Innate Immunity: Inflammation and Wound Healing

Innate immunity

defense mechanisms that are present at birth and provide initial response to invasion and injury

Adaptive immunity

develops over lifetime of the individual and provides long-term protection against specific invaders

Innate barriers

form first line of defense at body’s surfaces, preventing damage from the environment and thwarting infection by pathogenic microorganisms

Inflammatory response

activated to protect the body from further injury, fight infection, and promote healing

Physical barriers

comprise tightly associated epithelial cells of the skin and of the linings of the gastrointestinal (GI), genitourinary, and respiratory tracts.

Biochemical barriers

synthesizing and secreting substances meant to trap or destroy microorganisms (epithelial-derived chemicals), mucus, perspiration, saliva, tears, and earwax are all examples

Lysozyme

enzyme, which attacks the cell walls of gram-positive bacteria

Antimicrobial peptides

defensins and collectins that kill or inhibit the growth of disease-causing bacteria, fungi, and viruses

Defisins

antimicrobial peptides that defend against bacterial infection by disrupting bacterial membranes, also contribute to host protection by modulating host immune cell movement and function and maintaining the integrity of mucosal barriers

Collectins

soluble glycoproteins that facilitate the ability of macrophages to recognize and kill pathogenic microorganisms and can activate the lectin pathway of the complement system

Normal microbiome

skin, mucous membranes, and the lining of the GI, respiratory, and genitourinary tracts, are colonized with an array of microorganisms

Opportunistic pathogens

in microbiome, harmless under normal conditions but can cause disease in immunocompromised individuals who lack the usual defense mechanisms

Dysbiosis

negative changes in the microbiome

Protective functions of inflammation

1. prevention of infection and further damage caused by invading microorganisms

2. limitation of scope of inflammatory process

3. preparation of injury for healing and repair

4. facilitation of the development of adaptive immunity

Exudate

fluid that moves from the intravascular space into tissues or out of the body, consist of fluid, plasma proteins, and phagocytes

Plasma protein systems

essential to an effective inflammatory response, the complement system, the clotting system, and the kinin system; consists of multiple proteins and enzymes usually present in blood as inactive forms

Complement system

intensifies or complements the capacity of antibodies and phagocytes to clear pathogens and damaged cells and activate inflammation with proteins

C3b

serves as opsonins that coat the surface of bacteria, increasing their susceptibility to phagocytosis by inflammatory cells

C5a

functions as a chemotactic factor by diffusing from a site of inflammation and, like a magnet, attracting leukocytes to that site

C3a & C5a

sometimes called anaphylatoxins, induce rapid degranulation of mast cells to release histamine

Histamine

a substance that induces vasodilation and increased capillary permeability

Membrane Attack Complex

leads to bacterial destruction and tissue injury by creating pores in the outer membranes of cells or bacteria

Classical pathway (complementary system)

is activated by antibodies, which are components of the adaptive immune system

Antigens

targets that antibodies bind to which are typically proteins or carbohydrates produced by infectious microorganisms

Alternative pathway (complementary system)

activated directly by substances found on the surface of infectious microorganisms, include lipopolysaccharides (endotoxins) found on bacterial membranes as well as carbohydrates (zymosan) found on yeast cell walls

Lectin pathway (complementary system)

independent of antibodies and is activated by several plasma proteins, particularly mannose-binding lectin (MBL)

Mannose-binding lectin (MBL)

plasma protein that binds to bacterial polysaccharides that contain the carbohydrate mannose and activates the complement cascade

Clotting system

group of plasma proteins, which, when activated sequentially, form a blood clot, through intrinsic & extrinsic pathways turning into a common pathway

Blood clot

meshwork of fibrin strands and platelets, serve to plug damaged vessels and stop bleeding, trap microorganisms, and provide a framework for future repair and healing

Factor X

acts as the starting point for the common pathway of the clotting system, leads to activation of fibrin

Kinin system

activated by Hageman factor (fator XII), closely related to clotting system, creates bradykinin

Braydykinin

causes dilation of blood vessels, also acts in concert with prostaglandins to induce pain, trigger smooth muscle cell contraction, and increase vascular permeability

Protease inhibitors (C1 inhibitor)

inhibit activation of the complement system

Carboxypeptidase

inactivates the toxic activities of C3a and C5a

Kininase

degrades kinins

Histaminase

degrades histamine and kallikrein

Hereditary anigiodema

caused by a genetic defect in protease C1-inh, self-limiting edema of cutaneous and mucosal layers

Pattern recognition receptors (PRRs)

receptors of mast cells, macrophages, and dendritic cells, which monitor the environment for products of cellular damage and infectious microorganisms

Pathogen-associated molecular patterns

molecules expressed by infectious agents either found on their surface or released as soluble molecules

Damage-associated molecular patterns (DAMPs)

which are products of cellular damage

Toll-like receptors (TLRs

important group of PRRs, which recognize a large variety of PAMPs located on the surface of microorganisms, initiates a cascade of intracellular signaling pathways, leading to activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in the cell nucleus

Nucleotide-binding-like receptors (NLRs)

are intracellular receptors in lymphocytes, macrophages, and dendritic cells, recognize intracellular microorganisms and damaged cells and initiate the production of proinflammatory mediators

Inflammasomes

large cytoplasmic complexes that activate numerous cytokines and are implicated in a wide variety of diseases

Scavenger receptors

membrane receptors primarily expressed on macrophages, recognition and subsequent phagocytosis of bacterial pathogens and damaged cells

C-type lectin receptors (CLRs)

type of scavenger receptor that binds to both PAMPs and DAMPs, important in recognizing fungal antigens

Complement receptors

recognize several components of the complement system, resulting in chemotaxis and activation of innate immune cells

Cytokine receptors

recognize both proinflammatory and antiinflammatory cytokines

Mast cells

significant and potent activators of the inflammatory response, have abundant granules containing biochemical mediators, which are released in instances of pathogen invasion and tissue injury

Mast cell induced inflammation

due to releasing potent soluble substances through: 1. degranulation—release of the contents of mast cell granules 2. synthesis—the new production and release of mediators in response to a stimulus

Histamine

potent effects on many other cells, particularly those that control circulation, such as endothelial cells, smooth muscle cells, and myocardial cells, bind to H1, H2, H3, and H4 receptors.

Antihistamines

drugs that block the binding of histamine to the H1 receptor, resulting in decreased vascular effects

Chemotaxis

directional movement of cells along a chemical gradient formed by a chemotactic factor

Macrophages

synthesize and release of inflammatory mediators and through the process of phagocytosis, consume foreign pathogens and cancer cells

Cytokines

family of intercellular signaling molecules that are secreted, bind to specific membrane receptors, and regulate innate and adaptive immunity

Tumor necrosis factor alpha (TNF-α)

plays a role in promoting the innate response to virtually any injury or infection by enhancing chemotaxis and adherence of neutrophils, phagocytosis, and immune cell proliferation

Interleukins (ILs)

1. Regulation of CAMs, which are proteins that facilitate leukocyte binding with other cells or with the extracellular matrix

2. Attraction of leukocytes to a site of inflammation (chemotaxis)

3. Proliferation and maturation of leukocytes in bone marrow

4. General enhancement or suppression of inflammation and the adaptive immune response

Interleukin 1 (IL-1)

enhances both innate and adaptive immunity, endogenous pyrogen (fever-causing cytokine) that reacts with receptors on cells of the hypothalamus

Interleukin 6 (IL-6)

directly induces hepatocytes in the liver to produce many of the proteins needed for inflammation, also stimulates the growth and differentiation of blood cells in the bone marrow and the growth of fibroblasts required for wound healing

Interferons (IFNs)

members of a family of cytokines that protect against viral infections and modulate the immune response

Dendritic cells

recognize invaders with PRRs and phagocytose them, they migrate through lymphatic vessels to lymph nodes, where they present antigens from the phagocytosed invaders to the adaptive immune system

Hemostasis (coagulation)

Injury to blood vessels initiates the clotting cascade and activates platelets

Vasodilation

increases the diameter of blood vessels, increases the volume of blood delivered to the injured site, and slows the velocity of blood flow

Increased vascular permeability

blood vessels become porous, secondary to retraction of endothelial cells, thus opening vascular tight junctions and enlarging the spaces between these cells

Leukocyte cell adhesion

adhere to the inner walls of vessels, where they migrate through the enlarged spaces between endothelial cells and into the surrounding tissue

Neutrophils

circulate in the blood in large numbers and are attracted to the area of injury by chemotactic factors, primary role of the neutrophil is to phagocytize pathogenic microbes and remove cellular debris and dead cells from lesions

Phagocytosis

ingestion of microbes, foreign particles, or cell fragments: four steps:

1. recognition and adherence (through PRRs)

2. engulfment and formation of phagosomes

3. fusion

4. destruction

Margination

tight binding to the endothelium, done by phagocytes

Diapedesis (or emigration)

after margination, when another adhesion molecule us expressed, phagocytes go through the openings between the endothelial cells.

Opsonins

coat the target bacteria or cell act as a “glue,” tightening the affinity between the phagocyte and the target (C3b)

Eosinophil

innate immune cell, primary defense against parasites and also degrade substances from mast cells

Basophil

contents of granules include histamine and heparin (anticoagulation)

Lymphocytes

primary cells of adaptive immune response, pathogens and cancers, B type produces antibodies, T type reglates other immune cells, kills viruses and cancer cells

Natural killer cells

eliminate virally infected and cancerous cells, inhibitory and activating receptors that allow differentiation

Pyrogens

substances that produce fever

Leukocytosis

increase in the number of circulating white blood cells beyond the upper limit of normal

Repair

replacement of destroyed tissue with scar tissue

Scar tissue

composed primarily of collagen, fills in the lesion, restoring tissue integrity and strength

Proliferative phase

begins 3 to 4 days after the injury, wound is sealed and fibrin clot is replaced by tissue, is characterized by invasion of macrophages

Angiogenesis

process of formation of new blood vessels and is important step in wound healing

Granulation tissue

grows into wound from surrounding healthy connective tissue, consists of tissue stem cells, new lymphatic vessels, and new capillaries, all derived from the analogous structures found in the surrounding healthy tissue

Epithelialization

process by which epithelial stem cells grow into the wound from surrounding healthy tissue

Remodeling and maturation

process that begins weeks after injury and continues for months, fibroblasts secrete collagen and other connective tissue proteins

Dysfunctional wound healing

caused by ischemia, excessive bleeding, infection, excessive fibrin, obesity, diabetes

Keloid

raised scar that extends beyond the original boundaries of the wound, invading surrounding tissue

Hypertrophic scar

raised but remains within the original boundaries of the wound, tends to regress over time

Dehiscence

scenario in which the wound pulls apart at the suture line, occurs 5 to 12 days after suturing, associated with wound infection and suture rupture caused by excessive strain

Contracture

wound contraction that becomes excessive resulting in an anatomic deformity