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Department of Surgery, Division of Trauma, University of Medicine and Dentistry of New Jersey/New Jersey Medical School, Newark, New Jersey
Correspondence: Carl J. Hauser, M.D., FACS, UMDNJ/New Jersey Medical School, Department of Surgery, MSB G-524, 185 South Orange Avenue, Newark, NJ 07103. E-mail: hausercj{at}UMDNJ.edu
Many inflammatory mediators activate neutrophils (PMN) partly by increasing cytosolic calcium concentration ([Ca2+]i). Modulation of PMN [Ca2+]i might therefore be useful in regulating inflammation after shock or sepsis. The hemodynamic effects of traditional Ca2+ channel blockade, however, could endanger unstable patients. Store-operated calcium influx (SOCI) is known now to contribute to Ca2+ flux in "nonexcitable" cells. Therefore, we studied the role of SOCI in human PMN responses to the proinflammatory ligand PAF. PMN [Ca2+]i was studied by spectrofluorometry with and without external calcium. We studied the effects of PAF on Mn2+ entry into and on Ca2+ efflux from thapsigargin (Tg)-treated cells. Influx was assessed in the presence and absence of the blockers SKF-96365 (SKF), TMB-8, and 2-APB. Half of PAF [Ca2+]i mobilization occurs via calcium influx. The kinetics of calcium entry were typical of SOCI rather than receptor-mediated calcium entry (RMCE). SKF had multiple nonspecific effects on [Ca2+]i. Inhibition of store emptying by TMB-8 and 2-APB blocked all calcium entry, demonstrating influx was store depletion-dependent. PAF has no direct effect on calcium efflux. Where SOCI is maximal, PAF has no further effect on calcium-channel traffic. PAF-induced calcium signals are highly dependent on SOCI and independent of RMCE. SOCI-specific blockade might modulate PMN-mediated inflammation and spare cardiovascular function in shock and sepsis.
Key Words: platelet-activating factor • calcium channels • store-operated influx • G protein-coupled receptors • neutrophils • inflammation
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