Innate Immunity: InflammationChapter 6

Immunity First line of defense

Innate resistance – physical (skin/epithelial layer, GI & Resp Tract), , mechanical (Cough, sneeze, vomit, cilia action in trachea) & biochemical barriers (antimicrobial peptides, lung secretions, mucus, saliva, tears, earwax)

Second line of defense Inflammation – vascular response – dilation, histamines

increase vessel leakage, wbc action, cytokines, leucokines, fever. Usually redness and heat with swelling.

Third line of defense Adaptive (acquired) immunity – antibody production

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

First Line of Defense Biochemical barriers

Synthesized and secreted saliva, tears, earwax, sweat, and sebum

Antimicrobial peptides Cathelicidins, defensins, and collectins

Normal bacterial flora

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

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

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

Plasma Protein Systems Complement system

Can destroy pathogens directly Activates or collaborates with every other

component of the inflammatory response Pathways

Classical Lectin Alternative

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

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

Plasma Protein Systems

Plasma Protein Systems

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

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

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 H1 receptor (proinflammatory)

H2 receptor (anti-inflammatory)

Histamine Receptors

H1 receptor Proinflammatory Present in smooth muscle cells of the bronchi

H2 receptor Anti-inflammatory Present on parietal cells of the stomach mucosa

Induces the secretion of gastric acid

Mast Cell Degranulation Chemotactic factors

Neutrophil chemotactic factor Attracts neutrophils

Eosinophil chemotactic factor of anaphylaxis (ECF-A) Attracts eosinophils

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

Mast Cells

Mast Cells

Mast Cells

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

Phagocytosis

Phagocytosis Steps

Opsonization, recognition, and adherence Engulfment Phagosome formation Fusion with lysosomal granules Destruction of the target

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

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

Monocytes and Macrophages

Phagocytes Eosinophils

Mildly phagocytic Duties

Defense against parasites and regulation of vascular mediators

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

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

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

Cytokines

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

Cytokines

Local Manifestations of Inflammation Results from vascular changes and

corresponding leakage of circulating components into the tissue Heat Redness Swelling Pain

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

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.

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

Chronic Inflammation

Chronic Inflammation Characteristics

Dense infiltration of lymphocytes and macrophages

Granuloma formation Epithelioid cell formation Giant cell formation

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

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)

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

Healing Reconstructive phase

Fibroblast proliferation Collagen synthesis Epithelialization Contraction

Myofibroblasts

Cellular differentiation

Healing Maturation phase

Continuation of cellular differentiation Scar tissue formation Scar remodeling

Healing

Dysfunctional Wound Healing Dysfunction during inflammatory response

Hemorrhage Fibrous adhesion Infection Excess scar formation Wound sepsis Hypovolemia Hypoproteinemia Anti-inflammatory steroids

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

Dysfunctional Wound Healing

Dysfunctional Wound Healing Wound disruption

Dehiscence Wound pulls apart at the suture line

Excessive strain and obesity are causes

Increases risk of wound sepsis

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

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