Innate Immunity - Inflammation and 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  Ad...

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 (toll linked receptors)  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-  Help control vascular 4. effects of  Are associated with 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.  It helps get things through the cell 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.  Helps control respiratory function  Emphysema may be caused by a1-antitrypsin deficieny 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.  KNOW THIS- main adaptive system of 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.  Heat: From vasodilation and increased blood flow  Redness: From vasodilation and increased blood flow  Swelling: From exudate accumulations and fluid from capillary permeability  Pain: From pressure exerted by exudate accumulations, prostaglandins, and bradykinins (from the arachandonic cascade)  Loss of function: May also occur.  i.e. compartment syndrome 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  Acute pain is caused by a-delta fiber; chronic pain is caused by c-fiber  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 minimal tissue loss. tissue replacement.  Original tissue  Open wound structure and function  Wounds that cause that have been scar formation. restored. 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