Effects of macrophage inducible nitric oxide synthase in murine septic lung injury
Effects of macrophage inducible nitric oxide synthase in murine septic lung injury
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DOI：
10.1152/ajplung.00248.2005
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发表时间：
2006-06-01
影响因子：
4.9
通讯作者：
Mehta, S
中科院分区：
文献类型：
--
作者：
Farley, KS;Wang, LF;Mehta, S
诱导型一氧化氮合酶（iNOS）在脓毒性急性肺损伤（ALI）小鼠脓毒性肺蛋白泄漏中起重要作用。然而，肺泡巨噬细胞（AM） iNOS在感染性ALI中的作用尚不清楚。因此，我们通过选择性AM消耗（通过气管内注射氯膦酸脂质体）和随后的AM重建（通过气管内注射供体iNOS+/+或iNOS-/- AM）来评估AM iNOS在小鼠脓毒性ALI中的特异性作用。通过盲肠结扎和穿孔诱导脓毒症，在4 h时评估ALI: Evans蓝（EB）染色法检测蛋白渗漏，髓过氧化物酶（MPO）活性检测中性粒细胞浸润，RT-PCR检测肺iNOS mRNA表达。在iNOS+/+小鼠中，AM消耗降低了败血症引起的肺微血管蛋白泄漏的增加(0.3 +/- 0.1 vs. 1.4 +/- 0.1 μ g EB中心点g肺（-1）中心点min(-1)；P < 0.05)和MPO活性（37 +/- 4 vs. 67 +/- 8 U/g肺，P < 0.05）。在AM缺失的iNOS+/+小鼠中，用iNOS-/- AM重建AM（0.9 +/- 0.3 μ g EB中心点g肺（-1）中心点min(-1)）可以恢复脓毒性肺蛋白泄漏，而用iNOS-/-供体AM则不能。在iNOS+/+小鼠中，尽管肺MPO活性增加，但脓毒症并未诱导肺蛋白泄漏或iNOS mRNA表达。然而，iNOS+/+小鼠的AM耗竭和随后用iNOS-/-供体AM重建导致了明显的败血症诱导的肺蛋白泄漏和iNOS表达。所有am重组组脓毒性肺MPO水平相似。因此，脓毒性肺蛋白渗漏完全依赖于功能性AM的存在，特别是AM中的iNOS。AM inos依赖的肺蛋白泄漏不是通过肺中性粒细胞内流的改变介导的。
Inducible nitric oxide synthase (iNOS) contributes importantly to septic pulmonary protein leak in mice with septic acute lung injury (ALI). However, the role of alveolar macrophage (AM) iNOS in septic ALI is not known. Thus we assessed the specific effects of AM iNOS in murine septic ALI through selective AM depletion (via intratracheal instillation of clodronate liposomes) and subsequent AM reconstitution (via intratracheal instillation of donor iNOS+/+ or iNOS-/- AM). Sepsis was induced by cecal ligation and perforation, and ALI was assessed at 4 h: protein leak by the Evans blue (EB) dye method, neutrophil infiltration via myeloperoxidase (MPO) activity, and pulmonary iNOS mRNA expression via RT-PCR. In iNOS+/+ mice, AM depletion attenuated the sepsis-induced increases in pulmonary microvascular protein leak (0.3 +/- 0.1 vs. 1.4 +/- 0.1 mu g EB center dot g lung(-1) center dot min(-1); P < 0.05) and MPO activity(37 +/- 4 vs. 67 +/- 8 U/g lung; P < 0.05) compared with that shown in non-AM-depleted mice. In AM-depleted iNOS+/+ mice, septic pulmonary protein leak was restored by AM reconstitution with iNOS-/- AM(0.9 +/- 0.3 mu g EB center dot g lung(-1) center dot min(-1)) but not with iNOS-/- donor AM. In iNOS+/+ mice, sepsis did not induce pulmonary protein leak or iNOS mRNA expression, despite increased pulmonary MPO activity. However, AM depletion in iNOS+/+ mice and subsequent reconstitution with iNOS-/- donor AM resulted in significant sepsis-induced pulmonary protein leak and iNOS expression. Septic pulmonary MPO levels were similar in all AM-reconstituted groups. Thus septic pulmonary protein leak is absolutely dependent on the presence of functional AM and specifically on iNOS in AM. AM iNOS-dependent pulmonary protein leak was not mediated through changes in pulmonary neutrophil influx.