blood vessels and the dilation of the postcapillary venules Retraction of endothelial cells lining the capillaries Receptors  H 1 receptor (proinflammatory)  H 2 receptor (anti-inflammatory)

Mosby items and derived items © 2006 by Mosby, Inc. 16 Histamine  Receptors H 1 receptor  Proinflammatory  Present in smooth muscle cells of the bronchi H 2 receptor  Anti-inflammatory  Present on parietal cells of the stomach mucosa Induces the secretion of gastric acid

Mosby items and derived items © 2006 by Mosby, Inc. 17 Mast Cell Degranulation  Chemotactic factors Neutrophil chemotactic factor  Attracts neutrophils Eosinophil chemotactic factor of anaphylaxis (ECF-A)  Attracts eosinophils

Mosby items and derived items © 2006 by Mosby, Inc. 18 Mast Cell Synthesis of Mediators  Leukotrienes Product of arachidonic acid from mast cell membranes Similar effects to histamine in later stages  Prostaglandins Similar effects to leukotrienes; they also induce pain  Platelet-activating factor Similar effect to leukotrienes and platelet activation

Mosby items and derived items © 2006 by Mosby, Inc. 19 Mast Cells

Mosby items and derived items © 2006 by Mosby, Inc. 20 Mast Cells

Mosby items and derived items © 2006 by Mosby, Inc. 21 Mast Cells

Mosby items and derived items © 2006 by Mosby, Inc. 22 Phagocytosis  Process by which a cell ingests and disposes of foreign material  Production of adhesion molecules  Margination (pavementing) Adherence of leukocytes to endothelial cells  Diapedesis Emigration of cells through the endothelial junctions

Mosby items and derived items © 2006 by Mosby, Inc. 23 Phagocytosis

Mosby items and derived items © 2006 by Mosby, Inc. 24 Phagocytosis  Steps Opsonization, recognition, and adherence Engulfment Phagosome formation Fusion with lysosomal granules Destruction of the target

Mosby items and derived items © 2006 by Mosby, Inc. 25 Phagocytes  Neutrophils Also referred to as polymorphonuclear neutrophils (PMNs) Predominate in early inflammatory responses Ingest bacteria, dead cells, and cellular debris Cells are short lived and become a component of the purulent exudate

Mosby items and derived items © 2006 by Mosby, Inc. 26 Phagocytes  Monocytes and macrophages Monocytes are produced in the bone marrow, enter the circulation, and migrate to the inflammatory site, where they develop into macrophages Macrophages typically arrive at the inflammatory site 3 to 7 days after neutrophils Macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, and secretory products

Mosby items and derived items © 2006 by Mosby, Inc. 27 Monocytes and Macrophages

Mosby items and derived items © 2006 by Mosby, Inc. 28 Phagocytes  Eosinophils Mildly phagocytic Duties  Defense against parasites and regulation of vascular mediators

Mosby items and derived items © 2006 by Mosby, Inc. 29 Phagocytes  Natural killer (NK) cells Function is to recognize and eliminate cells infected with viruses and some function in eliminating cancer cells  Platelets Activation results in degranulation and interaction with components of the coagulation system

Mosby items and derived items © 2006 by Mosby, Inc. 30 Cytokines  Interleukins Produced primarily by macrophages and lymphocytes in response to a pathogen or stimulation by other products of inflammation Many types Examples  IL-1 is a proinflammatory cytokine  IL-10 is an anti-inflammatory cytokine

Mosby items and derived items © 2006 by Mosby, Inc. 31 Cytokines  Interferon Protects against viral infections Produced and released by virally infected host cells in response to viral double-stranded RNA Types  IFN-alpha and IFN-beta Induce production of antiviral proteins  IFN-gamma Increases microbiocidal activity of macrophages

Mosby items and derived items © 2006 by Mosby, Inc. 32 Cytokines

Mosby items and derived items © 2006 by Mosby, Inc. 33 Cytokines  Tumor necrosis factor–alpha Secreted by macrophages in response to PAMP and toll-like receptor recognition  Induces fever by acting as an endogenous pyrogen  Increases synthesis of inflammatory serum proteins  Causes muscle wasting (cachexia) and intravascular thrombosis

Mosby items and derived items © 2006 by Mosby, Inc. 34 Cytokines

Mosby items and derived items © 2006 by Mosby, Inc. 35 Local Manifestations of Inflammation  Results from vascular changes and corresponding leakage of circulating components into the tissue Heat Redness Swelling Pain

Mosby items and derived items © 2006 by Mosby, Inc. 36 Exudative Fluids  Serous exudate Watery exudate: indicates early inflammation  Fibrinous exudate Thick, clotted exudate: indicates more advanced inflammation  Purulent exudate Pus: indicates a bacterial infection  Hemorrhagic exudate Exudate contains blood: indicates bleeding

Mosby items and derived items © 2006 by Mosby, Inc. 37 Systemic Manifestations of Inflammation  Fever Caused by exogenous and endogenous pyrogens Act directly on the hypothalamus  Leukocytosis Increased numbers of circulating leukocytes  Increased plasma protein synthesis  Acute-phase reactants C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin, etc.

Mosby items and derived items © 2006 by Mosby, Inc. 38 Chronic Inflammation  Inflammation lasting 2 weeks or longer  Often related to an unsuccessful acute inflammatory response  Other causes of chronic inflammation: High lipid and wax content of a microorganism Ability to survive inside the macrophage Toxins Chemicals, particulate matter, or physical irritants

Mosby items and derived items © 2006 by Mosby, Inc. 39 Chronic Inflammation

Mosby items and derived items © 2006 by Mosby, Inc. 40 Chronic Inflammation  Characteristics Dense infiltration of lymphocytes and macrophages Granuloma formation Epithelioid cell formation Giant cell formation

Mosby items and derived items © 2006 by Mosby, Inc. 41 Resolution and Repair  Regeneration  Resolution Returning injured tissue to the original structure and function  Repair Replacement of destroyed tissue with scar tissue Scar tissue  Composed primarily of collagen to restore the tensile strength of the tissue

Mosby items and derived items © 2006 by Mosby, Inc. 42 Resolution and Repair  Débridement Cleaning up the dissolved clots, microorganisms, erythrocytes, and dead tissue cells  Healing Filling in the wound Sealing the wound (epithelialization) Shrinking the wound (contraction)

Mosby items and derived items © 2006 by Mosby, Inc. 43 Healing  Primary intention Wounds that heal under conditions of minimal tissue loss  Secondary intention Wounds that require a great deal more tissue replacement  Open wound

Mosby items and derived items © 2006 by Mosby, Inc. 44 Healing  Reconstructive phase Fibroblast proliferation Collagen synthesis Epithelialization Contraction  Myofibroblasts Cellular differentiation

Mosby items and derived items © 2006 by Mosby, Inc. 45 Healing  Maturation phase Continuation of cellular differentiation Scar tissue formation Scar remodeling

Mosby items and derived items © 2006 by Mosby, Inc. 46 Healing

Mosby items and derived items © 2006 by Mosby, Inc. 47 Dysfunctional Wound Healing  Dysfunction during inflammatory response Hemorrhage Fibrous adhesion Infection Excess scar formation Wound sepsis Hypovolemia Hypoproteinemia Anti-inflammatory steroids

Mosby items and derived items © 2006 by Mosby, Inc. 48 Dysfunctional Wound Healing  Dysfunctional during reconstructive phase Impaired collagen matrix assembly  Keloid scar  Hypertrophic scar Impaired epithelialization  Anti-inflammatory steroids, hypoxemia, and nutritional deficiencies Impaired contraction  Contracture

Mosby items and derived items © 2006 by Mosby, Inc. 49 Dysfunctional Wound Healing

Mosby items and derived items © 2006 by Mosby, Inc. 50 Dysfunctional Wound Healing  Wound disruption Dehiscence  Wound pulls apart at the suture line Excessive strain and obesity are causes  Increases risk of wound sepsis

Mosby items and derived items © 2006 by Mosby, Inc. 51 Pediatrics  Neonates have transiently depressed inflammatory and immune function  Neutrophils are not capable of efficient chemotaxis  Neonates express complement deficiency  Deficient in collectins and collectin-like proteins

Mosby items and derived items © 2006 by Mosby, Inc. 52 Elderly  Impaired inflammation is likely a result of chronic illness Diabetes, cardiovascular disease, etc.  Chronic medication intake decreases the inflammatory response  Healing response is diminished due to loss of the regenerative ability of the skin  Infections are more common in the elderly