Inflammation - Week 3 PAT 201 Fall 2024 PDF

Inflammation PAT 201 Fall 2024 Week 3 1 Allostatic Load A way of measuring the cumulative wear and tear on the body Caused by repeated activation of multiple physiologic systems over time in response to environmental demands in an effort to maintain intern...

Inflammation PAT 201 Fall 2024 Week 3 1 Allostatic Load A way of measuring the cumulative wear and tear on the body Caused by repeated activation of multiple physiologic systems over time in response to environmental demands in an effort to maintain internal equilibrium Has the potential to tax the body and brain and lead to the emergence of diseases and disorder 2 Allostatic Load (cont’d) Exposure to frequent stressors that cause: repeated physiologic arousal lack of adaptation to stressors inability to shut off the stress response A response that is not sufficient to deal with the stressor Frequent and longer exposures to stress accelerate the wear and tear on the body and brain. 3 Allostatic Load (cont’d) Socioeconomic status, ethnicity, gender dysphoria, sexual orientation, and aging are associated with high allostatic load. Can you think of some others? divorce poverty discrimination racism marginalization social determinants of health more? 4  Natural, nonspecific response that limits the spread of invading microorganisms or injury What can trigger inflammation? Many conditions (e.g., physical trauma, What is burns, infection, hypersensitivity reactions, tissue necrosis) inflammation? Nonspecific as inflammation proceeds in same manner regardless of cause Excessive inflammation causes symptoms that range from minor discomfort to severe, disabling pain, fever, and changes in mobility 5 Immunity Types of immunity Lines of defense Innate resistance: Natural barriers First line and the inflammatory response Natural barriers: physical, mechanical and biochemical Second line Inflammation Adaptive (acquired) immunity Third line Adaptive (acquired) immunity 6 Second Line of Defense: Inflammation Programmed to respond to cellular or tissue damage Occurs in tissues with a blood supply Rapidly initiated (within seconds) Depends on activity of cellular and chemical components Nonspecific Takes place in approximately the same way, regardless of the type of stimulus / occurrence in past No memory cells 7 Second Line of Defense: Inflammation (cont.) Inflammatory response (cont.) Cardinal signs redness, heat, swelling, pain, loss of function Vascular response blood vessel dilation, increased vascular permeability and leakage Cellular response white blood cell (WBC) adherence to the inner walls of the vessels, and migration through the vessels (diapedesis) 8 Microbiome: Body’s surfaces are colonized with an array of microorganisms Everyone has a unique microbiome Begins to acquire this early in life and is unique based on an individual’s environment, diet, exposure to toxins, animals etc. Body surfaces/anatomic locations have their own specialized microbiome These microorganisms do not normally cause disease under normal conditions but can cause disease in immunocompromised people who lack the usual defense mechanisms. Interacts with the body in a beneficial way to foster healthy defense systems: Induces protective immune responses & supports immune tolerance of innocuous microorganisms Produces enzymes that aid digestion of fatty acids & polysaccharides Synthesizes metabolites Releases antibacterial substances Competes with pathogens for nutrients Blocks attachment of the pathogens to the epithelium 9 Microbiome & Disease Body & microbiome act in harmony with each other to induce or suppress the immune response (symbiosis) When this symbiosis is altered, immunity is negatively impacted and can contribute to many diseases Factors that may alter the microbiome: Stress Diet e.g. high fat = inflammation of gut Toxic metabolites from food Research showing links to: Alzheimer's, diabetes, atherosclerosis, bowel disease, cancer, and more… Good news! Studies showing how the microbiome can be intentionally altered to improve immunity! E.g.: probiotics, prebiotics, and fecal microbial transplantation 10 Rogers, 2023, p. 205 11 Sequence of Events in the Acute Inflammatory Response Rogers, 2023, p. 209 12 Purposes of Inflammation 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 13  Quick Check-in! The characteristic vascular changes at the site of an injury produce: A) Blood vessel constriction after dilation B) Increased permeability and leakage C) Tightening of the capillary endothelial cell junctions D) Pallor and swelling where the injury occurred Copyright © 2019, Elsevier Inc. All rights reserved. 14 Components of Inflammation 15 Plasma Protein Systems Protein systems that provide a All contain inactive enzymes (proenzymes) biochemical barrier against invading pathogens are the: Sequentially activated–cascade First proenzyme is converted to an 1) complement system active enzyme The activation of the first component 2) clotting system of a system results in sequential 3) kinin system activation of other components 16  Can destroy pathogens directly Activates or collaborates with other components of the inflammatory response 1) Complement Pathways Classical: Antibodies and antigens System 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 17  Forms a fibrinous mesh at an injured or inflamed site Main substance and end product is fibrin, an insoluble protein 2) Clotting Prevents the spread of infection Keeps microorganisms and foreign bodies at the site (Coagulation) of inflammation for removal Forms a clot that stops bleeding System 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 18  Functions to activate and assist inflammatory 3) Kinin cells System Primary product is bradykinin causes dilation of blood vessels, pain, smooth muscle contraction, vascular permeability, and leukocyte chemotaxis Kininase enzymes in plasma/tissues degrade kinins 19 Control and Interactions of Plasma Protein Systems Three systems highly interactive Interactions among the three plasma protein systems are finely regulated to: prevent injury to the host tissue guarantee activation when needed Multiple mechanisms are available to either activate or inactivate (regulate) these plasma protein systems 20  Plasma Protein Systems in Inflammation Fig. 7.3 Rogers, 2023.pg. 208 21 Plasma Protein Systems: Tight Regulation Interactions among the three plasma protein systems control inflammation and inhibit the three plasma protein systems Carboxypeptidase: Inhibits C3a and C5a Kininases: Inhibits kinins Histaminase: Inhibits histamine C1-esterase inhibitor (C1-inh): Inhibits all three pathways 22 Key mediators of inflammation Table 39.2 Adams et al., 2025, p. 610 23 Cellular Mediators of Inflammation Cellular mediators Biochemical mediators Mast cells Originate from destroyed Granulocytes (neutrophils, or damaged cells eosinophils, basophils) Modulate the localization Monocytes and and activities of other macrophages inflammatory cells Natural killer (NK) cells and Tissue regeneration or lymphocytes repair (resolution) Cellular fragments (platelets) 24  Cellular Receptors: Innate Immunity Pattern recognition receptors (PRRs) Recognize pathogen-associated molecular patterns (PAMPs) or damage-associated molecular patterns (DAMPs) Cellular Toll-like receptors (TLRs) direct and early recognition Complement receptors: Recognize complement Receptors fragments Scavenger receptors: Promote phagocytosis Inflammatory response Initiated when tissue injury occurs or when PAMPs are recognized by PRRs on cells of the innate immune system. 25  Cytokines: Family of intercellular-signaling molecules; bind to specific cell receptors and Role of regulate innate or adaptive immunity Are either proinflammatory or anti- Cytokines inflammatory 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) 26 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 27  Protect against viral infections and modulate Interferons inflammatory response (IFNs) 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 28 Chemokines Type of cytokines that primarily attract leukocytes to site of inflammation 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 29 Mast Cells Are cellular bags of granules located in loose connective tissues close to blood vessels Skin, digestive lining, and respiratory tract Mast cell activation: Physical injury, chemical agents, immunologic processes, and TLRs Mediators are released in two ways: 1) Degranulation 2) Synthesis 30 Mast Cell Degranulation Involves immediate release of histamine, chemotactic factors and cytokines 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 (anti-inflammatory): Is present on parietal cells of the stomach mucosa. Induces the secretion of gastric acid 31  Effects of Histamine through H1 and H2 Receptors Figure 7.5 Rogers, 2023. p. 211 32 Mast Cell Chemotactic factors Neutrophil chemotactic factor Degranulation Attracts neutrophils Eosinophil chemotactic factor of (Cont.) anaphylaxis (ECF-A) Attracts eosinophils 33  Leukotrienes Are the product of arachidonic acid from mast cell membranes Mast Cell Have similar effects to histamine Are more important in the later stages of Synthesis inflammation Prostaglandins of Have similar effects to leukotrienes; they also Mediators induce pain Platelet-activating factor Effect is similar to leukotrienes; they also activate platelets 34  Effect of Mast Cell Degranulation and Synthesis Figure 7.4 Rogers, 2023 p. 211 35 Endothelium Maintains normal blood flow Endothelial cells produce nitric oxide NO and PGI2 maintain blood flow and pressure (relax (NO) and prostacyclin (PGI2) vascular smooth muscle) and inhibit platelet activation expresses receptors that help leukocytes leave the During inflammation, the endothelium circulation retracts to allow fluid to pass into the tissues Damage to endothelium promotes clotting 36 Platelets Interact with components of Stop bleeding Circulate in bloodstream Vascular injury results in platelet coagulation cascade activation products of tissue destruction Degranulate Release mediators (e.g., serotonin) Synthesis thromboxane TXA2 – potent vasoconstrictor; A2 (TXA2) from prostaglandin induces platelet aggregation Phagocytes Primary role of most granulocytes (neutrophils, eosinophils, basophils) and monocytes/macrophages is phagocytosis Neutrophils Predominate in early inflammatory responses; arriving 6-12 hours after injury 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 (burns) Phagocytosis of bacteria in nonsterile lesions 38 Phagocytes (Cont.) Eosinophils Basophils Two specific functions: Are similar to but are not mast cells 1) body’s primary defense against Are an important source for cytokine parasites IL-4; regulator of adaptive immune 2) Help regulate vascular mediators response (e.g released from mast cells) Associated with allergies and asthma 39  Provide link between innate and acquired immune responses Primary phagocytic cells located in peripheral Dendritic cells organs and skin Migrate to lymphoid tissue and interact with T lymphocytes to cause acquired immune response Guide development of T-cells (helper cells) 40  Monocytes that are produced in the bone marrow, enter circulation, migrate to the inflammatory site, and develop into macrophages Monocytes Monocytes are also precursors to macrophages in tissues and Kupffer cells (liver); alveolar macrophages (lungs); and microglia (brain) macrophages Macrophages are larger and more active as phagocytes than monocytes Important cellular initiators of inflammation; promote wound healing 41  Is the process by which a cell ingests and disposes of foreign material Is the destruction of microorganisms and cellular debris Phagocytosis Production of adhesion molecules occurs Margination Leukocytes adhere to (pavementing) occurs endothelial cells Cells emigrate through Diapedesis occurs the endothelial junctions 42 Phagocytosis (Cont.) Steps Opsonization (recognition of the target and adherence of phagocyte to it) Engulfment Small pseudopods surround microorganism Phagosome formation Fusion with lysosomal granules Creates a phagolysosome Destruction of the target 43  Phagocytosis Visualization Figure 7.8 C Rogers, 2023. pg. 216 44 Phagocytosis and Oxygen-Dependent Killing Mechanisms Respiratory burst (oxygen dependent) Oxygen-independent killing mechanisms α1-antitrypsin Helps minimize the destructive effects of the enzymes released by the dying phagocytes 45  Include Natural Killer (NK) cells, T cells and B cells Lymphocytes : Natural NK cells predominate innate immune lymphocytes Killer Cells Recognize and eliminate cells that are infected with viruses and cancer cells in the blood 46 Quick Knowledge Check: Phagocyte Edition (1) Neutrophils: Arrive _________ Have a _________ life-span Monocytes: Differentiate into ______________ Arrive _____________ 47 Quick Knowledge Check: Phagocyte Edition (2) Phagocytosis involves: 1. Opsonization, engulfment, and formation of a phagosome 2. A reduction in nitric oxide production 3. Formation of a phagosome by mast cells 4. A respiratory burst produced by the release of the primary lysosomal granules Acute and chronic inflammation 49  Review Figure 7.4 in McCance & Huether (2019) 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 Loss of function: May also occur 50 Rogers, 2023, p. 205 51  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 Initiates healing 52 Exudative Fluids Exudate: Fluid and cells, such as protein and debris Serous exudate Watery: Indicates early inflammation Fibrinous exudate Thick, clotted: Indicates more advanced inflammation Purulent (suppurative) exudate Pus: Indicates a bacterial infection Hemorrhagic exudate Exudate containing blood: Indicates bleeding 53 Systemic Manifestations of Inflammation Fever Caused by exogenous and endogenous (e.g. 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 54 Common Laboratory Measures of Inflammation An increase in the total number of WBCs in combination with an Hepatic synthesis of many plasma abnormal differential count suggests proteins is increased during that there may be an ongoing infection inflammation and/or inflammatory response CBC Measurement of acute-phase Differential count reactants Fibrinogen ESR “sed rate” C-reactive protein 55 Chronic Inflammation Is inflammation that Is often related to an lasts 2 weeks or longer unsuccessful acute Other causes inflammatory response High lipid and wax content of a microorganism Ability to survive inside the macrophage Toxins Chemicals, particulate matter, or physical irritants 56  Chronic inflammatory response Figure 7.10 Rogers, 2023. p. 220 57  Chronic Characteristics inflammatory Dense infiltration of lymphocytes and macrophages response Granuloma formation Epithelioid cell formation (Cont.) Giant cell formation 58 Special considerations across the lifespan 59  Neonates Have transiently depressed Pediatrics: inflammatory and immune function Have neutrophils that are not capable Innate of efficient chemotaxis Have a deficient complement system Immunity Are deficient in collectins and collectin-like proteins Are susceptible to bacterial infections 60 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 61 Pharmacotherapy of inflammation 62 Inflammation: List of medications Classification Drug Glucocorticoid Prednisone Dexamethasone NSAID Ibuprofen Celecoxib 63 Review: What are the signs of inflammation? 64  Pharmacotherapy of inflammation Includes drugs that decrease the natural inflammatory response Most drugs are non-specific Diseases that may benefit from anti-inflammatory drugs: Allergic rhinitis Anaphylaxis Ankylosing spondylitis Contact dermatitis Crohn’s disease Glomerulonephritis Hashimoto’s thyroiditis Peptic ulcers Rheumatoid arthritis Systemic lupus erythematosus Ulcerative colitis Figure 39.1 Adams et al., 2025, p. 611 65 Nonsteroidal anti-inflammatory drugs (NSAIDs) Inhibit cyclooxygenase, which is an enzyme responsible for the formation of prostaglandins 🡪 reduction of inflammation and pain Have analgesic, antipyretic, and anti-inflammatory effects Indication: Treat mild to moderate inflammation Special considerations: older adults, pregnancy and lactation, infants younger than 6 months (why?), Reye’s syndrome in children treated with ASA What are some examples of NSAIDs? 66  Arachidonic Acid Pathway Arachidonic acid is released from cell membrane phospholipids using phospholipase Then…arachidonic acid is converted by enzymes within two different pathways Leukotriene Pathway Cyclooxygenase Pathway Cyclooxygenase enzymes (COX-1; COX-2) Can be expressed under normal conditions i.e. homeostasis Lipoxygenase enzyme (LOX) (COX-1 & COX-2) or in response to triggering event i.e. injury (COX-2) Leukotrienes Prostaglandins & Thromboxane Smooth muscle contraction, constricts pulmonary airways Maintain organ function, protect gastric mucosa, mediate (bronchoconstriction), vasoconstriction, vascular pain & inflammation, vasodilation/vasoconstriction, permeability 67 bronchoconstriction, platelet function What Do COX Enzymes Do? 68 Adapted from: https://science.sciencemag.org/content/336/6087/1386/tab-figures-data CREDIT: C. BICKEL/SCIENCE  Classification: NSAID Indications for use: relieve mild to moderate pain, fever, and inflammation Mechanisms of action: inhibition of prostaglandin synthesis Ibuprofen Desired effects: reduction of pain, body temperature and inflammation Adverse effects: dizziness, decrease in platelet function, GI ulceration with occult or gross bleeding Nursing Implications: Should be taken with food or milk. Clients should be instructed to report signs of bleeding and to avoid alcohol. 69 Celecoxib Classification: Second generation NSAID Indications for use: mild to moderate pain and inflammation associated with RA, osteoarthritis, dysmenorrhea, dental procedures, headache, and ankylosing spondylitis; anti-pyretic; prophylaxis of adenomas or colorectal polyps; limited due to an increased risk of myocardial infarction (MI) and stroke Mechanisms of action: blocks COX-2 without inhibiting COX-1 🡪 analgesic, anti- inflammatory, and antipyretic effects without causing GI irritation Desired effects: Reduction of pain, fever and inflammation Adverse effects: chronic kidney disease and liver impairment; increased risk of potentially fatal cardiovascular thrombotic events, MI, and stroke; risk of bleeding, ulcers, and stomach or intestine perforation Nursing Implications: What would the nurse monitor for? What would happen if a client took too much celecoxib? 70 Corticosteroids Glucocorticoids Mineralocorticoids 71 Systemic glucocorticoids Wide therapeutic application Short-term use due to potentially serious adverse effects Suppress histamine release and inhibit the synthesis of prostaglandins by COX-2; inhibit the immune system by suppressing certain functions of phagocytes and lymphocytes 🡪 reduce inflammation Serious adverse effects: suppression of the normal functions of the adrenal gland (adrenal insufficiency), hyperglycemia, mood changes, cataracts, peptic ulcers, electrolyte imbalances, and osteoporosis; mask infections 72 Prednisone Classification: Synthetic glucocorticoid Indications for use: anti-inflammatory (short-term); maintain adrenal function (long-term) Mechanisms of Action: decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation Desired effects: prevent inflammation, reduce risk of bronchospasm in patients with asthma or certain cancers; immunosuppressive at higher dose Major Adverse effects: Cushing’s syndrome (long-term use): includes hyperglycemia, fat redistribution to the face, and bones that easily fracture, fluid retention, gastric ulcer Nursing Implications: Clients may need insulin or oral antihyperglycemics to treat hyperglycemia, may need anti-ulcer medications. Prednisone interacts with many drugs. Knowing the adverse effects, what would the nurse monitor for? 73 Dexamethasone Classification: Synthetic glucocorticoid Indications for use: Inflammation, allergies, neoplasms, cerebral edema, septic shock, collagen disorders, dexamethasone suppression test for Cushing syndrome, adrenocortical insufficiency, TB, meningitis, acute exacerbations of MS Mechanisms of action: Suppresses migration polymorphonuclear leukocytes, fibroblasts, reversing increased capillary permeability and lysosomal stabilization, suppresses normal immune response, no mineralocorticoid effects Desired effects: Decreased inflammation, relieve nausea related to cancer treatment Major Adverse effects: hypertension, seizures, hyperglycemia, immunosuppression Nursing Implications: screen for existing infection. Baseline assessments e.g, BP and serum glucose, electrolytes and CBC. But wait…isn’t this what we are trying to do? Why is immunosuppression a concern? 74