The microcirculation and inflammation: site of action for glucocorticoids.
The glucocorticoid hormones and their synthetic derivatives are potent suppressors of inflammatory and allergic pathologies. Their widespread efficacy is the result of multiple modes of action occurring predominantly at the level of the microcirculation. Indeed the glucocorticoids interfere with the function of all of the cellular components of the microcirculation associated with an inflammatory response. These agents inhibit vasodilatation of the arteriolar and capillary beds. therefore preventing the increase in blood flow that characterizes the initial stages of the inflammatory response. They also prevent increases in vascular permeability in the capillary and post-capillary venule, thereby reducing exudate formation. Finally, the glucocorticoids potently suppress leukocyte emigration across post-capillary venules. However, this promiscuity of the glucocorticoids to act at multiple sites also endows this class of (drugs with major side effects associated with chronic treatment. We propose that one way to progress forward is to understand better the effects of glucocorticoids within the microcirculation. This may aid identification of specific molecular sites of action and therefore the development of novel glucocorticoid molecules with fewer side effects.
Perretti
M
M
Department of Biochemical Pharmacology, The William Harvey Research Institute, London, England. M.Perretti@qmw.ac.uk
Ahluwalia
A
A
D000818:Animals; D017305:Annexin A1 / Q000502:physiology; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001160:Arterioles / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D051546:Cyclooxygenase 2; D003907:Dexamethasone / Q000494:pharmacology; D015777:Eicosanoids / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000187:drug effects; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007527:Isoenzymes / Q000494:pharmacology; D008565:Membrane Proteins; D008833:Microcirculation / Q000187:drug effects*; D010741:Phospholipases A / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases / Q000494:pharmacology; D014657:Vasculitis / Q000188:drug therapy* / Q000473:pathology; D014664:Vasodilation / Q000187:drug effects; D014699:Venules / Q000187:drug effects
D017305:Annexin A1; D000893:Anti-Inflammatory Agents; D015815:Cell Adhesion Molecules; D015777:Eicosanoids; D005938:Glucocorticoids; D007527:Isoenzymes; D008565:Membrane Proteins; D003907:Dexamethasone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D010741:Phospholipases A