Involvement of oxidative stress in the pathogenesis of ARDS associated with viral pneumonia

一氧化氮(NO)和活性氧(ROS)被认为与ARDS的发病有关。NO/ROS也被报道诱导酪氨酸和鸟氨酸的硝化，分别导致3-硝基酪氨酸(3-NT)和8-硝基-cGMP的形成。在这项研究中，我们发现流感病毒(IFV)感染的小鼠肺中3-NT和8-硝基-cGMP水平显著增加。在感染的小鼠的肺中也检测到强烈的抗氧化酶-血红素加氧酶-1的诱导。在8-硝基-cGMP形成的同时，HO-1表达上调，提示8-硝基-cGMP或3-NT的形成可能参与了IFV感染小鼠的氧化应激反应。因此，我们推测3-NT的形成也可能影响人类ARDS的疾病活动性。我们对有/无IFV感染的ARDS患者和对照组的血浆3-NT水平进行了病例对照研究。合并IFV感染的ARDS患者血清3-NT水平显著高于对照组。此外，高3-NT水平的ARDS患者比低3-NT水平的患者有更好的生存率。这些数据表明，NO/ROS介导的3-NT或8-Nitro-cGMP的形成可能参与了一种独特的信号转导，有助于机体对IFV诱导的暴发性肺炎/ARDS的防御或组织修复。

Nitric oxide(NO) and reactive oxygen species(ROS) have been suggested to be involved in the pathogenesis of ARDS. NO/ROS have also been reported to induce nitration of tyrosine and guanine leading to the formation of 3-nitrotyrosine(3-NT) and 8-nitro-cGMP, respectively. In this study, we found significant increase of 3-NT and 8-nitro-cGMP levels in the lungs of influenza virus(IFV)-infected mice. Strong induction of an antioxidant enzyme heme oxygenase-1 was also detected in the lung of infected mice. Upregulation of HO-1 in parallel with the formation of 8-nitro-cGMP suggested that formation of 8-nitro-cGMP or 3-NT may be involved in the oxidative stress responses in the IFV-infected mice. Therefore, we postulated that formation of 3-NT might also influence on the disease activity of ARDS in humans. We performed a case-control study for plasma 3-NT levels of ARDS patients with/without IFV infection and of control subjects. The ARDS patients with IFV infection had significantly higher 3-NT levels than the control subjects. Additionally, ARDS patients with high 3-NT levels had better survival rate compared to patients with low 3-NT levels. These data thus suggest that NO/ROS-mediated formation of 3-NT or 8-nitro-cGMP may be involved in a unique signal transduction contributing to the host defense or tissue repair against IFV-induced fulminant pneumonia/ARDS.