1st Department of Critical Care and Pulmonary Medicine and "Marianthi Simou" Applied Biomedical Research and Training Center, Medical School, Evangelismos Hospital, University of Athens, Athens, Greece.
3rd Department of Critical Care Medicine, Evgenideio Hospital, Medical School, University of Athens, Athens, Greece.
Inflammation. 2018 Oct;41(5):1873-1887. doi: 10.1007/s10753-018-0831-6.
Inspiratory resistive breathing (IRB), a hallmark of obstructive airway diseases, is associated with strenuous contractions of the inspiratory muscles and increased negative intrathoracic pressures that act as an injurious stimulus to the lung. We have shown that IRB induces pulmonary inflammation in healthy animals. p38 kinase is activated in the lung under stress. We hypothesized that p38 is activated during IRB and contributes to IRB-induced pulmonary inflammation. Anesthetized, tracheostomized rats breathed spontaneously through a two-way valve. Resistance was connected to the inspiratory port to provoke a peak tidal inspiratory pressure 50% of maximum. Following 3 and 6 h of IRB, respiratory system mechanics were measured and bronchoalveolar lavage (BAL) was performed. Phosphorylated p38, TNF-α, and MIP-2α were detected in lung tissue. Lung injury was estimated histologically. SB203580 (p38 inhibitor) was administered prior to IRB (1 mg kg). Six hours of IRB increased phosphorylated p38 in the lung, compared with quietly breathing controls (p = 0.001). Six hours of IRB increased the numbers of macrophages and neutrophils (p = 0.01 and p = 0.005) in BAL fluid. BAL protein levels and lung elasticity increased after both 3 and 6 h IRB. TNF-α and MIP-2α increased after 6 h of IRB (p = 0.01 and p < 0.001, respectively). Increased lung injury score was detected at 6 h IRB. SB203580 administration blocked the increase of neutrophils and macrophages at 6 h IRB (p = 0.01 and p = 0.005 to 6 h IRB) but not the increase in BAL protein and elasticity. TNF-α, MIP-2α, and injury score at 6 h IRB returned to control. p38 activation contributes to IRB-induced pulmonary inflammation.
吸气阻力呼吸（IRB）是气道阻塞性疾病的一个标志，它与吸气肌的剧烈收缩和胸腔内负压的增加有关，而这些因素会对肺部造成损伤。我们已经证明，IRB 会在健康动物中引起肺部炎症。在应激状态下，p38 激酶在肺部被激活。我们假设，p38 在 IRB 期间被激活，并导致 IRB 引起的肺部炎症。在麻醉、气管切开的大鼠中，它们通过双向阀自主呼吸。将阻力连接到吸气口，以引起最大潮气量吸气压力的 50%的峰值。在进行 3 小时和 6 小时的 IRB 后，测量呼吸系统力学并进行支气管肺泡灌洗（BAL）。检测肺组织中磷酸化的 p38、TNF-α 和 MIP-2α。通过组织学评估肺损伤。在进行 IRB 之前（1mg/kg）给予 SB203580（p38 抑制剂）。与安静呼吸对照组相比，IRB 后 6 小时，肺中的磷酸化 p38 增加（p=0.001）。IRB 后 6 小时，BAL 液中的巨噬细胞和中性粒细胞数量增加（p=0.01 和 p=0.005）。在 3 小时和 6 小时的 IRB 后，BAL 蛋白水平和肺弹性增加。IRB 后 6 小时，TNF-α 和 MIP-2α 增加（p=0.01 和 p<0.001）。在 6 小时的 IRB 时检测到肺损伤评分增加。SB203580 给药阻断了 6 小时 IRB 时中性粒细胞和巨噬细胞的增加（p=0.01 和 p=0.005 至 6 小时 IRB），但不能阻断 BAL 蛋白和弹性的增加。IRB 后 6 小时，TNF-α、MIP-2α 和损伤评分恢复到对照水平。p38 激活有助于 IRB 引起的肺部炎症。
