Lecture 4: Inflammation 1

Lecture 4: Inflammation 1 Immunity Basics · innate immunity: non-specific defense ↳ skin, mucous membranes, phagocytes, NK cells, inflammation, complement, fever etc. · adaptive immunity: specific defense ↳ antibody mediated (B-cells) ↳ cell-mediated (T-cells) - - Blood Basics ① Plasma · 55% of whole blood volume · 92% water, also electrolytes, nutrients, plasma proteins · plasma proteins: (albumin, globulin, fibrinogen) ↳ low if body proteins low (malnutrition, starvation) ↳ synthesized in liver ↳ carriers of substances ("affinity" for specific ones)= PPB ② Cells (aka formed elements) · 45% of whole blood volume · RBC, WBC, platelets · synthesized by hematopoiesis (erythropoiesis, leukopoiesis) WBC: Leukocytes · Monocytes, neutrophils, eosinophils, basophils · remember: leukopoiesis from myeloid stem cells, immune response, chemotaxis · Neutrophils ↳ 50-70% of all WBC ↳ first to injury ↳ engulf & digest ↳ apoptose after engulfing 1-10 bacteria ↳ release inflammatory mediators (prostaglandins, leukotrienes, etc) Inflammation · Inflammation is innate, non-specific defense ↳ onset in minutes = acute ↳ triggered by noxious stimulus in tissues · Inflammatory mediators released: ↳ histamine and prostaglandin ↳ pro-inflammatory activation: complement, cytokines - NO release (WBC response) ① Vascular Stage: vasodilation, increased vascular permeability ② Cellular Stage: WBC migration into tissues Innate Immunity: Inflammation · (caused by nonspecific noxious stimulus) · allergy: allergen · tissue injury · infection: bacteria, viruses, fungi, parasites... · autoimmune disease · disease · etc. ③ Signalling & Phagocytosis Stage: pro-inflammatory mediators attract more WBC and induce synthesis, phagocytosis of noxious stimulus + opsonization · Mast cells: primary secretors of histamine · Histamine: primary mediator of inflammation associated with allergies Mast Cells · hematopoietic precursor cells · distributed throughout tissues · activated by noxious stimuli · degranulation: release of inflammatory mediators (histamine + prostaglandin) Inflammation: Histamine · Histamine is the primary chemical mediator of inflammation that's stored/released from mast cells · H1 receptors: found in smooth muscles of the vascular system, digestive tract, and bronchial tree · H2 receptors: stimulation releases large amounts of HCI (found in stomach) · H1 Histamine Effects: ↳ capillary vasodilation & permeability (edema) ↳ bronchoconstriction ↳ pain ↳ itching ↳ Urticaria (flat red rash) ↳ increased HR - Hypersensitivity "Allergy" · 3 types of pathological sequelae ↳ most common: type I hypersensitivity, IgE mediated · Noxious stimuli: Allergen (antigen that initiates response) eg. pollen, dust, animal dander, foods, drugs (eg. Morphine) ↳ pathology: - first exposure: (allergen antigen)-specific antibodies (IgE type) synthesized & secreted via B-cells → IgE antibodies attach to mast cells and sensitize it - second exposure: antigen distributes, attaches to IgE crosslinking it → mast cell degranulates → histamine etc. secreted · Signs & symptoms: local → systemic + life threatening anaphylaxis ↳ response must be in 15 minutes · treatment: depends on severity of response Suffix -ine H1 Receptor Antagonists "Antihistamines" · blocks histamine receptors for decreased CNS distribution ① First Generation drugs ② Second Generation drugs · drowsy · non-drowsy · crosses BBB = CNS effects A · fexofenadine (Allegra) · diphenhydramine (Benadryl, Allerdryl), · Ioratadine (Claritin) · Chlorpherinamine (in Benylin) · Cetirizine (Reactine) fast melt tabs ↳ onset 10-20 min ↳ duration 24 hours → long half-lives main difference -A · desloratadine (Aerius) - - Topical Antihistamines · eye symptoms: ↳ olopatadine/Patanol ↳ eyedrops · skin symptoms: ↳ benadryl cream Allergy Testing · allergen administered via topical or superficial injection · usually small concentrated dose Allergy De-sensitization Treatment · once allergen's identified · low levels of allergen-specific serum IM injections over many months/years · dynamics: formation of IgG (slow response antibodies to an immune threat, low potency as an allergy trigger) ↳ IgG binds with antigen before antigen reaching IgE on mast cells ↳ no receptor, no antigen-IgE crosslinking → no reaction Inflammation in Tissue Injury · signs & symptoms: swelling, heat, redness, pain ↳ destruction of pathogen and containment of injury · release of inflammatory mediators ↳ histamine, prostaglandins, bradykinin, leukotrienes · release of pro-inflammatory mediators ↳ cytokines, complement, pyrogen (if pathogens present) · Prostaglandins are made from Arachidonic Acid (fatty acid) → uses COX enzyme · there are many kinds of prostaglandins, can be synthesized in all body tissues as a protective mechanism with various actions COX Enzymes - NSAIDS · Cyclooxygenase (COX) enzyme required for prostaglandin synthesis · 2 types: COX-1 and COX-2 · NSAID: COX inhibition reduces inflammation primarily due to cellular injury ↳ as a result modulates pain and fever → anti-inflammatory, analgesic, antipyretic effects Selective COX-2 inhibitors · drug: Celecoxib (celebrex) ↳ prescription only (except topical creams) ↳ "black box" CV warning ↳ other brands removed from market due to cardiovascular complications and death · NOT 1st line therapy eg. patients who can't inhibit platelets - Don’t give NSAID to children: Reye’s syndrome Non-selective COX inhibitors · COX-1 and COX-2 inhibited · drugs: ① Acetylsalicylic acid (Aspirin aka ASA) ↳ + Enteric coated ASA (ECASA) ② Ibuprofen (Advil, Motrin) ③ Ibuprofen-like: a. Voltaren (Diclofenac) b. Naproxen (Aleve, Naprosyn) c. Ketorolac (Toradol) d. Indomethacin (20x ASA potency → prescription only) - nuclear binding ↑ receptor https://www.youtube.com/watch?v=-6MFCy_dFew Glucocorticoids · naturally occuring endogenous hormone made by the adrenal cortex · secreted by HPA axis + circadian rhythm ↳ end product is cortisol ADME: ↳ lipophilic, nuclear receptor binding · lipophilic · effects: · overall high PPB ↳ glucogenesis · Prednisone (prodrug) ↳ protein degradation ↳ lipolysis ↳ prostaglandin synthesis inhibition by COX-2 ↳ histamine release suppression ↳ suppression of phagocytes/lymphocytes (low immunity) · Super potent when given as a drug ↳ high efficacy! ↳ ideal for acute or severe case Suffix -one Medications: · Hydrocortisone, Cortisone · Prednisone, Prednisolone · Methylprednisolone · Dexamethasone