Innate Immunity & Wound Healing PDF

Chapter 7 Innate Immunity: Inflammation and Wound Healing Linda Wunder, PhD, CRNA, APRN, FAANA Copyright © 2019, Elsevier Inc. All rights reserved. Immunity ´ Types of immunity ´ Innate resistance: Natural barriers and the inflammatory response ´ Adaptive (acqu...

Chapter 7 Innate Immunity: Inflammation and Wound Healing Linda Wunder, PhD, CRNA, APRN, FAANA Copyright © 2019, Elsevier Inc. All rights reserved. Immunity ´ Types of immunity ´ Innate resistance: Natural barriers and the inflammatory response ´ Adaptive (acquired) immunity ´ Lines of defense ´ First line ´ Natural barriers: physical, mechanical and biochemical ´ Second line ´ Inflammation ´ Third line ´ Adaptive (acquired) immunity Copyright © 2019, Elsevier Inc. All rights reserved. 2 First Line of Defense ´ Physical and mechanical barriers ´ Skin and low temp/pH of skin ´ Linings of the gastrointestinal, genitourinary, and respiratory tracts ´ Highly interconnected junctions ´ Sloughing off of cells ´ Coughing and sneezing ´ “Washing” ´ Vomiting ´ Urinating ´ Mucus and cilia Copyright © 2019, Elsevier Inc. All rights reserved. 3  First Line of Defense (Cont.) ´ Biochemical barriers ´ Synthesize and secrete substances to trap or destroy microorganisms. ´ Antibacterial peptides in mucus, perspiration (sweat), saliva, tears, and earwax ´ Antimicrobial peptides ´ Cathelicidins, defensins (α defensins in neutrophil granules and β defensins), and collectins (lungs) ´ Normal microbiome ´ Inhibits colonization by pathogens; releases chemicals that prevent infection. ´ Vaginal: Lactobacillus ´ Intestinal: Ammonia, phenols, and indoles Copyright © 2019, Elsevier Inc. All rights reserved. 4 Second Line of Defense ´ Inflammatory response ´ Causes ´ Infection, mechanical damage, ischemia, nutrient deprivation, temperature extremes, and radiation ´ Cellular and chemical components ´ Nonspecific ´ Takes place in approximately the same way, regardless of the type of stimulus or whether exposure to the same stimulus has occurred in the past. ´ Rapidly initiated ´ No memory cells Copyright © 2019, Elsevier Inc. All rights reserved. 5 Second Line of Defense (Cont.) ´ Inflammatory response (cont.) ´ Cardinal signs ´ Redness, heat, swelling, pain, loss of function ´ Vascular response ´ Blood vessel dilation, increased vascular permeability and leakage, white blood cell (WBC) adherence to the inner walls of the vessels, and migration through the vessels (diapedesis) Copyright © 2019, Elsevier Inc. All rights reserved. 6 Second Line of Defense (Cont.) ´ Inflammatory response (cont.) ´ Once in the tissues, the cells and chemicals associated with the inflammatory response ´ prevent and limit infection and further damage. ´ limit and control the inflammatory process. ´ interact with components of the adaptive immune system. ´ prepare the area of injury for healing. Copyright © 2019, Elsevier Inc. All rights reserved. 7 Plasma Protein Systems ´ Protein systems that provide a biochemical barrier against invading pathogens are the ´ complement system. ´ clotting system. ´ kinin system. ´ All contain inactive enzymes (proenzymes). ´ Sequentially activated–cascade ´ First proenzyme is converted to an active enzyme. ´ The activation of the first component of a system results in sequential activation of other components. Copyright © 2019, Elsevier Inc. All rights reserved. 8 Plasma Protein Systems (Cont.) ´ Complement system ´ Can destroy pathogens directly ´ Activates or collaborates with every other component of the inflammatory response. ´ Pathways ´ Classical: Antibodies and antigens ´ Lectin: Mannose-containing bacterial carbohydrates ´ Alternative: Gram-negative bacterial and fungal cell wall polysaccharides ´ Functions ´ Anaphylatoxic activity resulting in mast cell degranulation; leukocyte chemotaxis; opsonization; cell lysis Copyright © 2019, Elsevier Inc. All rights reserved. 9 Plasma Protein Systems (Cont.) Copyright © 2019, Elsevier Inc. All rights reserved. 10  Plasma Protein Systems (Cont.) ´ Clotting (coagulation) system ´ Forms a fibrinous mesh at an injured or inflamed site. Main substance in fibrinous mesh is insoluble protein called fibrin. ´ Prevents the spread of infection. ´ Keeps microorganisms and foreign bodies at the site of inflammation for removal. ´ Forms a clot that stops bleeding. ´ Provides a framework for repair and healing. ´ Pathways ´ Extrinsic: Is activated by the tissue factor outside the vascular space. ´ Intrinsic: Is activated in the vascular space when the vessel wall is damaged. Copyright © 2019, Elsevier Inc. All rights reserved. 11 Plasma Protein Systems (Cont.) ´ Kinin system ´ Functions to activate and assist inflammatory cells. ´ Kinin is primarily bradykinin. ´ Causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis. ´ Kininases degrade kinins. Copyright © 2019, Elsevier Inc. All rights reserved. 12 Plasma Protein Systems (Cont.) ´ Interactions among the three plasma protein systems are finely regulated to prevent injury to the host tissue and to guarantee activation when needed. ´ Multiple mechanisms are available to either activate or inactivate (regulate) these plasma protein systems. Copyright © 2019, Elsevier Inc. All rights reserved. 13 Plasma Protein Systems (Cont.) Copyright © 2019, Elsevier Inc. All rights reserved. 14 Plasma Protein Systems (Cont.) ´ Interactions among the three plasma protein systems control inflammation and inhibit the three plasma protein systems. ´ Carboxypeptidase: Inhibits C3a and C5a ´ Histaminase: Inhibits histamine ´ Arylsulfatase: Inhibits histamine ´ Kinase: Inhibits kinins ´ C1-esterase inhibitor: Inhibits complement Copyright © 2019, Elsevier Inc. All rights reserved. 15 Cellular Mediators of Inflammation ´ Cellular mediators ´ Mast cells ´ Granulocytes (neutrophils, eosinophils, basophils) ´ Monocytes and macrophages ´ Natural killer (NK) cells and lymphocytes ´ Cellular fragments (platelets) ´ Biochemical mediators ´ Originate from destroyed or damaged cells. ´ Modulate the localization and activities of other inflammatory cells. ´ Tissue regeneration or repair (resolution). Copyright © 2019, Elsevier Inc. All rights reserved. 16  Cellular Mediators of Inflammation (Cont.) ´ Cell surface or cellular receptors ´ Pattern recognition receptors (PRRs) ´ Toll-like receptors (TLRs): Recognize pathogen-associated molecular patterns (PAMPs). ´ Complement receptors: Recognize complement fragments. ´ Scavenger receptors: Promote phagocytosis. ´ PAMPs ´ Damage-associated molecular patterns (DAMPs) ´ Inflammatory response ´ Is initiated when tissue injury occurs or when PAMPs are recognized by PRRs on cells of the innate immune system. Copyright © 2019, Elsevier Inc. All rights reserved. 17 Cellular Mediators of Inflammation (Cont.) ´ Cellular products ´ Chemokines or cytokines: Regulate innate or adaptive resistance by affecting other neighboring cells. ´ Are either proinflammatory or antiinflammatory. ´ Actions are pleiotropic: The same molecule may have a large variety of different biologic activities, depending on the particular target cell to which it binds. ´ Are either synergistic or antagonistic. ´ Include interleukins, interferons, and tumor necrosis factor (TNF). Copyright © 2019, Elsevier Inc. All rights reserved. 18 Cytokines ´ Interleukins (ILs) ´ Are produced primarily by macrophages and lymphocytes in response to a microorganisms or stimulation by other products of inflammation. ´ Help regulate inflammation. ´ Many types exist. ´ Examples ´ IL-1 is a proinflammatory cytokine: Causes fever. ´ IL-6 is a proinflammatory cytokine: Helps with healing. ´ IL-10 is an antiinflammatory cytokine. ´ Transforming growth factor–beta (TGF-β) is an antiinflammatory cytokine. Copyright © 2019, Elsevier Inc. All rights reserved. 19 Cytokines (Cont.) ´ Interferons (IFNs) ´ Protect against viral infections. ´ Are produced and released by virally infected host cells in response to viral double-stranded ribonucleic acid (RNA). ´ Do not directly kill viruses but prevent them from infecting additional healthy cells. ´ Types ´ IFN-α and IFN-β ´ Induce the production of antiviral proteins. ´ IFN-γ ´ Increases microbiocidal activity of macrophages. Copyright © 2019, Elsevier Inc. All rights reserved. 20 Chemokines ´ Induce WBC chemotaxis. ´ Are produced by macrophages, fibroblasts, and endothelial cells. ´ More than 40 different kinds exist. ´ Vast majority are classified as either CC-chemokines (β-chemokines) or CXC-chemokines (α-chemokines). ´ CC-chemokines affect mainly monocytes, lymphocytes, and eosinophils. ´ CXC-chemokines generally affect neutrophils. Copyright © 2019, Elsevier Inc. All rights reserved. 21 Mast Cells ´ Are cellular bags of granules located in loose connective tissues close to blood vessels. ´ Skin, digestive lining, and respiratory tract ´ Activation ´ Physical injury, chemical agents, immunologic processes, and TLRs ´ Chemicals are released in two ways ´ Degranulation ´ Synthesis of lipid-derived chemical mediators Copyright © 2019, Elsevier Inc. All rights reserved. 22 Mast Cell Degranulation ´ Releases histamine ´ Causes temporary and rapid constriction of the large blood vessels and dilation of the postcapillary venules. ´ Endothelial cells that line the capillaries are retracted. ´ Receptors ´ H1 receptor (proinflammatory): Is present in smooth muscle cells of the bronchi. ´ Induces bronchoconstriction. ´ H2 receptor (antiinflammatory): Is present on parietal cells of the stomach mucosa. ´ Induces the secretion of gastric acid. Copyright © 2019, Elsevier Inc. All rights reserved. 23 Mast Cell Degranulation (Cont.) ´ Chemotactic factors ´ Neutrophil chemotactic factor ´ Attracts neutrophils. ´ Eosinophil chemotactic factor of anaphylaxis (ECF-A) ´ Attracts eosinophils. Copyright © 2019, Elsevier Inc. All rights reserved. 24  Mast Cell Synthesis of ´ Mediators Leukotrienes ´Are the product of arachidonic acid from mast cell membranes. ´Have similar effects to histamine. ´Are more important in the later stages of inflammation. ´ Prostaglandins ´Have similar effects to leukotrienes; they also induce pain. ´ Platelet-activating factor ´Effect is similar to leukotrienes; they also activate platelets. Copyright © 2019, Elsevier Inc. All rights reserved. 25 Endothelium ´ Maintains normal blood flow. ´ Endothelial cells produce nitric oxide (NO) and prostacyclin (PGI2). ´ NO and PGI2 maintain blood flow and pressure and inhibit platelet activation. ´ NO maintains vascular tone. ´ During inflammation, the endothelium ´ expresses receptors that help leukocytes leave the circulation. ´ retracts to allow fluid to pass into the tissues. ´ Damage to endothelium promotes clotting. Copyright © 2019, Elsevier Inc. All rights reserved. 26 Platelets ´ Are cellular fragments formed from megakaryocytes. ´ Platelets are also called thrombocytes. ´ Activation of platelets stops bleeding and degranulation. ´ Platelets contain alpha and dense granules. Copyright © 2019, Elsevier Inc. All rights reserved. 27 Phagocytes ´ Neutrophils ´ Are also referred to as polymorphonuclear neutrophils (PMNs). ´ Predominate in early inflammatory responses. ´ Ingest bacteria, dead cells, and cellular debris. ´ Are short-lived and become components of the purulent exudate (pus). ´ Primary roles ´ Removal of debris in sterile lesions ´ Phagocytosis of bacteria in nonsterile lesions Copyright © 2019, Elsevier Inc. All rights reserved. 28 Phagocytes (Cont.) Eosinophils Basophils ´ Provide the defense ´ Are similar to but are against parasites and not mast cells. regulate vascular ´ Are an important mediators. source for cytokine IL-4. ´ Help control vascular ´ Are associated with effects of inflammation. allergies and asthma. ´ Their role is uncertain. Copyright © 2019, Elsevier Inc. All rights reserved. 29 Phagocytes (Cont.) ´ Dendritic cells ´ Provide link between innate and acquired immune responses. ´ Phagocytic cells ´ Located in peripheral organs and skin. ´ Migrate to lymphoid tissue and interact with T lymphocytes to cause acquired immune response. ´ Guide development of T-cells (helper cells). Copyright © 2019, Elsevier Inc. All rights reserved. 30  Phagocytes (Cont.) ´ Monocytes and macrophages ´Monocytes that are produced in the bone marrow, enter circulation, migrate to the inflammatory site, and develop into macrophages. ´Monocytes are precursors to macrophages in tissues. ´ Kupffer cells (liver); alveolar macrophages (lungs); and microglia (brain) ´Macrophages are larger and more active as phagocytes than monocytes, and are important cellular initiators of inflammation; they help in wound healing. Copyright © 2019, Elsevier Inc. All rights reserved. 31 Phagocytosis ´ Is the process by which a cell ingests and disposes of foreign material. ´ Is the destruction of microorganisms and cellular debris. ´ Production of adhesion molecules occurs. ´ Margination (pavementing) occurs. ´ Leukocytes adhere to endothelial cells. ´ Diapedesis occurs. ´ Cells emigrate through the endothelial junctions. Copyright © 2019, Elsevier Inc. All rights reserved. 32 Phagocytosis (Cont.) ´ Steps ´ Opsonization (“glue” between the phagocyte and the target cell by C3b making the foreign cell more susceptible to phagocytosis), recognition, and adherence ´ Engulfment ´ Small pseudopods surround adherent microorganism. ´ Phagosome formation ´ Fusion with lysosomal granules ´ Creates a phagolysosome. ´ Destruction of the target ´ Uses primary and secondary granules. Copyright © 2019, Elsevier Inc. All rights reserved. 33 Phagocytosis (Cont.) Copyright © 2019, Elsevier Inc. All rights reserved. 34 Phagocytosis (Cont.) ´ Respiratory burst ´ Oxygen-dependent killing mechanism ´ α1-antitrypsin ´ Helps minimize the destructive effects of the enzymes released by the dying phagocytes. Copyright © 2019, Elsevier Inc. All rights reserved. 35 Phagocytosis (Cont.) ´ Natural killer (NK) cells: Recognize and eliminate cells that are infected with viruses and cancer cells in the blood. ´ Lymphocytes: Are the main components of the adaptive immune response. Copyright © 2019, Elsevier Inc. All rights reserved. 36 Local Manifestations of Inflammation ˜ Local manifestations of inflammation result from vascular changes and corresponding leakage of circulating components into the tissue. Ø Heat: From vasodilation and increased blood flow Ø Redness: From vasodilation and increased blood flow Ø Swelling: From exudate accumulations and fluid from capillary permeability Ø Pain: From pressure exerted by exudate accumulations, prostaglandins, and bradykinins Ø Loss of function: May also occur. Copyright © 2019, Elsevier Inc. All rights reserved. 37 Local Manifestations of Inflammation (Cont.) ´ Functions ´ Dilute toxins. ´ Carry plasma proteins and leukocytes to the injury site. ´ Carry bacterial toxins and debris away from the site. Copyright © 2019, Elsevier Inc. All rights reserved. 38  Exudative Fluids ´ Exudate: Fluid and cells, such as protein and debris ´ Serous exudate ´ Watery exudate: Indicates early inflammation. ´ Fibrinous exudate ´ Thick, clotted exudate: Indicates more advanced inflammation. ´ Purulent (suppurative) exudate ´ Pus: Indicates a bacterial infection. ´ Hemorrhagic exudate ´ Exudate containing blood: Indicates bleeding. Copyright © 2019, Elsevier Inc. All rights reserved. 39 Systemic Manifestations of Inflammation ´ Fever ´ Caused by exogenous and endogenous (IL-1) pyrogens ´ Acts 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 A, and ceruloplasmin Copyright © 2019, Elsevier Inc. All rights reserved. 40 Chronic Inflammation ´ Is inflammation that lasts 2 weeks or longer. ´ Is often related to an unsuccessful acute inflammatory response. ´ Other causes ´ High lipid and wax content of a microorganism ´ Ability to survive inside the macrophage ´ Toxins ´ Chemicals, particulate matter, or physical irritants Copyright © 2019, Elsevier Inc. All rights reserved. 41  Chronic Inflammation (Cont.) ´ Characteristics ´ Dense infiltration of lymphocytes and macrophages ´ Granuloma formation ´ Epithelioid cell formation ´ Giant cell formation Copyright © 2019, Elsevier Inc. All rights reserved. 42 Wound Healing ´ Regeneration ´ Most favorable outcome ´ Resolution ´ Returning injured tissue to the original structure and function ´ Repair ´ Replacement of destroyed tissue with scar tissue ´ Scar tissue ´ Primarily composed of collagen to restore the tensile strength of the tissue Copyright © 2019, Elsevier Inc. All rights reserved. 43  Wound Healing (Cont.) ˜ Wound healing process ´Filling in the wound ´Sealing the wound (epithelialization) ´Shrinking the wound (contraction) Copyright © 2019, Elsevier Inc. All rights reserved. 44 Wound Healing (Cont.) Primary Intention Secondary Intention ´ Wounds that heal ´ Wounds that require under conditions of significantly more tissue minimal tissue loss. replacement. ´ Original tissue structure ´ Open wound and function that have ´ Wounds that cause been restored. scar formation. Copyright © 2019, Elsevier Inc. All rights reserved. 45 Wound Healing (Cont.) ´ Primary intention Copyright © 2019, Elsevier Inc. All rights reserved. 46 Wound Healing (Cont.) ´ Secondary intention Copyright © 2019, Elsevier Inc. All rights reserved. 47  Wound Healing ´ Phase I: Inflammation ´Coagulation and infiltration ´Platelets, neutrophils, macrophages ´Fibrin mesh of blood clot acts as scaffold ´Platelets release growth factors. ´Neutrophils and macrophages clean the wound. ´Debridement occurs. ´Blood vessels and lymph drain away debris. ´Vascular dilation and permeability reverse. Copyright © 2019, Elsevier Inc. All rights reserved. 48 Wound Healing (Cont.) ´ Phase II: Reconstruction ´ Wound begins to heal. ´ Healing begins 3–4 days after the injury and continues for 2 weeks. ´ Fibroblast proliferation occurs. ´ Collagen synthesis by fibroblasts. ´ Epithelialization—cells from healthy tissue grow into wound. ´ Wound contracts through the actions of myofibroblasts. ´ Cellular differentiation occurs. Copyright © 2019, Elsevier Inc. All rights reserved. 49 Wound Healing (Cont.) ´ Reconstructive phase (cont.) Copyright © 2019, Elsevier Inc. All rights reserved. 50 Wound Healing (Cont.) ´ Phase III: Remodeling and Maturation ´ Healed wound is remodeled. ´ This phase begins several weeks after injury and may last for 2 years. ´ Cellular differentiation continues. ´ Scar tissue forms. ´ Scar remodeling occurs. Copyright © 2019, Elsevier Inc. All rights reserved. 51 Wound Healing (Cont.) ´ Maturation phase (cont.) Copyright © 2019, Elsevier Inc. All rights reserved. 52 Dysfunctional Wound Healing ´ Dysfunction during inflammatory response ´ Ischemia ´ Hemorrhage ´ Hypovolemia ´ Fibrous adhesions ´ Excess scar formation ´ Infection ´ Wound sepsis ´ Hypoproteinemia ´ Medications Copyright © 2019, Elsevier Inc. All rights reserved. 53 Dysfunctional Wound Healing (Cont.) ´ Dysfunction during reconstructive phase ´ Impaired collagen matrix assembly ´ Causes: Malnutrition ´ Keloid scar ´ Hypertrophic scar ´ Impaired epithelialization ´ Antiinflammatory steroids, hypoxemia, and nutritional deficiencies ´ Cleaning with povidone-iodine and hydrogen peroxide ´ Impaired contraction ´ Contractures: Result from excessive myofibroblast-derived tension. Copyright © 2019, Elsevier Inc. All rights reserved. 54 Dysfunctional Wound Healing (Cont.) ´ Keloids Copyright © 2019, Elsevier Inc. All rights reserved. 55 Dysfunctional Wound Healing (Cont.) ´ Wound disruption ´ Dehiscence ´ Wound pulls apart at the suture line. ´ Causes: Excessive strain, wound sepsis, and obesity ´ Occurs 5–12 days after suture. ´ Characteristics ´ Serous drainage is increased. ´ Feels like something “gave way.” ´ Surgery is required. Copyright © 2019, Elsevier Inc. All rights reserved. 56 Pediatrics: Innate Immunity ´ Neonates ´ Have transiently depressed inflammatory and immune function. ´ Have neutrophils that are not capable of efficient chemotaxis. ´ Have a deficient complement system. ´ Are deficient in collectins and collectin-like proteins. ´ Are susceptible to bacterial infections. Copyright © 2019, Elsevier Inc. All rights reserved. 57  Aging: Innate Immunity in the Older Adult ´ Impaired or delayed inflammation is likely a result of chronic illness. ´ Diabetes mellitus and cardiovascular disease, among others ´ Medications may interfere with wound healing. ´ Infections are more common in older adults. ´ Lungs, urinary tract, and skin are often affected. ´ Older adults have diminished immune function. ´ Expression and function of several, if not all, TLRs, are decreased. Copyright © 2019, Elsevier Inc. All rights reserved. 58