Fan Jie, Li Yuehua, Vodovotz Yoram, Billiar Timothy R, Wilson Mark A
Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15240, USA.
Shock. 2007 Aug;28(2):213-8. doi: 10.1097/shk.0b013e318033ec9d.
Alveolar macrophages (AMs) play an important role in the development of posttrauma lung inflammation through initiating polymorphonuclear neutrophil (PMN) migration by direct interactions with PMN, which is in turn mediated by the expression of chemokines and cytokines. We have recently reported that hemorrhagic shock-activated PMN sensitize AM to bacteria LPS for the up-regulation of Toll-like receptor (TLR)2; in turn, this TLR2 up-regulation results in the amplification of expression of cytokines and chemokines in the AM in response to the bacterial products LPS and peptidoglycan, associated with enhanced PMN sequestration in the lung. We sought to address the mechanism underlying the augmentation of TLR2 in AM by shock-activated PMN. We found that hemorrhagic shock/resuscitation (shock) followed by a low dose of i.t. LPS markedly increased TLR2 mRNA expression in AM in wild-type (WT) mice. In contrast, in mice lacking the gp91 subunit of nicotinamide adenine dinucleotide phosphate (reduced form) oxidase (gp91) or in neutropenic WT mice, the increase in TLR2 mRNA was attenuated. Coculture of AM with PMN derived from WT-shocked mice caused a significantly higher level of TLR2 expression in the AM in response to LPS. However, this increase in TLR2 expression was less evident when the AMs were cocultured with PMN derived from gp91 mice subjected to shock. The antioxidant polyethylene glycol catalase markedly decreased MyD88-dependent activation of IL-1 receptor associated kinase 4 and TLR2 expression in the AM in response to LPS. Thus, PMN nicotinamide adenine dinucleotide phosphate (reduced form) oxidase sensitizes hemorrhagic shock-primed AM to LPS, at least in part via enhancing IL-1 receptor associated kinase 4 activity.
肺泡巨噬细胞（AMs）通过与多形核中性粒细胞（PMN）直接相互作用启动PMN迁移，在创伤后肺部炎症的发展中起重要作用，而这又由趋化因子和细胞因子的表达介导。我们最近报道，出血性休克激活的PMN使AMs对细菌脂多糖（LPS）敏感，从而上调Toll样受体（TLR）2；反过来，这种TLR2上调导致AMs中细胞因子和趋化因子表达的放大，以响应细菌产物LPS和肽聚糖，这与肺部PMN滞留增加有关。我们试图探讨休克激活的PMN增强AMs中TLR2的机制。我们发现，出血性休克/复苏（休克）后给予低剂量的腹腔内LPS，可显著增加野生型（WT）小鼠AMs中TLR2 mRNA的表达。相比之下，在缺乏烟酰胺腺嘌呤二核苷酸磷酸（还原型）氧化酶（gp91）的gp91亚基的小鼠或中性粒细胞减少的WT小鼠中，TLR2 mRNA的增加减弱。将AMs与来自WT休克小鼠的PMN共培养，可使AMs中TLR2表达水平在响应LPS时显著升高。然而，当AMs与来自遭受休克的gp91小鼠的PMN共培养时，TLR2表达的这种增加不太明显。抗氧化剂聚乙二醇过氧化氢酶显著降低了AMs中MyD88依赖性的白细胞介素-1受体相关激酶4的激活和TLR2表达，以响应LPS。因此，PMN烟酰胺腺嘌呤二核苷酸磷酸（还原型）氧化酶至少部分通过增强白细胞介素-1受体相关激酶4的活性，使出血性休克预处理的AMs对LPS敏感。
