Inflammation Summary - Allergy, Histamine & Neutrophils - PDF

Inflammation 1 H. Schaefer see reading list in course schedule H. Schaefer, MN 1  Immunity basics Innate immunity – born with – Physical barriers – WBC: neutrophils, eosinophils,… Acquired immunity – acquired aka ‘humoral’ – WBCs: ly...

Inflammation 1 H. Schaefer see reading list in course schedule H. Schaefer, MN 1  Immunity basics Innate immunity – born with – Physical barriers – WBC: neutrophils, eosinophils,… Acquired immunity – acquired aka ‘humoral’ – WBCs: lymphocytes (B-cells, Tcells) – Antibody-mediated: B cells Activated by an antigen – a molecule able to provoke this response Synthesize ‘antibodies’ – proteins called ‘immunoglobulins’ (in blood) – Antibodies inactivate invading pathogens + mark them for phagocytic destruction – Cell-mediated: T cells T-cells recognize foreign markers, antigens, and destroy directly + activate phagocytic cells High viral efficacy H. Schaefer, MN 2  Innate immunity Adaptive immunity Physical barriers Skin/mucous membranes Cellular barriers Phagocytes T cells: memory & e.g. macrophage, neutrophil signalling NK cells B cells - antibodies (immunoglobulins) B cells - memory Mast cells Process barriers Inflammation Cytokines e.g. interferons & interleukins Complement system Fever Opsonins E.g. ’tags H. Schaefer, MN 3 H. Schaefer, MN 4  Blood basics Fluid connective tissue – Cells, fibers (e.g. precursor ‘fibrinogen’), fluid matrix Blood flow’s goal is perfusion of organs Supplies nutrients to all cells – even cells without direct flow rely on diffusion of these nutrients from areas with blood flow (e.g. cartilage) – when absent = cellular necrosis (e.g. stroke) Fx: – Transport of nutrients (glucose, lipids,..), gasses, hormones, electrolytes – Waste away from cells (e.g. lactic acid, creatinine, CO2, …) – Body temperature regulation (hypothalamus => vasodilation = heat loss through blood flow) – Clotting – Osmotic pressure – fluid movement (e.g. albumin, …) – Protection (immunity e.g. WBC) H. Schaefer, MN 5  Blood aka ‘whole blood’ Plasma – 55% of whole blood volume – H20, solutes (e.g. electrolytes, nutrients), blood proteins H20: 92% of plasma – Blood proteins: low if body’s protein is low ! (e.g. malnutrition, starvation,..) E.g. Albumins, Globulins, Fibrinogen synthesized in liver carriers of substances (‘affinity’ to specific ones) = PPB – E.g. Albumin some are ‘antibodies’ - immunoglobulins Cells (aka ‘formed elements’) – 45% of whole blood volume – Red (RBC), White (WBC), Platelets – Synthesized via ‘hemopoiesis’ (hematopoiesis) H. Schaefer, MN 6 Hemopoiesis/hematopoiesis stem cell: in bone marrow H. Schaefer, MN 7 H. Schaefer, MN 8  WBCs: leukocytes (“BEMN”) Synthesized from hematopoietic ‘myeloid’ stem cells: leukopoiesis Immune response migration & mobility toward stimulus: ‘chemotaxis’ – Migrate out of blood vessels, into tissues – Mobile – can flow toward the stimulus Neutrophils: – 50-70% of all WBCs – 1st to injury, within 90 minutes to injury site – Highly responsive to e.g. bacteria – Engulf & digest (digestive enzymes) Apoptose after engulfing 1-10 bacteria Release inflammatory mediators to aggregate more WBCs – Prostaglandins, leukotrienes, … H. Schaefer, MN 9 10  CBC & differential immature neutrophils aka ‘band neutrophils’ FYI: numbers (not tested, reference range is provided in lab results) H. Schaefer, MN 11  WBC responders: Neutrophils – WBC Especially if bacteria present – Depletion of mature neutrophils causes immature neutrophil presence: bands Lymphocytes – WBC – Especially if viruses present Eosinophils – WBC – Especially if allergens present Non-specific markers e.g. C-reactive protein (pro-inflammatory protein) – If tissue inflammation is present H. Schaefer, MN 12  Inflammation: summary Inflammation is an innate, non-specific response – onset: minutes (acute inflammation) – triggered by noxious stimulus in tissues * Noxious stimuli, e.g.: Allergen (=> allergy) Pathogen (infection): bacteria, viruses, fungi, parasites, …. Tissue injury Autoimmune disease Disease process (e.g. neoplasm) H. Schaefer, MN 13 ‘noxious’ stimulus (aka trigger) H. Schaefer, MN 14  Mast cell degranulation: inflammatory mediators released Noxious stimulus => inflammatory mediator release * mast cells are primary secretors – => e.g. histamine & prostaglandin – other pro-inflammatory mediators: – complement system, cytokines – nitric oxide release (endothelial + more from WBCs) Prostaglandins H. Schaefer, MN 15  Mast cells: distributed throughout tissues activated by noxious stimuli 16  Stages: 1. VASCULAR STAGE: vasodilation, increased vascular permeability 2. CELLULAR STAGE: WBC migration into tissue (e.g. Neutrophils, Macrophages, NK cells) toward the noxious stimulus via margination, transmigration, chemotaxis 3. & 4. SIGNALLING & PHAGOCYTOSIS STAGEs: inflammatory mediators attract more WBCs & induce own synthesis; phagocytosis of noxious stimulus => tissue healing 17 Inflammation S&S: swelling, redness, pain, pus, … H. Schaefer, MN 18 Cont. H. Schaefer, MN 19 Inflammation: Histamine Primary mediator of sensory stimulated inflammation E.g. allergy stored within the mast cells - released upon mast cell contact with allergen - agonist to H1-receptors (‘G-protein’ type) Smooth muscles of the vascular system, digestive tract, and bronchial tree, CNS Effects: Capillary vasodilation & permeability Stimulation of nerve endings => pain Bronchoconstriction Tachycardia Itching Urticaria H. Schaefer MN  Hypersensitivity ‘allergy’ various types most common: type I hypersensitivity (IgE modulated) Noxious stimuli: allergen (antigen that triggers the response) – e.g. pollen, dust, animal dander, peanuts, drugs (e.g. morphine) – within 15 minutes of exposure => pathophysiology *: – 1st exposure- allergen (antigen): WBC activation - TH2 signalling to B- cells => specific antibodies (IgE type) synthesized & secreted – those IgE antibodies are present in tissues (high numbers) & attach to mast cells (approx. within 1-2 weeks) – 2nd exposure – antigen distributes & attaches to the IgE, ‘crosslinking it’ => mast cell degranulates quickly & effectively => histamine etc…. secreted S&S: local -> systemic -> systemic life threatening (anaphylaxis) Tx: depends on severity of response H. Schaefer, MN 21  * patho: allergic response https://www.youtube.com/watch?v=y3bOgdvV-_M H. Schaefer MN Tx: Histamine 1 antagonists aka Antihistamines 1st & 2nd generation sedation vs no sedation First generation: cross BBB = CNS effects Second generation: histamine - excitatory CNS no CNS distribution neurotransmitter, causes wakefulness ‘non-drowsy’ => antagonism of CNS H1 = Drugs: drowsiness fexofenadine (Allegra) Drugs: loratadine (Claritin) diphenhydramine (Benadryl, cetirizine (Reactine) e.g. Allerdryl) fast melt tabs chlorpherinamine (ingredient in Onset 10-20 min e.g. Benylin) Duration 24 hrs desloratadine (Aerius) H. Schaefer MN  Topical antihistamines eye symptoms: (olopatadine) Patanol eye drops skin symptoms: Benadryl cream H. Schaefer MN  Scenario: Patient touches a plant, e.g. stinging nettle S&S: localized urticaria (hives), pruritus; no change to VS; no other deficits noted Dx: localized allergy Tx: H. Schaefer, MN 25  Scenario: Patient comes to a friend’s house, the friend has a cat. Within 15 minutes, starts to have s&s: Watery eyes (epiphora) Itchy eyes (allergic conjunctivitis) Runny nose (rhinorrhea) Sneezing Slightly itchy skin throughout (pruritus) Dx: systemic allergy, non-life threatening Tx: ______ & monitor! ALLERGY is a progressive state H. Schaefer, MN 26  Scenario, cont.: the cat allergy quickly worsens S&S: itching, diffused urticaria throughout, difficulty breathing (bronchoconstriction), tachycardia NOT all of these must be present note: VS affected Dx: anaphylaxis Tx: antihistamines + life saving drugs more potent/more direct route/more receptors targeted H. Schaefer, MN 27  Allergy testing: allergen administered via topical or superficial injection H. Schaefer, MN 28 Allergy de-sensitization tx once allergen/s’ identified => low amounts of allergen-serum IM injected over many months/years dynamics: stimulation of TH1 & T-reg. (regular) cells TH1 => B-cell formation of IgG slow response antibodies to an immune threat IgG competes with IgE at receptor IgG combines with antigen (allergen) forming a unit which does not crosslink at the mast cell (no fit) T-reg. fx = suppression of immune system H. Schaefer, MN 29 H. Schaefer, MN 30 Cont. H. Schaefer, MN 31 Inflammation S&S: swelling, redness, pain destruction of pathogen & containment of injury non-specific H. Schaefer, MN 32 Inflammation in tissue injury tissues & mast cells: release of inflammatory mediators e.g. prostaglandin Synthesis of prostaglandins from Arachidonic Acid (fatty acid) precursor => inflammation Prostaglandins – many kinds Synthesized in all body tissues Protective mechanism Various actions H. Schaefer MN Prostaglandin types, e.g. FYI H. Schaefer, MN 34 COX enzymes CYCLOOXYGENASE (COX) enzyme required for prostaglandin synthesis 2 types of COX: COX-1 & COX-2 => synthesis of prostaglandin precursor & further prostaglandin differentiation H. Schaefer MN Tx: COX inhibition drug class: non-stereoidal anti-inflammatories (NSAID) reduces inflammation primarily due to cellular injury + as a result modulates pain & fever effect: anti-inflammatory, analgesic, antipyretic Selective COX-2 inhibitors: Non-selective COX inhibitors: Drug: celecoxib (Celebrex ®) Drugs: Rx only (except topical creams) Acetylsalicylic acid (Aspirin aka ASA) ‘black box’ CV warning + Enteric coated ASA (ECASA) other brands removed from market due to cardiovascular complications Ibuprofen (Advil, Motrin) including death (e.g. Vioxx) Ibuprofen-like: NOT 1st line therapy!!! Voltaren (Diclofenac) Naproxen (Aleve, Naprosyn) Ketorolac (Toradol) Indomethacin (20xASA potency) = Rx only H. Schaefer MN  Caution: no Aspirin (ASA) for kids! Reye’s syndrome H. Schaefer MN  NSAIDs, e.g. A patient played flag football on the weekend, and twisted ‘sprained’ his ankle Dx: soft tissue injury due to torsion Tx: NSAIDs: Ibuprofen PO, Voltaren crm + ice + elevate + rest H. Schaefer, MN 38  https://www.google.com/search?q=dr+mike+glucocorticoids&rlz=1C5 Dr. Mike CHFA_enCA824CA824&oq=dr+mike+glucocorticoids&aqs=chrome..69i 57j69i64.6076j0j4&sourceid=chrome&ie=UTF- 8#fpstate=ive&vld=cid:095dec13,vid:-6MFCy_dFew 39 Glucocorticoids: steroidal drugs glucocorticoid = endogenous hormone Adrenal cortex secretion lipophillic; nuclear receptor binding; some are prodrugs effects: endogenous substance for survival during fasting: stimulates gluconeogenesis stimulates protein degradation facilitates lipolysis related to inflammation: Prostaglandin synthesis inhibition (COX-2) Histamine release suppression Suppression of phagocytes/lymphocytes as a drug: many times more potent high efficacy for tissue inflammation Considerations: efficacy, route of administration; risk vs benefit H. Schaefer MN Drugs: (suffix: -one) Hydrocortisone, Cortisone Prednisone, Prednisolone Methylprednisolone Dexamethasone H. Schaefer MN 42