YW - NSAIDs and PGs Flashcards
What triggers local inflammation?
Tissue damage/infection activates various cell types:
- Peripheral tissue
- Platelets
- Endothelial cells
- Mast cells
- Peripheral nerves
How do these cells contribute to inflammation?
They release autacoids like
- histamine
- 5-HT, cytokines
- chemokines
- bradykinin
- nitric oxide
- eicosanoids
What are the main effects of these autacoids? (5)
- Vasodilation
- increased vascular permeability
- leukocyte recruitment
- pain
–> Healing
What is the desired outcome of inflammation?
Initial inflammation triggers healing; however, chronic inflammation can be detrimental
How do inflammatory mediators influence the immune response?
They induce complex cellular and molecular responses through gene expression changes.
- Rapid changes: Activate proinflammatory signaling pathways.
- Sustained changes: Modify the adaptive immune response (maturation, phenotype, motility of immune cells)
How do corticosteroids exert anti-inflammatory effects? (2)
They bind to nuclear receptors, regulating gene expression.
- Increase anti-inflammatory gene expression (e.g., annexin-1).
- Reduce pro-inflammatory gene expression (e.g., COX-2)
What are the limitations of using corticosteroids for inflammation? (4)
Long-term use can have undesirable effects:
- Suppress immune response, increasing susceptibility to infection.
- Cause metabolic disturbances (impact on steroid production).
- Lead to iatrogenic Cushing’s syndrome (widespread systemic dysfunction).
- Suppress growth in children (important for bone development)
What is the role of the eicosanoid pathway in inflammation?
It’s a lipid-dependent signaling pathway involved in inflammation.
- Phospholipase A2 (PLA2) releases arachidonic acid (AA) from cell membranes.
- AA is further metabolized into various eicosanoids
What are the different eicosanoids that can be produced from AA? (4)
- Prostaglandins (PGE1)
- Thromboxane A2
- Leukotrienes (Leukotriene A)
- Platelet activating factor (PAF)
How do NSAIDs (nonsteroidal anti-inflammatory drugs) work?
They inhibit COX (cyclooxygenase) enzyme activity, thereby decreasing prostaglandin production and reducing inflammation
What steps are involved in eicosanoid-like signalling? (6)
1. Activate lipid metabolism (Phospholipase A2)
2. Generate signaling metabolite by further metabolism: Arachidonic acid is then metabolized into a signaling molecule through a series of enzymatic reactions
3. Release metabolite to allow intercellular signalling
4. Activate cognate Receptor: Once inside the cell, the signaling molecule binds to a specific receptor on the cell surface, triggering a cellular response
5. Transport signal into cell by specific transport: The signaling molecule is then transported into the target cell by specific transporters
6. Inactivate with specific enzymes: The signaling molecule is eventually inactivated by specific enzymes, ensuring the signal doesn’t persist indefinitely.
How do different eicosanoids contribute to inflammation? (3)
Different eicosanoids have varying effects:
- Prostaglandins (e.g., PGE2): Protect gastric mucosa, vasodilation, hyperalgesia (increased pain sensitivity).
- Thromboxane (TxA2): Vasoconstriction, bronchoconstriction, platelet aggregation.
- Leukotrienes: Bronchoconstriction, increased vascular permeability.
What are the two main types of COX enzymes, and how do they differ?
Arachidonic Acid → Cyclooxygenase → Prostoglandins
- NSAIDs inhibtis COX action
COX 1
- Housekeeping
COX 2
- Mediates inflammatory response
