Chapter 6 Innate Immunity: Inflammation

Cell Mediators of Inflammation

- Cellular components: granulocytes, platelets, monocytes, and lymphocytes

First Line of Defense

- Physical and mechanical barriers * skin * linings of GI, GU, and respiratory tracts: sloughing off of cells, coughing & sneezing, flushing, vomiting, mucus & cilia - Biochemical barriers * synthesized & secreted saliva, tears, earwax, sweat, & sebum * normal bacterial flora: vaginal- lactobacillus, intestinal- produce ammonia, phenols, etc. that inhibit colonization by pathogens

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 - Debridement: cleaning up dissolved clots, microorganisms, erythrocyte, & dead tissue cells - Healing * filling in the wound * sealing the wound (epithelialization) * shrinking the wound (contraction)

Platelets

- activation results in degranulation & interaction with components of the coagulation system

Complement System

- can destroy pathogens directly - activates or collaborates with every other component of the inflammatory response

Mast Cells

- cellular bags of granules located in loose connective tissues close to blood vessels * skin, digestive lining, respiratory tract - activation * physical injury, chemical agents, immunologic process * chemical release in two ways: degranulation & synthesis of lipid-derived chemical mediators

Control of Inflammation

- histaminase- inhibits histamine - arylsulfatase- inhibits histamine - C-1 esterase inhibitor- inhibits complement - Kinins and clotting

Eosionphils

- mildly phagocytic - duties: defense against parasites & regulation of vascular mediators

Inflammation in Pediatrics

- neonates have transiently depressed inflammatory & immune function - neutrophils not capable of efficient chemotaxis - neonates express complement deficiency - deficient in collectins & collectin-like proteins

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)

Vascular Response

- transient vasoconstriction- seconds - vasodilation - increased capillary permeability - exudation of fluid and cells - cellular migration (margination/adherence, migration)

Monocytes & Macrophages

- types of phagocytes - monocytes produced in bone marrow, enter circulation, & migrate to the inflammatory site, where they develop into macrophages - macrophages typically arrive at inflammatory site 3 to 7 days after neutrophils - macrophage activation results in increased size, plasma membrane area, glucose metabolism, number of lysosomes, & secretory products

Systemic Manifestations of Inflammation

- fever * caused by exogenous & endogenous pyrogens * act directly on the hypothalamus - Leukocytosis * increased numbers of circulating leukocytes * left shift, increase in immature cells (bands) - Increased plasma protein synthesis * acute-phase reactants: C-reactive protein, fibrinogen, haptoglobin, amyloid, ceruloplasmin

Immunity

- first line of defense: innate resistance - second line of defense: inflammation - third line of defense: adaptive (acquired) immunity

Coagulation (clotting) System

- forms a fibrinous meshwork at an injured or inflamed site * prevents the spread of infection * keeps microorganisms & foreign bodies at the site of greatest inflammatory cell activity * forms a clot that stops bleeding * provides a framework for repair & healing - main substance is an insoluble protein call fibrin

Natural Killer (NK) Cells

- function: recognize & eliminate cells infected with viruses & some function in eliminating cancer cells

Kinin System

- functions to activate and assist inflammatory cells - primary kinin is bradykinin - cause dilation of blood vessels, pain, smooth muscle contraction, vascular permeability

Inflammation in Older Adults

- impaired inflammation 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 older adults

Chemokines

- induce WBC chemotaxis - produced by macrophages, fibroblasts, endothelial cells

Chronic Inflammation

- inflammation lasting 2 weeks or longer - often related to an unsuccessful acute inflammatory response - other causes * high lipid & wax content of microorganism * ability to survive inside the macrophage * toxins * chemicals, particulate matter, or physical irritants

Goals Of Inflammation

- limit control the inflammatory process - prevent and limit infection and further damage - control bleeding - interact with components of the adaptive immune system - prepare the area of injury for healing

Phagocytosis

- process by which a cell ingests & disposes of foreign material - production of adhesion molecules - margination * adherence of leukocytes to endothelial cells * emigration of cells through endothelial junctions - steps: recognition & adherence; engulfment; phagosome formation; fusion with lysosomal granules; destruction of the target

Local Manifestations of Inflammation

- results from vascular changes & corresponding leakage of circulating components * 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

Interleukins

- type of cytokine - produced primarily by macrophages & lymphocytes in response to a pathogen or stimulation by other products of inflammation - many types * IL-1: proinflammatory cytokine * IL-10: anti-inflammatory cytokine - interluekins are important in the late inflammatory response

Interferon

- type of cytokine - protects against viral infections - produced & released by virally infected host cells in response to viral double-stranded RNA - Types * INF-alpha & INF-beta: induce production of antiviral proteins * INF- gamma: increases microbiocidal activity of macrophages

Neutrophils

- type of phagocyte - also referred to as polymorphonuclear neutrophils (PMNs) - predominate in early inflammatory responses - ingest bacteria, dead cells, and cellular debris - cells are short lived & become a component of the purulent exudate * high PMNs: indicate bacterial infection

Complement is:

A. A series of proteins in the blood

Diapedesis is a process in which:

A. Neutrophils migrate from the bloodstream to an injured tissue site.

Scar tissue is:

A. Nonfunctional collagenous and fibrotic tissue.

The C3b subcomponent of complement:

A.opsonizes microbes to facilitate phagocytosis.

The sequence of inflammatory events within the vasculature is:

B. Arteriolar vasoconstriction, vasodilation, increased capillary permeability, plasma leakage, and site of injury edema.

Mast cell degranulation releases:

B. Histamine, IL-4, and eosinophil chemotactic factor of anaphylaxis

Interferon:

B. Prevents viruses from infecting health host cells.

Collectins:

B. Protect against respiratory infections

Swelling during acute inflammation is caused by:

B. The fluid exudate

The activation of Hageman factor impacts all three plasma protein systems by:

C. Activation of the kinin system by a fragment of Hageman factor.

The alternative complement pathway is activated by:

C. Gram-negative bacterial and fungal cell wall polysaccahrides.

Interleukin 10:

C. suppresses growth of lymphocytes and production of proinflammatory cytokines.

Innate resistance or immunity;

D. Depends on physical, mechanical, and biochemical barriers

Characteristic systemic manifestations of acute inflammation include:

D. Fever caused by the release of IL-1 by neutrophils and macrophages.

Chronic inflammation is characterized by:

D. Lymphocytic and macrophagic infiltration

The sequence for phagocytosis is:

D. Margination, diapedesis, recognition, adherence, ingestion, fusion with lysosomes inside the phagocyte, and destruction of the target.

The inflammatory response:

D. Minimizes injury and promotes healing.

Recognition of abnormal environment components so calls can respond to these substances is by binding to cell surface receptors. Cells involved in innate resistance have:

D. Pattern recognition receptors (PRRs)

Dysfunctional Wound Healing

Dysfunction during inflammatory response - hemorrhage - fibrous adhesion - infection - excess scar formation - wound sepsis - hypovolemia - hypproteinemia - anti-inflammatory steroids Dysfunction during reconstructive phase - impaired collagen matrix assembly * hypertrophic scar - impaired epitheliliazation * anti-inflammatory steroids, hypoxemia, & nutritional deficiencies - Impaired contraction: contracture Wound Disruption - Dehiscence * wound pulls apart at the suture line: excessive strain & obesity are causes * increased risk of wound sepsis

Primary defenders against parasites and help regular vascular mediators released from mast cells by preventing more inflammatory activity than is needed.

Eosinophils

Filled with new capillaries and is surrounded by fibroblasts and macrophages

Granulation Tissue

Mast Cell Degranulation

Histamine - vasoactive amine that causes temporary, rapid constriction of the large blood vessels & the dilation of the postcapillary venues - retraction of endothelial cells lining the capillaries - receptors * H1 receptor (proinflammatory) * H2 receptor (anti-inflammatory) Chemotactic Factors - neutrophil chemotactic factor: attracts neutrophils - eosinophil chemotactic factor of anaphylaxis (ECF-A): attracts eosinophils

Second Line of Defense

Inflammatory Response - causes: infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, radiation, etc - local manifestations - vascular response: blood vessel dilation, increased vascular permeability and leakage, WBC adherence to the inner walls of the vessels & migration through the vessels

Mast Cell Synthesis of Mediators: Late Response

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 & platelet activation

"large eater" --large phagocytic cells that wander actively in the interstitial fluid, eating any bacteria and virus-infected cells they encounter/ function for a longer time and later in the response involved in activation of adaptive immune system

Macrophages

They recognize and eliminate virus-infected cells and cancerous cells.

Natural Killer Cells

Predominant phagocytes arriving early at inflammatory and infection sites

Neutrophils

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

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 (includes secretion of gastric acid)

Return injured tissues to an approximation of their original structure and physiologic function.

Resolution

Soluable tumor necrosis factor-alpha:

Soluable tumor necrosis factor-alpha: