Inflammation and Anti-Inflammatory Drugs Flashcards
Define Inflammation
Response to tissue injury (e.g. bacterial, fungal, parasitic infection, burns, cuts, trauma, cold, heat, chemical agents etc)
What is the function of inflammation?
To destroy, dilute, and partition off the injurious insult, host defence, tissue repair, tumor rejection
What are the beneficial effects of inflammation?
- Stimulation of immune response: allows inflammatory cell recruitment and dilute bacterial toxin
- Entry of antibodies/ complement components: opsonisation of microorganism leading to their lysis or phagocytosis
- Delivery of nutrients and oxygen
- Fibrin formation
- Mediator (and drug) transport
What are the beneficial effects of inflammation?
- Stimulation of immune response: allows inflammatory cell recruitment and dilute bacterial toxin
- Entry of antibodies/ complement components: opsonisation of microorganism leading to their lysis or phagocytosis
- Delivery of nutrients and oxygen
- Fibrin formation
- Mediator (and drug) transport
What are the detrimental effects of inflammation?
- Collagenases and other proteases are liberated and could digest normal tissue leading to to tissue and vascular damage
- Swelling can be serious in an enclosed space (e.g. cranial cavity –> may impede blood flow)
- Inappropriate or prolonged inflammatory response (allergic inflammatory response)
Describe the inflammatory response
- Interaction of a PAMP with TLRs triggers sentinel cells to respond
- Sentinel cells produce cytokines and low MWt inflammatory mediators
- Mediators act on vascular endothelial cells of postcapillary venules causing expression of adhesion molecules and increase vascular permeability
- Leukocytes adhere through interaction between their own integrins and adhesion molecules on endothelial cells
- Halt leukocyte flow through microcirculation
- Migration out of vessels and attracted by chemotaxins
What are PRRs?
Pattern Recognition Receptors
Recognise danger signals like PAMPs and DAMPs
Ex.
FPR (formyl peptide receptor) family that recognises N-formylated peptides characteristic of bacterial protein synthesis
What are TLRs?
Toll-like Receptors found on sentinel cells
Humans have a repertoire of 10 TLRs.
Structurally, they are transmembrane glycoproteins belonging to the receptor tyrosine kinase family.
Phylogenetically they are highly conserved
What vascular events occur due to the immune response?
- Dilation of small arterioles –> increase blood flow
- Slowing of blood flow
- Increase in permeability of the postcapillary venules
What is the function of the neutrophils?
Can engulf, kill and digest microorganisms.
Together with eosinophils, they have surface receptors for C3b, which acts as an opsonin that forms a link between neutrophil and invading bacterium
Acidic vacuole induces enzymatic degradation of microorganism
What is the function of eosinophil?
Similar capacities to neutrophils
Have granules filled with substances, which when released, kill multicellular protein
Includes eosinophil cationic protein, a peroxidase enzyme, the eosinophil major basic protein and a neurotoxin
Describe monocyte to macrophage process
Monocytes migrate to the site of insult via chemotaxis and use additional chemokines, such as MCP-1 and RANTES
Once in tissue, monocyte differentiate into macrophages (M1 or M2) depending on cytokines
What is the function of Macrophages?
Macrophages engulf tissue debris and dead cells, as well as phagocytosing and killing most microorganisms
Play a role in antigen-presenting
What is the role of Mast Cells?
They have surface receptors for both IgE and C3a and C5a. Ligands acting on these receptors trigger mediator release
Preformed packets of cytokines that can release instantaneously (by Ca2+ mediated exocytosis)
How is histamine released?
Released from mast cells by exocytosis during inflammatory or allergic reactions.
Stimuli include complement components C3a and C5a, which interact with specific surface receptors, and the combination of antigen with cell-fixed immunoglobulin (Ig)E antibodies.
What are the main actions of histamine?
- stimulation of gastric secretion (H2)
- contraction of most smooth muscle, except blood vessels (H1)
- cardiac stimulation (H2)
- vasodilatation (H1)
- Increased vascular permeability (H1)
What are prostanoids?
Long-chain fatty acids derived from arachidonic acid
Cyclooxygenase (COX) acts on AA to produce cyclic endoperoxides
COX1 - constitutive and COX2 - inflammatory mediators
What are the actions of prostanoids?
PGI2 acts on IP-receptors to cause vasodilation and inhibition of platelet aggregation
PGE2 in inflammatory responses and mediator of fever
PGE2 decreases lysosomal enzyme release and the generation of toxic oxygen metabolites from neutrophils, as well as the release of histamine from mast cells
What are leukotrienes?
Synthesised from Arachidonic Acid
5- Lipoxygenase acts on AA to produce 5-HPETE which in turn is converted to LTA4
LTA4 is either converted to LTB4 or to a series of cysteinyl-leukotrienes, LTC4, LTD4 and LTE4
What are the actions of LTB4?
Powerful leukocyte chemotactic agent and leukocyte activator (stimulates proliferation and cytokine production)
What are the actions of cysteinyl leukotrienes?
- Contraction of bronchial muscle
- Vasodilation in most vessels, but coronary vasoconstriction
What mediators cause vasodilation?
PGE2, PGI2, VIP and CGRP
What mediators cause swelling of endothelial cell?
Histamine and Bradykinin
What mediators cause inflammation?
LTB4, FMLP, C5a, IL-8 etc
How do NSAIDs work?
Inhibition of arachidonic acid COX-2 in inflammatory cells and causes a decrease in PG synthesis
What are the actions of NSAIDs?
- Anti-inflammatory: decrease in vasodilator and results in less vasodilation and oedma
- Analgesic effect: decrease PG generation - less sensitive nociceptive nerve endings to inflammatory mediators
- Antipyretic effects: decrease in PGs responsible for elevating the hypothalamic set point for temperature control
What is the role of glucocorticoids?
Inhibit formation of inflammatory mediators by intracellular actions on steroid response elements (gene transcription)
Decrease in cytokine and COX-2 expression
Increase in synthesis of lipocortin-1 which inhibits PLA2
What is the glucocorticoid receptor signaling pathway?
- Cortisol enters through the membrane
- Cortisol binds to the glucocorticoid receptor 3. Glucocorticoid receptor translocates to nucleus where they bind to glucocorticoid response elements (GREs) in promoter region
- May also bind directly or indirectly to transcriptional co-activator molecules
- Histone modification and Chromatin modifications
What are leukotrienes modifiers?
Drugs that block the effects of leukotrienes for treatment if asthma
Leukotrienes are associated with an allergic response and inflammation
Give examples of leukotrienes modifiers
- 5-LO inhibitors: block 5-lipoxygenase (zleuton)
- FLAP inhibitors
- LTB4 antagonists
