Absence of heme oxygenase-1 expression in the lung parenchyma exacerbates endotoxin-induced acute lung injury and decreases surfactant protein-B levels
Absence of heme oxygenase-1 expression in the lung parenchyma exacerbates endotoxin-induced acute lung injury and decreases surfactant protein-B levels
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DOI：
10.1170/t657
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发表时间：
2005-01-01
影响因子：
1.6
通讯作者：
Perrella, MA
中科院分区：
文献类型：
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作者：
Fredenburgh, LE;Baron, RM;Perrella, MA
急性呼吸窘迫综合征（ARDS）是一种以严重急性肺损伤、炎性细胞向肺募集、促炎细胞因子上调和氧化应激增加为特征的破坏性疾病过程。上皮细胞损伤、弥漫性肺泡损伤和表面活性物质功能障碍导致难治性低氧性呼吸衰竭。对于ARDS没有特异性有效的治疗方法，并且迫切需要新的治疗方法。在这项研究中，我们评估了细胞保护和抗炎酶血红素氧合酶（HO）-1在雾化吸入内毒素诱导的急性肺损伤模型中的作用。HO-1 null（HO-1（-/-））小鼠在脂多糖（LPS）雾化后表现出严重的生理性肺功能障碍，但具有与野生型（WT）小鼠相似的炎症反应。然而，与相似处理的WT小鼠相比，在LPS处理的HO-1（-/-）小鼠的肺中观察到表面活性蛋白-B（SP-B）表达的显著降低。使用相互骨髓移植（BMT）产生HO-1嵌合小鼠，我们发现肺实质中HO-1的缺乏，而不是骨髓源性炎性细胞中的HO-1，负责增强SP-B下调和严重的生理性肺功能障碍。这些发现对我们理解ARDS的病理生理学有意义，并可能指导未来的治疗策略。
Acute respiratory distress syndrome (ARDS) is a devastating disease process characterized by severe acute lung injury, inflammatory cell recruitment to the lung, upregulation of pro-inflammatory cytokines and increased oxidative stress. Epithelial cell injury, diffuse alveolar damage and surfactant dysfunction ensue leading to refractory hypoxemic respiratory failure. There are no specific effective therapies for ARDS and novel therapeutic approaches are desperately needed. In this study we assessed the role of the cytoprotective and anti-inflammatory enzyme heme oxygenase (HO)-1 in a model of nebulized endotoxin-induced acute lung injury. HO-1 null (HO-1(-/-)) mice exhibited severe physiologic lung dysfunction following lipopolysaccharide (LPS) nebulization, but had similar inflammatory responses as wild-type (WT) mice. However, a dramatic reduction in surfactant protein-B (SP-B) expression was observed in the lungs of LPS-treated HO-1(-/-) mice compared with similarly treated WT mice. Using reciprocal bone marrow transplantation (BMT) to generate HO-1-chimeric mice, we found that absence of HO-1 in the lung parenchyma, not in bone marrow-derived inflammatory cells, was responsible for enhanced SP-B downregulation and severe physiologic lung dysfunction. These findings have implications for our understanding of the pathophysiology of ARDS and may guide future therapeutic strategies.