Inflammatory Mediators PDF

Inflammatory mediators https://chironptva.com/inflammation-acute-vs-chronic/ Overview Definition, types, function, eicosanoids, Inflammatory mediators histamine, cytokines, chemokines, glucocorticoids Inflammatory mediators Concepts...

Inflammatory mediators https://chironptva.com/inflammation-acute-vs-chronic/ Overview Definition, types, function, eicosanoids, Inflammatory mediators histamine, cytokines, chemokines, glucocorticoids Inflammatory mediators Concepts Inflammation is – very generally speaking – the body’s immune system’s response to stimulus. Inflammation happens when the immune system fights against something that may turn out to be harmful. Without inflammation, wounds would fester and infections could become deadly. Inflammation is often characterized by redness, swelling, warmth, and sometimes pain and some immobility. https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0072482/ Inflammatory mediators Definition What is inflammation? Tissue response to injury/pathogen Why is inflammation necessary? Numerous reasons! a) Prevent/Remove infection. b) Stimulate the processes required for repair. Inflammatory mediators Definition Latin: īnflammō – to ignite or “set alight”. Can be either acute (temporary) or chronic (persistent). Chronic inflammation can lead to disease (asthma, rheumatoid arthritis). Inflammation is a complex process which requires communication between the site of damage/infection (e.g. epithelial cell, endothelial cell etc.) and the immune system (innate immunity). Innate Immunity: non-specific, immediate (WBCs, cough, mucous, skin); antigen-independent. There are many inflammatory mediators! Inflammatory mediators Causes Injury! Physical: cuts, impact injuries, surgical trauma, hypoxia (e.g. due to ischemia). Pathogenic: microbial infection, parasites (e.g. lungs, skin). Toxins (eg from bacteria, thorns, plants) All trigger an ACUTE INFLAMMATORY RESPONSE. Inflammatory mediators Acute inflammation Dilation of Recruitment Chemotaxis Phagocytosis Resolution vessels of cells 1 2 3 4 1. The vasculature around a site of injury reacts to recruit cells of the immune system. 2. Circulating immune cells migrate from these vessels into the injured tissue. Inflammatory mediators Acute inflammation Dilation of Recruitment Chemotaxis Phagocytosis Resolution vessels of cells 1 2 3 4 1. The vasculature around a site of injury react to recruit cells of immune system. 2. Circulating immune cells migrate from these vessels into the injured tissue. 3. Neutralise/remove inciting stimulus. 4. Repair damaged tissue → healing → terminate acute inflammatory response. Controlled by inflammatory mediators Inflammatory mediators Types Eicosanoids Complement Inflammatory Cytokines mediators Histamine Other agents Inflammatory mediators MEDIATOR FUNCTION Released by basophil/mast cells – initiator of inflammatory Histamine response. Inflammatory effects are mostly within the vasculature, regulates “vasoactivity/permeability”. Early response to injury – recognises pathogenic antigens → leukocyte chemotaxis. Involved in inflammation: recruitment Complement (e.g. C3/C5) of phagocytes, enhanced phagocytosis, bacterial membrane attack. Eicosanoids Cytokine/complement stimulate enzymatic release of (e.g. prostaglandins, arachidonic acid (fatty acid). Arachidonic acid → leukotrienes) prostaglandins/leukotrienes – wide range of functions. Cytokines (chemokines, Orchestrate a plethora of processes associated with interferons, interleukins immunity and inflammation. Stimulate repair. etc) Nitric oxide (NO): Vasodilation. Bradykinin: increased vascular permeability. Other agents Bacterial products (e.g. LPS lipopolysaccharide): chemotaxis. Inflammatory mediators Innate immunity Haematopoiesis Innate immunity CELL TYPE FUNCTION Reside in tissue, phagocytose cellular and foreign debris. Macrophage Antigen presenting cell (→ acquired immunity response). Neutrophil Phagocytose bacteria Eosinophil Defend against parasites. Release histamine, leukotrienes and other Basophil / Mast cell mediators after exposure to antigen. Inflammatory mediators Pharmacological targets Depends on the disease: acute or chronic inflammation? Strategies include: 1. Modulation of eicosanoids. 2. Modulation of histamine signalling. Inflammatory mediators Eicosanoids Example of an “autacoid”: substance that is rapidly synthesised in response to specific stimuli, and act locally Eicosanoids are a chemically diverse family of autacoids derived from arachidonic acid (comes from membrane phospholipids → phospholipase A2 processing). Inflammatory mediators Eicosanoids Play a critical role in inflammation: Prostaglandins/leukotrienes Major source of pharmacological intervention: NSAIDs (Non-steroidal anti-inflammatory drugs) as COX inhibitors Cyclooxygenase-2 inhibitors Leukotriene inhibitors Inflammatory mediators Eicosanoids (Metabolism/synthesis) Membrane Phospholipid Rate-determining PHOSPHOLIPASE A2 step Isoprostanes Cytochrome P450 Epoxygenases ARACHIDONIC ACID LIPOXYGENASE Epoxyeicosa-tetraenoic acid CYCLOOXYGENASE (EETs) Lipoxins PROSTAGLANDINS LEUKOTRIENES Prostacyclins Thromboxane Inflammatory mediators Cyclooxygenase (COX) pathway Leads to the formation of PROSTAGLANDINS (regulation of vascular/bronchial tone) which results in the synthesis of PROSTACYCLINS (vasodilator, cytokine release). Two enzymes involved: COX-1 and COX-2. 60% sequence homology, but differ in; cellular, genetic, physiological, pathologic and pharmacological profiles. Inflammatory mediators COX-1 and COX-2 Property COX-1 COX-2 Inducible (not normally present in Expression Constitutive tissue) Tissue location Ubiquitous Inflamed tissue Cellular location ER ER and nuclear membrane Pro-inflammatory and mitogenic Role Protection/maintenance functions Inflammatory mediators (e.g. Induced by N/A cytokines, bacterial products) DUE TO THESE DIFFERENCES (particularly in location), COX-1 and COX-2 ultimately perform DIFFERENT FUNCTIONS Inflammatory mediators COX-1 and COX-2 (Activity) Membrane Phospholipid Arachidonic acid COX-1/COX-2 ARACHINODIC ACID PGG2 LOX COX Lipoxins PGH2 PROSTAGLANDINS LEUKOTRIENES Prostacyclins Thromboxane Thromboxane Other (platelet PGE2 prostaglandins aggregation) PGE2-receptor (GPCR): Vasodilation, hyperalgesia, fever, immunomodulation Inflammatory mediators Membrane Phospholipid Lipoxygenase pathway LIPOXYGENASE (LOX) enzymes produce Leukotrienes (LT) and lipoxins. Various isoforms, main player: 5-LOX (also ARACHINODIC ACID LOX 15-LOX → lipoxins). COX Lipoxins PROSTAGLANDINS LEUKOTRIENES Prostacyclins Thromboxane LTD4 Arachidonic acid 5-LOX LTB4 LTC4 LTE4 LTF4 5HPETE LTA4 CYSTEINYL LEUKOTRIENES Inflammatory mediators Pharmacological intervention of the arachidonic acid pathways Eicosanoid (PG and LT) signalling is involved in most stages of inflammation: Edema Vasoconstriction Vasodilation Chemotaxis (swelling) Pain and Increased Vascular permeability Fever Hyperalgesia Hence inhibiting arachidonic acid pathways will alter the inflammatory response. Inflammatory mediators Pharmacological intervention (COX-1/COX-2 inhibitors) One of the most frequently used family Membrane Phospholipid of drugs in medicine. Non-steroidal anti-inflammatory Drugs (NSAIDs). Suppress underlying inflammatory response (not cure). ARACHINODIC ACID Combine anti-inflammatory, antipyretic LOX COX and analgesic properties. Lipoxins PROSTAGLANDINS LEUKOTRIENES Prostacyclins Thromboxane Inflammatory mediators NSAIDs Many types! – most are polycyclic carboxylic acid derivatives. Selective COX-2 inhibitor All act as REVERSIBLE competitive inhibitors of COX (except aspirin: irreversible) – block AA binding. Generally, NSAIDs inhibit COX-1 and COX-2 (hence can cause side effects – especially if used long term...). Inflammatory mediators NSAIDs (COX-1/COX-2 (non-selective) inhibitors) DRUG GROUP EXAMPLE SALICYLATES Aspirin PROPIONIC ACIDS Ibuprofen, naproxen, ketoprofen ACETIC ACID DERIVATIVES Indomethacin, diclofenac OTHERS Piroxicam, mefenamate, nabumetone (NB: Paracetamol (acetaminophen) is not really an NSAID – antipyretic / analgesic) COX-2 selective drugs: arms race back in the 1990s after its identification. However, only CELECOXIB has been approved (due to uncertainty in safety profile → increased thrombogenicity). Also, more expensive. Inflammatory mediators Leukotriene (LT) inhibitors LTD4 Arachidonic acid 5-LOX LTC4 LTE4 LTF4 5HPETE LTA4 CYSTEINYL LEUKOTRIENES Surprisingly, the only 5-LOX inhibitor in clinical use is zileuton (asthma) – not widely used. Preference for inhibition of LT signalling is LT receptor itself. Montelukast and zafirlukast are cysteinyl LT receptor (CysLT1) antagonists. Significantly improve bronchial tone and asthma symptoms Inflammatory mediators Histamine Histamine has a wide spectrum of actions involving many systems (CNS, GIT, Heart etc.). Plays a prominent role in IgE-mediated type I hypersensitivity reaction, a.k.a ALLERGIC REACTION. Localised allergic reaction to “allergen” (→ acquired immune response – T cells). ACUTE INFLAMMATION: effects manifested through H1 receptor. Histamine production by degranulating mast cell on exposure to antigen https://tacanow.org/family-resources/mast-cell-activation-syndrome-and-autism/ Inflammatory mediators Histamine Histamine has a wide spectrum of actions involving many systems (CNS, GIT, Heart etc.). Essential mediator for immune and inflammatory response. Released by MAST CELLS (amongst others). HISTAMINE FUNCTIONS RELATED TO INFLAMMATION VIA H1 RECEPTOR TISSUE EFFECT OF HISTAMINE Venule/arteriole dilation Vascular smooth muscle Venoconstriction Contraction and separation of Vascular endothelium endothelial cells Lungs Bronchoconstriction → asthma https://teachmeanatomy.info/the-basics/ultrastructure/blood-vessels/ Inflammatory mediators Anti-histamine therapies Two approaches: 1. Inhibit histamine release by mast cells (degranulation). 2. Inhibit histamine receptor Inflammatory mediators Anti-histamine therapies Anti-histamine – receptor drugs: inverse agonists (not antagonists). Many examples: first generation drugs and second generation drugs (more selective to H1 receptor). All block the histamine receptor. https://en.wikipedia.org/wiki/Inverse_agonist Inflammatory mediators Anti-histamine therapies CHEMICAL DRUG GENERATION CLINICAL USE TYPE Allergic rhinitus Diphenhydramine 1st Ethanolamine Anaphylaxis Motion sickness Mepyramine 1st Ethylenediamines As above Cyproheptadine 1st Piperidine As above Cetirizine 2nd Piperazine Allergic rhinitus Loratidine 2nd Piperidine Allergic rhinitus Inflammatory mediator Mast cell degranulation Mainly for treatment of asthma e.g. Cromolyn, nedocromil. Inhibit the immediate allergic response to an antigen but does not relieve an allergic response once it has been initiated. Prophylactic therapy (preventative). “mast cell stabilising agents”: prevent release of histamine from mast cells (Cromoglicic acid). https://www.resmedjournal.com/article/s0954-6111(11)00332-5/fulltext Inflammatory mediators Cytokines and chemokines Inflammatory mediators Cytokines and chemokines Immunomodulatory agents (protein molecules), can have anti- inflammatory or pro-inflammatory functions. cytokines: interleukins (IL-#), TNFα, TGFβ chemokines: CC and CXC chemokines Secreted by various cell types (epithelial cells, immune cells), they control chemotaxis and leukocyte activity/haematopoiesis. Many types – essentially orchestrate the acute inflammatory response. Contribute considerably to chronic inflammatory diseases. Inflammatory mediators Cytokines and chemokines Cytokines involved in inflammatory diseases: TNFα and IL-1 – rheumatoid arthritis (RA). Treatments include: Adalimumab (Humira) - anti-TNFα (eg for rheumatoid arthritis) Etanercept: Irreversibly blocks the TNFα binding domain on the TNFα receptor Anakinra: inhibits IL-1 binding /signalling Inflammatory mediators Glucocorticoid (GC) receptors Ligand binding occurs intracellularly. GC receptor binds to DNA and regulates gene transcription directly. transcription factors. Amongst other things, the GC regulates INFLAMMATORY CYTOKINES → proteins that mediate the inflammatory response. Inflammatory mediators Glucocorticoid (GC) receptors CORTISOL Glucocorticoid OUT Glucocorticoid IN receptor GC/GC receptor GC/GC receptor complex binding Translocation to NUCLEUS nucleus Gene transcription GENE Cellular response TRANSCRIPTION Inflammatory mediators Steroid-based anti-inflammatories Cortisol (hydrocortisone, a corticosteroid) regulates gene expression of cytokines during inflammation. Glucocorticoids (GC) binding to the GR causes: Translocation to the nucleus → binding to DNA → gene transcription of anti-inflammatory cytokines OR silencing of pro-inflammatory cytokines https://www.researchgate.net/figure/Cellular-mechanism-of-action-of-corticosteroids-in-the-inhibition-of-inflammation-Three_fig1_320479597 Inflammatory mediators Steroid-based anti-inflammatories GC drugs include: Dexamethasone, Beclomethasone: mainstay therapies for inflammatory based diseases. Summary Inflammation is an essential defence mechanism. However, it is an extremely complex orchestration of many molecules that stimulate a variety of cell type. Acute inflammation that does not terminate properly can cause persistent inflammation and disease. There are a host of drugs used to control the inflammatory process.