CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice.
Polymorphonuclear neutrophil (PMN) extravasation/sequestration in the lung and a dysregulated inflammatory response characterize the pathogenesis of acute lung injury (ALI). Previously, we have shown that hemorrhage (Hem) serves to prime PMN such that subsequent septic challenge [cecal ligation and puncture (CLP)] produces a pathological, inflammatory response and consequent lung injury in mice. Keratinocyte-derived chemokine (KC) and macrophage inflammatory protein-2 (MIP-2) are murine CXC chemokines found elevated in the lungs and plasma following Hem/CLP and have been reported by others to share a common receptor (CXCR2). Based on these data, we hypothesize that blockade of CXCR2 immediately following Hem would suppress KC and MIP-2 priming of PMN, thereby reducing the inflammatory injury observed following CLP. To assess this, Hem mice (90 min at 35+/-5 mmHg) were randomized to receive 0, 0.4, or 1 mg antileukinate (a hexapeptide inhibitor of CXCRs) in 100 microl phosphate-bufferd saline (PBS)/mouse subcutaneously, immediately following resuscitation (Ringer's lactate-4x drawn blood volume). Twenty-four hours post-Hem, mice were subjected to CLP and killed 24 h later. The results show that blockade of CXCR2 significantly (P<0.05, Tukey's test) reduced PMN influx, lung protein leak, and lung-tissue content of interleukin (IL)-6, KC, and MIP-2 and increased tissue IL-10 levels. Plasma IL-6 was significantly decreased, and IL-10 levels increased in a dose-dependent manner compared with PBS-treated mice. A differential effect was observed in plasma levels of KC and MIP-2. KC showed a significant reduction at the 0.4 mg antileukinate dose. In contrast, plasma MIP-2 was significantly elevated at both doses compared with the PBS-treated controls. Together, these data demonstrate that blockade of CXCR2 signaling attenuates shock-induced priming and ALI observed following Hem and subsequent septic challenge in mice.
Lomas-Neira
Joanne L
JL
Aldrich 227, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903, USA. AAYALA@LIFESPAN.org
Chung
Chun-Shiang
CS
Grutkoski
Patricia S
PS
Miller
Edmund J
EJ
Ayala
Alfred
A
D000818:Animals; D002432:Cecum / Q000293:injuries; D018925:Chemokines / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D004195:Disease Models, Animal; D006470:Hemorrhage / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D008026:Ligation; D051379:Mice; D020556:Neutrophil Infiltration / Q000276:immunology; D009504:Neutrophils / Q000276:immunology*; D009842:Oligopeptides / Q000494:pharmacology; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000276:immunology*; D012128:Respiratory Distress Syndrome / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D018805:Sepsis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology
D018925:Chemokines; D009842:Oligopeptides; D023063:Receptors, Interleukin-8B; C118980:antileukinate