Mediators of the innate immune response Flashcards
Purpose of inflammation
Body attempting to dilute, destroy or isolate a noxious agent and repair damage. The most potent immune defence.
Cause of inflammation
Agents can be physical, chemical or biological.
Process of inflammation
Characterized by generation of inflammatory mediators and accumulation of fluid and leukocytes from blood into extracellular tissues Can be resolved into 3 distinct phases - 1. Initiation 2. Amplification 3. Termination/ resolution
Initiation of inflammation
Structural changes leading to increased blood flow and extravasation of fluid.
Emigration of cells of the innate immune system to the site of injury via chemotaxis.
Amplification of inflammation
Elevated cellular metabolism and releaee of inflammatory mediators which promote both local and systemic responses.
Chemotactic factors attract immune cells that invade surrounding tissues to fight infection (causes collateral damage).
Termination/resolution of inflammation
Accomplished by specific inhibition or dissipation of mediators.
Growth factor then promotes cell proliferation or repair in injured area.
Injured area may return to normal following repair or may proceed and form abscesses/ enter chronic phase.
Hallmark signs of inflammation
Injury, rubor, calor, tumor, dolor, loss of function.
Vascular response to inflammation
Vasodilation
Capillary permeability/oedema
Pain
Cellular response to inflammation
Migration and pavementing of WBCs Emigration Chemotaxis Phagocytosis Controlled by soluble chemical messengers (chemokines and cytokines) released from activated leukocytes and vascular endothelial cells.
Coagulations role in immune response
Acts at the site of lesions to trap exudate, microorganisms and foreign bodies
Kinin pathway
Acts to increase vasodilation and eicosanoid synthesis
Activates B1 and B2 GPCRs, B1 is inducable by inflammatory stimuli.
Complement
Comrpises of >30 plasma and cell surface proteins
C1 - C9 are serum components
Engaged hy the innate immune system, and one of the main effectors of the adaptive immune response.
Mostly made in the liver and exists as inactive proenzymes that are then cleaved to generate the active enzyme components.
Functions of complement
Formation of MAC (membrane attack complex) that lyses gram-negative bacteria, viruses and cells.
Potentiates inflammation by binding to the receptors on mast cells causing the release of histamine (C3a, C4a, and C5a are anaphylatoxins)
Chemoattractant (C5a) increases the recruitment of inflammatory cells.
C3b, C4b and C5b enhance opsonisation by phagocytic cells.
MB-Lectin pathway
Homologous to the classical pathway
MBL forms complex with MASPs that structurally resemble C1 complex
Active MBL-bound MASP complex activates C4 and C2 zymogens which go on to activate C3 convertase
C3 convertase leads to formation of terminal complement proteins and therefore opsonisation and cell lysis.
Defective regulation of complement and disease
Complement is the key link between innate and adaptive imune responses via effects on multiple cell types.
Erroneous activation of insufficient regulation lead to disease.
C5a has a mojor role in psoriasis and asthma.
Deposition of immune complexes activates C1q in systematic lupus and RA.
Is the complement pathway druggable?
Ser proteases and anaphlatoxin receptors and druggable targets.
Difficult to generate good drugs against as complement has a complex regulation which is not fully understood and finding the balance between supressing enhanced activation without compromising defensive function is difficult.
An example of a drug is compstatin, this is a C3 inhibitor that is in phase 2 triaks for treatment of age related macular degeneration.
Histamine
Complexes with macroheparin and an acidic protein in intracellular granules of mast cells and basohpils.
Released by exocytosis following inflammatory/allergic reaction.
Stimulated by binding of C5a and C3a to complement receptors.
Binding of antigen and cross-linking of IgE receptors increases intracellular calcium concentration, therefore increasing exocytosis.
The H4 receptor on basoohils,eosinophils,mast cells and dendritic cells helps regulate histamine release. When coupled with Gi and PLCb histamine release increases.
H4 antagonists now being developed as future treatment for asthma.
Nitric oxide
iNOS is involved in inflammation
All inflammatory cells increase iNOS synthesis following cytokine exposure.
NO binds and activates soluble guanylate cyclase, increasing cGMP.
iNOS-derived NO has mainly pro-inflammatory actions (increases vasodilation, vascular permeability and pro-inflammatory PG production.)
NO and its derivatives are cytotoxic to microbes (and host if NO is excessive)
Eicosanoids
Derived from arachidonic acid
Fate controlled by the COX pathway
PG12, PGE2, PGD2 - vasodilate, increase bloocflow to inflamed areas.
PG12, PGD2 - Decrease platelet aggregation
PG12, PGE2 - Hyperanalgesia
PG12 - mostly from endothelium
PGE2 - produced in inflammatory conditions, pyrogen (increases COX-2 and PGE2 in hypothalamus)
PGD2 - mostly from mast cells, activated by allergen.
TXA2 - Antagonises PG effects, mostly from platelets, decreases vasodilation and increases platelet aggregation.
Non-steroidal anti-inflammatory drugs (NSAIDs)
Example -
Non selective - aspirin, ibuprofen, paracetamol
COX-2 Selective - rofecoxib, celecoxib.
Analgesic (CNS and peripheral effects)
Antipyretic (CNS effects)
Anti-inflammatory (inhibits PGs)
NSAIDs block cyclooxygenase reaction.
COX-1
Constituitively expressed
Roles in -
Inhibition of acid secretion/ maintenance of mucosa to protect stomach lining.
Platelet function
Side effects of NSAIDs due to COX-1 inhibition.
COX-2 selective inhibition would therefore be better. Selective NSAIDs could bind to the selective sidepocket that only COX-2 has and only inhibit COX-2
Lipoxygenase pathway
CysLTs are vasodilators (except in the heart and lungs), potent bronchoconstrictors, important in airway inflammation.
LTB4 - increase PMN adherence, chemotaxis, lymphocyte and macropage function. Is mostly from neutrophils, important in akk types of inflammatory response.
12-HETE - increases PMN and macrophage chemotaxis.
Lipoxygenases - cytosolic enzymes found in lung platelets, mast cells and white blood cells.
Drugs targetting LT pathways
Zileuton/ziflo -
A potent 5-Lipoxygenase inhibitor
Orally administered
Aporoved for prevention and treatment of chronic asthma.
Contraindications in patients with impaired liver function.
Zafirlukast/accolate -
LTD4 and LTE4 receptor-Selective peptidergic competitive antagonist.
Orally administered
Approved for prevention and treatment of asthma
Cannot be used in acute asthma attack
Contraindications in patients with impaired liver function.
