Detrimental role of the airway mucin Muc5ac during ventilator-induced lung injury.
Detrimental role of the airway mucin Muc5ac during ventilator-induced lung injury.
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作者：
急性肺损伤(ALI)在危重病患者中具有较高的发病率和死亡率。目前，呼吸道粘蛋白在ALI中的功能作用尚不清楚。我们假设，在肺损伤期间，过度的粘液产生可能是有害的。最初的气道粘蛋白转录图谱显示，在周期性机械拉伸暴露肺上皮细胞(CALU-3)时，MUC5AC具有选择性和强大的诱导作用。其他研究证实，在体外或在体内呼吸机诱导的肺损伤期间，周期性机械拉伸暴露期间，MUC5AC转录本或蛋白的诱导具有时间和拉伸剂量依赖性。ALI患者的支气管肺泡灌洗液中的MUC5AC蛋白增加了58倍。MUC5AC启动子的研究表明，核因子κB参与了ALI时MUC5AC的诱导。此外，携带Muc5ac−/−基因靶向缺失的小鼠在损伤性换气过程中肺部炎症和肺水肿减轻。我们观察到Muc5ac−/−小鼠的中性粒细胞向肺内的转运被选择性地减弱。这意味着内源性Muc5ac的产生在肺损伤过程中促进了肺中性粒细胞的运输。总之，这些研究揭示了ALI期间内源性Muc5ac产生的有害作用，并提出了在治疗肺损伤时抑制粘蛋白产生的药理策略。
Acute lung injury (ALI) is associated with high morbidity and mortality in critically ill patients. At present, the functional contribution of airway mucins to ALI is unknown. We hypothesized that excessive mucus production could be detrimental during lung injury. Initial transcriptional profiling of airway mucins revealed a selective and robust induction of MUC5AC upon cyclic mechanical stretch exposure of pulmonary epithelia (Calu-3). Additional studies confirmed time- and stretch-dose-dependent induction of MUC5AC transcript or protein during cyclic mechanical stretch exposure in vitro or during ventilator-induced lung injury in vivo. Patients suffering from ALI showed a 58-fold increase in MUC5AC protein in their bronchoalveolar lavage. Studies of the MUC5AC promoter implicated nuclear factor κB in Muc5ac induction during ALI. Moreover, mice with gene-targeted deletion of Muc5ac−/− experience attenuated lung inflammation and pulmonary edema during injurious ventilation. We observed that neutrophil trafficking into the lungs of Muc5ac−/− mice was selectively attenuated. This implicates that endogenous Muc5ac production enhances pulmonary neutrophil trafficking during lung injury. Together, these studies reveal a detrimental role for endogenous Muc5ac production during ALI and suggest pharmacological strategies to dampen mucin production in the treatment of lung injury.
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DOI：
10.1056/nejmra0910061
发表时间：
2010-12-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Fahy JV;Dickey BF
通讯作者：
Dickey BF
影响因子：
8.8
作者：
Eltzschig HK
通讯作者：
Eltzschig HK
影响因子：
4.4
作者：
Cicko, Sanja;Lucattelli, Monica;Idzko, Marco
通讯作者：
Idzko, Marco
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1164/ajrccm.154.1.8680703
发表时间：
1996-07-01
影响因子：
24.7
作者：
Baughman, RP;Gunther, KL;Pattishall, EN
通讯作者：
Pattishall, EN