Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation
Tissue heme oxygenase-1 exerts anti-inflammatory effects on LPS-induced pulmonary inflammation
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DOI：
10.1038/mi.2015.39
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发表时间：
2016-01-01
影响因子：
8
通讯作者：
Reutershan, J.
中科院分区：
文献类型：
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作者：
Konrad, F. M.;Knausberg, U.;Reutershan, J.
血红素加氧酶-1（HO-1）已被证明在急性肺部炎症模型中显示抗炎特性。对于第一次，我们研究了白细胞HO-1的作用，使用HO-1（flox/flox）小鼠模型缺乏白细胞HO-1的脂多糖（LPS）诱导的急性肺部炎症。免疫组织学和流式细胞术表明，使用氯化血红素激活HO-1减少了多形核白细胞（PMN）迁移到野生型小鼠的肺动脉和支气管肺泡灌洗液（BAL），令人惊讶的是，也在HO 1（flox/flox）小鼠，强调了非髓细胞HO-1的抗炎潜力。然而，氯化血红素降低了两种动物品系中的CXCL 1、CXCL 2/3、肿瘤坏死因子-α（TNF α）和白细胞介素6（IL 6）水平。在野生型和HO 1（flox/flox）小鼠中，氯化血红素可减弱微血管通透性，表明非髓样HO-1在内皮完整性中起关键作用。小鼠肺中HO-1活性的测定显示HO-1（flox/flox）小鼠中没有代偿性增加。局部给药氯化血红素通过吸入减少所需的剂量，以减弱中性粒细胞迁移和微血管通透性的一个因素的40，强调其临床潜力。此外，HO-1刺激对肺部炎症的保护作用时，启动后的炎症刺激。总之，非髓样HO-1是至关重要的抗炎作用，这种酶对中性粒细胞迁移到不同的隔间的肺和微血管通透性。
Heme oxygenase-1 (HO-1) has been shown to display anti-inflammatory properties in models of acute pulmonary inflammation. For the first time, we investigated the role of leukocytic HO-1 using a model of HO-1(flox/flox) mice lacking leukocytic HO-1 that were subjected to lipopolysaccharide (LPS)-induced acute pulmonary inflammation. Immunohistology and flow cytometry demonstrated that activation of HO-1 using hemin decreased migration of polymorphonuclear leukocytes (PMNs) to the lung interstitium and bronchoalveolar lavage (BAL) in the wild-type and, surprisingly, also in HO1(flox/flox) mice, emphasizing the anti-inflammatory potential of nonmyeloid HO-1. Nevertheless, hemin reduced the CXCL1, CXCL2/3, tumor necrosis factor-a (TNF alpha), and interleukin 6 (IL6) levels in both animal strains. Microvascular permeability was attenuated by hemin in wild-type and HO1(flox/flox) mice, indicating a crucial role of non-myeloid HO-1 in endothelial integrity. The determination of the activity of HO-1 in mouse lungs revealed no compensatory increase in the HO-1(flox/flox) mice. Topical administration of hemin via inhalation reduced the dose required to attenuate PMN migration and microvascular permeability by a factor of 40, emphasizing its clinical potential. In addition, HO-1 stimulation was protective against pulmonary inflammation when initiated after the inflammatory stimulus. In conclusion, nonmyeloid HO-1 is crucial for the anti-inflammatory effect of this enzyme on PMN migration to different compartments of the lung and on microvascular permeability.