Department of Anesthesiology, Keio University School of Medicine, Tokyo, Japan.
J Immunol. 2010 Jan 15;184(2):836-43. doi: 10.4049/jimmunol.0901809. Epub 2009 Dec 9.
Whereas pneumonia is the most common cause of death and disability worldwide, most cases of pneumonia spontaneously resolve. Mechanisms that promote pneumonia resolution remain to be determined. Resolvin E1 (RvE1) is an endogenous mediator that displays proresolving actions in sterile inflammation. In this study, we developed a new model of aspiration pneumonia to evaluate the effect of RvE1 on acute lung injury caused by acid aspiration and subsequent bacterial challenge. Mice received hydrochloric acid into the left lung followed by the enteric pathogen Escherichia coli. I.v. administration of RvE1 (approximately 0.005 mg/kg) prior to acid injury selectively decreased lung neutrophil accumulation by 55% and enhanced clearance of E. coli. RvE1 significantly decreased lung tissue levels of several proinflammatory chemokines and cytokines, including IL-1beta, IL-6, HMGB-1, MIP-1alpha, MIP-1beta, keratinocyte-derived chemokine, and MCP-1, in a manner independent of the anti-inflammatory mediators IL-10 and lipoxin A4. In addition, animals treated with RvE1 had a marked improvement in survival. These findings in experimental aspiration pneumonia have uncovered protective roles for RvE1 in pathogen-mediated inflammation that are both anti-inflammatory for neutrophils and protective for host defense, suggesting that RvE1 represents the first candidate for a novel therapeutic strategy for acute lung injury and pneumonia that harnesses natural resolution mechanisms.
虽然肺炎是全球范围内最常见的导致死亡和残疾的原因，但大多数肺炎病例会自行痊愈。促进肺炎痊愈的机制仍有待确定。内源性介质 15-去氧-Δ12,14-前列腺素 J2（resolvin E1，RvE1）在无菌性炎症中具有促进炎症消退的作用。在这项研究中，我们开发了一种新的吸入性肺炎模型，以评估 RvE1 对胃酸吸入引起的急性肺损伤和随后细菌挑战的影响。将盐酸注入小鼠左肺，然后注入肠道病原体大肠杆菌。在酸损伤前静脉注射 RvE1（约 0.005mg/kg）可选择性使肺中性粒细胞积聚减少 55%，并增强对大肠杆菌的清除。RvE1 显著降低了肺组织中几种促炎趋化因子和细胞因子的水平，包括白细胞介素-1β（IL-1β）、白细胞介素-6（IL-6）、高迁移率族蛋白 B1（HMGB-1）、巨噬细胞炎性蛋白-1α（MIP-1α）、巨噬细胞炎性蛋白-1β（MIP-1β）、角质细胞衍生的趋化因子和单核细胞趋化蛋白-1（MCP-1），其方式独立于抗炎介质白细胞介素-10（IL-10）和脂氧素 A4。此外，用 RvE1 治疗的动物的存活率有显著提高。这些在实验性吸入性肺炎中的发现揭示了 RvE1 在病原体介导的炎症中具有保护作用，其对中性粒细胞具有抗炎作用，对宿主防御具有保护作用，这表明 RvE1 代表了一种利用天然消退机制治疗急性肺损伤和肺炎的新型治疗策略的首个候选者。
