CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice

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Abstract
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 μl phosphate‐bufferd saline (PBS)/mouse subcutaneously, immediately following resuscitation (Ringer’s lactate‐4× 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.
Funding Information
  • National Institutes of Health (HL73525)
  • Lifespan/Rhode Island Hospital