title: Inflammatory chemoreceptor cross-talk suppresses leukotriene B4 receptor 1-mediated neutrophil calcium mobilization and chemotaxis after trauma.
abstract: G protein-coupled chemoattractants recruit neutrophils (PMN) to sites of injury and infection. The leukotrienes (LT) and CXC chemokines (CXC) and their receptors (BLT1/BLT2 and CXCR1/CXCR2) are all known to play roles in these responses. Each system has been studied separately in vitro, but in vivo they act concurrently, and the clinical interactions between the two systems are unstudied. We prospectively studied calcium mobilization and chemotactic responses to LTB(4) in PMN from major trauma patients. The responses of the high affinity BLT1 receptor were suppressed at the 3-day postinjury time point, but recovered by 1 wk. Trauma patients had transient elevations of plasma LT and CXC levels. Functional deficits identical with those in trauma PMN were reproduced in vitro by exposing healthy PMN to CXCs at the elevated plasma concentrations found. Functional responses to LTB(4) were suppressed by cross-talk with CXC and BLT2 receptors that desensitize BLT1. Since the suppression of intracellular calcium mobilization was prominent, we also studied the role of suppressed cell calcium mobilization in the defective chemotactic responses to LTB(4). We noted that PMN chemotaxis to LTB(4) showed far more dependence on store-operated calcium entry than on the release of cellular calcium stores, and that store-operated calcium responses to BLT1 activation were markedly inhibited during the same time period as was chemotaxis. The intermittent release of inflammatory mediators after injury can blunt PMN responses to LTs by suppressing BLT1 as well as downstream calcium entry. Diminished LT receptor activity due to cross-talk with CXC receptors can inhibit PMN recruitment to infective sites. This may predispose injured patients to septic complications.
authors.affiliation: Department of Surgery, Division of Trauma, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Tarlowe
authors.forename: K B
authors.initials: KB
authors.lastname: Kannan
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Itagaki
authors.forename: John M
authors.initials: JM
authors.lastname: Adams
authors.forename: David H
authors.initials: DH
authors.lastname: Livingston
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Hauser
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002118:Calcium / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D020013:Calcium Signaling / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000502:physiology*; D005260:Female; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism / Q000502:physiology*; D016209:Interleukin-8 / Q000097:blood / Q000494:pharmacology; D007975:Leukotriene B4 / Q000097:blood / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D011446:Prospective Studies; D020239:Receptor Cross-Talk / Q000502:physiology*; D019707:Receptors, Chemokine / Q000378:metabolism / Q000502:physiology*; D023062:Receptors, Interleukin-8A / Q000378:metabolism / Q000502:physiology; D023063:Receptors, Interleukin-8B / Q000378:metabolism / Q000502:physiology; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D014947:Wounds and Injuries / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D018836:Inflammation Mediators; D016209:Interleukin-8; D019707:Receptors, Chemokine; D023062:Receptors, Interleukin-8A; D023063:Receptors, Interleukin-8B; D018102:Receptors, Leukotriene B4; D007975:Leukotriene B4; D002118:Calcium