Thermoregulation, Innate Immunity, Inflammation, & MODS PDF

THERMOREGULATION INNATE IMMUNITY INFLAMMATION ADAM ELLIOTT, MN NP NRSG 2501 PATHOPHYSIOLOGY WINTER 2024 CAPE BRETON UNIVERSITY IMMUNITY First line of defense ⚬ Innate (natural or native) immunity ￭ Physical, mechanical, biochemical barriers ￭ Skin, mucous membranes, low pH of stomach ￭ Constant Seco...

THERMOREGULATION INNATE IMMUNITY INFLAMMATION ADAM ELLIOTT, MN NP NRSG 2501 PATHOPHYSIOLOGY WINTER 2024 CAPE BRETON UNIVERSITY IMMUNITY First line of defense ⚬ Innate (natural or native) immunity ￭ Physical, mechanical, biochemical barriers ￭ Skin, mucous membranes, low pH of stomach ￭ Constant Second line of defense ⚬ Response to injury or infection – Inflammation ⚬ Mast cells, neutrophils, eosinophils basophils, monocytes, platelets, Natural killer cells ⚬ Immediate Response Third line of defense ⚬ Adaptive (acquired or specific) immunity ⚬ Specific response toward the antigen – B cells, T cells, antibodies if present ⚬ Delayed response at first exposure, immediate response after second exposure Copyright © 2019, Elsevier Canada, a division of Reed Elsevier Canada, Ltd. All rights reserved. FIRST LINE OF DEFENSE Physical barriers: ⚬ Skin ⚬ Linings of the gastro-intestinal, genitourinary, and respiratory tracts ￭ ￭ ￭ ￭ Sloughing off of cells Coughing, sneezing & vomiting Flushing — urine Mucus and cilia Epithelial cell–derived chemical barriers: ⚬ Secrete saliva, tears, earwax, sweat & mucus ⚬ Antimicrobial peptides Normal microbiome ⚬ Surface colonized by bacteria & fungi unique to the location, for example E. Coli in the intestine Broa SECOND LINE OF DEFENCE Inflammatory response (first immune response to injury) ⚬ Nonspecific; broad Caused by a variety of materials ⚬ Infection, tissue necrosis, ischemia, trauma, physical or chemical injury, foreign bodies, immune reaction Local manifestations ⚬ Redness, heat, swelling, pain, loss of function Vascular responses: ⚬ Vasodilation ⚬ Increased vascular permeability & leakage ⚬ WBC adherence to the inner walls of the vessels & migration thru vessels ⚬ Include complement, clotting factors, kinins, cytokines Copyright © 2019, Elsevier Canada, a division of Reed Elsevier Canada, Ltd. All rights reserved. THIRD LINE OF DEFENSE Initiated when innate immune system signals adaptive immunity cells (second exposure to antigen) ⚬ Delayed as a result of second exposure ⚬ Very specific - to specific antigen Cellular: ⚬ Antibodies, complement, cytokines ⚬ Include T-Cells, B-Cells, Macrophages, Dendritic Cells ￭ Memory by T and B cells Copyright © 2019, Elsevier Canada, a division of Reed Elsevier Canada, Ltd. All rights reserved. Page 138, Figure 6.3 INFLAMMATION Goals: ⚬ ⚬ ⚬ ⚬ Prevent and limit infection and further damage Limit and control the inflammatory process Initiate adaptive immune response Initiate healing SYSTEMIC VS. LOCAL Systemic Fever, Malaise, chills, fatigue, tachypnea, tachycardia Local Infection Edema, pain, erythema, decreased function, localized warmth. TEMPERATURE REGULATION Balance of heat production, heat conservation & heat loss Women have wider fluctuations than men. thermoregulation ⚬ Is controlled by the hypothalamus Heat production and conservation with hypothalamus, endocrine system & sympathetic nervous system ⚬ Skeletal muscle contraction ⚬ Chemical thermogenesis – heat generation in organisms ⚬ Vasoconstriction ⚬ Voluntary mechanisms Copyright © 2019, Elsevier Inc. All rights reserved. PEDIATRIC & AGING CONSIDERATIONS: TEMPERATURE REGULATION PEDIATRIC Infants produce sufficient body heat (brown fat) but are unable to conserve the heat produced. ⚬ Small body size & high body surface-to-weight ratio ⚬ Inability to shiver ⚬ Thin subcutaneous layer Must keep warm AGING Blood circulation & vasoconstriction/vasodilator responses are slowed. Metabolic rate is decreased. Shivering is decreased & ineffective. Sweating and the perceptions of heat and cold are dec. PATHOGENESIS OF FEVER, PYREXIA Three changes: Fever Often beneficial in killing microorganisms, however may enhance some effects from gram (-) endotoxins Leukocytosis ￭ Increase in WBCs Increased plasma proteins ￭ Increase in inflammation ￭ Proinflammatory or anti-inflammatory – inc in fibrinogen causes adhesion of erythrocytes Endogenous vs Exogenous pyrogens ⚬ Pyrogenic cytokines produced by the body vs Endotoxins produced by pathogens ⚬ Pyrogenic cytokines Act directly on the hypothalamus to produce fever (controls temp) Also antipyretic/cryogens which prevent dangerous temp rise ⚬ Pathogenic pyrogens produce fever via inflammatory response CIRCULATING LEVELS OF ACUTEPHASE REACTANTS DURING INFLAMMATION TABLE 6.4 PAGE 149 PATHOGENESIS OF FEVER (CONT.) Copyright © 2019, Elsevier Inc. All rights reserve BENEFITS OF FEVER Aids infectious response Kills many organisms Decrease the serum levels of iron, zinc, and copper ⚬ Deprives bacteria of food and nutrients Promotes lysosomal breakdown & autodestruction of cells Increase lymphocytic transformation, neutrophils, & phagocyte motility BENEFITS OF FEVER Production of fever simultaneously with lymphocyte activation constitutes the clearest and strongest evidence in favour of the protective role of fever. The protective processes of the immune response are optimal at high temperature (around 39.5 °C) Risks of Fever: Some fever effects are harmful and even lethal. This occurs mainly by overproduction of the cytokines - Contribute to sepsis POSSIBLE FEVER RESPONSES Older adults ⚬ Have a decreased or no fever response to infection Children ⚬ Develop higher temperatures than adults for relatively minor infections ⚬ May have febrile seizures Fever of unknown origin (FUO) ⚬ fevers higher than 38.3°C (101°F) that remain undiagnosed after 3 days of hosp. investigation or after 2 or more ER visits. Copyright © 2019, Elsevier Inc. All rights reserved. HYPERTHERMIA Elevation of body temp without increase of hypothalamic set point (not caused by pyrogens) Can cause nerve damage, coagulation, and death. 41°C - nerve damage; convulsions in adults 43°C - death Can be therapeutic, accidental, or associated with stroke or head trauma. Therapeutic hyperthermia ⚬ Medically induced hyperthermia that is used to destroy pathologic microorganisms or tumor cells Accidental hyperthermia ⚬ Heat cramps, heat exhaustion, heat stroke, malignant hyperthermia Copyright © 2019, Elsevier Inc. All rights reserved. STROKE / HEAD TRAUMA AND TEMPERATURE Prevention of hyperthermia in stroke and head trauma helps in limiting brain injury Administer antipyretics Mechanically cool the patient ⚬ Recommend to keep temp between 36.7 - 37.0 for first several days after stroke and head injury TRAUMA-INDUCED TEMPERATURE CHANGE CNS trauma ⚬ Neurogenic or central fever, not caused by infection Hemorrhagic shock ⚬ Triggers peripheral vasoconstriction and hypoxia, contributing to hypothermia Major surgery ⚬ Anesthesia induces hypothermia. Thermal burns with loss of skin: hypothermia Copyright © 2019, Elsevier Inc. All rights reserved. PLASMA PROTEIN SYSTEMS Protein systems: ⚬ Complement system ⚬ Clotting system ⚬ Kinin system All contain inactive enzymes (proenzymes) that are converted to active enzymes ￭ Substrate of the activated enzyme becomes the next component in the series (cascade) PLASMA PROTEIN SYSTEMS Complement system ⚬ Produces biologically active fragments that recruit phagocytes, activate mast cells, and destroy pathogens ⚬ Body’s most potent defenders, particularly against bacteria ⚬ The most important function of the cascade is activation of C3 and C5, which results in molecules that are: Opsonins Chemotactic Factors, and Anaphylatoxins. PLASMA PROTEIN SYSTEMS Clotting (coagulation) system ⚬ Forms a fibrinous meshwork at an injured or inflamed site ￭ Prevents the spread of infection ￭ Trap (localize) micro-organisms and foreign bodies ￭ Forms a clot that stops bleeding ￭ Provides a framework for repair and healing Main substance is an insoluble protein called fibrin Damaged vessel walls produce Factor XII which contributes to clotting and activates Kinin system PLASMA PROTEIN SYSTEMS Kinin system ⚬ Interacts closely with the clotting system (activated by Factor XII) ⚬ Functions to activate and assist inflammatory cells ⚬ Causes dilation of blood vessels & smooth muscle contraction, increases vascular permeability (causes edema) ⚬ Produces Bradykinin ⚬ Causes Pain CELLULAR COMPONENTS OF INFLAMMATION Cellular components: ⚬ Erythrocytes ￭ Carry oxygen to the tissues ⚬ Platelets ￭ small fragments involved in clotting ⚬ Leukocytes ￭ Granulocytes ⚬ basophils, eosinophils, neutrophils ￭ Monocytes ⚬ precursors to macrophages found in tissue ￭ Lymphocytes ⚬ Participate in the innate immune response. Include NK cells, T cells and B cells Act at the site of injury to confine damage, kill microorganisms, remove cellular debris, and activate healing and repair CYTOKINES Intercellular communication and cooperation are necessary for a successful inflammatory response. Cytokines are largely responsible for regulating the inflammatory response (activation and deactivation) Activate Chemokines ⚬ Responsible for attracting leukocytes to inflammatory sites ⚬ Attract macrophages and lymphocytes Activate Interleukins (IL) ⚬ Produced primarily by macrophages and lymphocytes in response to stimulation of PRRs (pathogen recognition receptors) or by other cytokines ￭ Many types to activate and deactivate IL-1 is proinflammatory IL-10 is anti-inflammatory MAST CELLS AND GRANULOCYTES Mast cells are cellular bags of granules located in the loose connective tissues close to blood vessels. ⚬ Skin, digestive lining, and respiratory tract ⚬ Contain histamine, cytokines, and chemotaxic factors Granulocytes (phagocytes in WBCs) Basophils are found in blood, function similarly to mast cells. Increase with allergy and respiratory disorders Eosinophils are body’s primary defense against parasites, and help regulate vascular mediators. Increase with acute inflammation, skin disorders. Neutrophils have short life, but create purulent exudate, and removes debris from the body through lymphatic system. PHAGOCYTES (CONT.) 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 24 hours or later after neutrophils and are more phagocytic than monocytes. PHAGOCYTOSIS (CONT.) Steps: ⚬ ⚬ ⚬ ⚬ ⚬ Adherence Engulfment Phagosome formation Fusion with lysosomal granules Destruction of the target 28 P H A G O C Y T O S I S ACUTE AND CHRONIC INFLAMMATION Acute ⚬ Self-limiting ⚬ Local manifestations—result from vascular changes and corresponding leakage of circulating components into the tissue ￭ Heat, swelling, redness, pain ￭ Exudative fluids CHRONIC INFLAMMATION Inflammation lasting > 2 wks Often 2to an unsuccessful acute inflammatory response ⚬ Exudate formation, suppuration & incomplete wound healing SHOCK Cardiovascular system fails to perfuse the tissues adequately Leads to impaired cellular metabolism Impaired oxygen use Impaired glucose use Manifestations vary based on stage ⚬ Hypotension ⚬ Tachycardia ⚬ Inc respiratory rate SHOCK Cardiogenic Hypovolemic Neurogenic Anaphylactic Septic Leads to.... MULTIPLE ORGAN DYSFUNCTION SYNDROME Progressive dysfunction of two or more organ systems from an uncontrolled inflammatory response to a severe illness or injury Initiating insult activates neuroendocrine system Stress hormones (cortisol, epinephrine, norepinephrine) all excreted. Vascular damage occurs as inflammatory mediators are released Vascular permiability causing edema, hypotension, hypoperfusion platelets and thromboplastin activated causing microvascular coagulation, complicating organ function MULTIPLE ORGAN DYSFUNCTION SYNDROME inappropriate coagulation may lead to DIC Because of the release of inflammatory mediators, four major plasma enzyme cascades are activated: complement, coagulation, fibrinolytic, and kinin. The effect of the activation of these hyperinflammatory and hypercoagulant state that maintains the interstitial edema formation, cardiovascular instability, endothelial damage, and clotting abnormalities characteristic of MODS. A massive systemic immune and inflammatory response then develops