1 George P. Livanos and Marianthi Simou Laboratories, Evangelismos Hospital, First Department of Pulmonary and Critical Care, and.
Am J Respir Cell Mol Biol. 2015 Jun;52(6):762-71. doi: 10.1165/rcmb.2014-0092OC.
Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.
吸气阻力呼吸（RB）在阻塞性肺疾病中很常见，会导致肺损伤。在哮喘、慢性阻塞性肺疾病和内毒素诱导的急性肺损伤等慢性和急性动物模型中，可溶性鸟苷酸环化酶（sGC）/环鸟苷酸（cGMP）途径受到下调。我们的目的是：（1）通过气管结扎在小鼠中描述增加的同时吸气和呼气阻力的影响；（2）研究 sGC/cGMP 途径在 RB 诱导的肺损伤中的作用。麻醉的 C57BL/6 小鼠通过限制气管表面积至 50%（气管结扎）进行 RB。RB 24 小时后，支气管肺泡灌洗液中的细胞数量和蛋白含量增加，肺部白细胞浸润明显，呼吸力学受到干扰（组织阻力和弹性增加，静态压力-容积曲线向右和向下移动，静态顺应性降低），与急性肺损伤的存在一致。RB 下调了肺中的 sGC 表达。sGC 抑制剂 1H-[1,2,4]恶二唑[4,3-]喹喔啉-1-酮的给药或在使用 sGCα1 基因敲除小鼠进行 RB 时，所有由 RB 引起的肺损伤表现均加重。相反，先前给予 sGC 激活剂 BAY 58-2667（拜耳公司，德国勒沃库森）可恢复 sGC 信号传导，可防止 RB 引起的肺损伤。引人注目的是，在 RB 后 24 小时直接用 BAY 58-2667 药理学激活 sGC 在 6 小时内逆转了已建立的肺损伤。这些发现提示，针对 sGC-cGMP 轴的药理学靶向治疗可能用于改善阻塞性肺疾病中的肺功能障碍。
