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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: Animals, Chemokine CCL2, Chemokine CXCL1, Chemotaxis, Leukocyte, Imidazoles, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Microcirculation, Microvessels, Platelet Activating Factor, Receptor, Melanocortin, Type 1, Splanchnic Circulation, Vasculitis.
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Does the melanocortin MC ( 1 ) receptor agonist BMS-470539 inhibit leucocyte trafficking in the inflamed vasculature? Context: Over three decades of research evaluating the biology of melanocortin (MC) hormones and synthetic peptides, activation of the MC type 1 (MC(1)) receptor has been identified as a viable target for the development of novel anti-inflammatory therapeutic agents. Here, we have tested a recently described selective agonist of MC(1) receptors, BMS-470539, on leucocyte/post-capillary venule interactions in murine microvascular beds. Intravital microscopy of two murine microcirculations were utilized, applying two distinct modes of promoting inflammation. The specificity of the effects of BMS-470539 was assessed using mice bearing mutant inactive MC(1) receptors (the recessive yellow e/e colony). BMS-470539, given before an ischaemia-reperfusion protocol, inhibited cell adhesion and emigration with no effect on cell rolling, as assessed 90 min into the reperfusion phase. These properties were paralleled by inhibition of tissue expression of both CXCL1 and CCL2. Confocal investigations of inflamed post-capillary venules revealed immunostaining for MC(1) receptors on adherent and emigrated leucocytes. Congruently, the anti-inflammatory properties of BMS-470539 were lost in mesenteries of mice bearing the inactive mutant MC(1) receptors. Therapeutic administration of BMS-470539 stopped cell emigration, but did not affect cell adhesion in the cremasteric microcirculation inflamed by superfusion with platelet-activating factor.
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Activation of MC(1) receptors inhibited leucocyte adhesion and emigration. Development of new chemical entities directed at MC(1) receptors could be a viable approach in the development of novel anti-inflammatory therapeutic agents with potential application to post-ischaemic conditions. Final Decision: yes