The deleterious effects of hypercapnia on the lungs

描述(申请人提供)：高碳酸血症(高二氧化碳分压)见于肺部疾病，如慢性阻塞性肺疾病(COPD)、囊性纤维化、支气管-肺发育不良和晚期神经肌肉疾病。此外，包括“允许性高碳酸血症”在内的一种机械通气策略通常用于机械通气的急性呼吸窘迫综合征(ARDS)患者。来自我们小组和其他人的数据挑战了现有的范式，即高碳酸血症对ARDS患者是有益的。相反，我们已经报道，二氧化碳水平升高对肺泡上皮功能和宿主免疫有直接的有害影响。我们发表的报告和前期研究的数据支持我们的假设，即高水平的二氧化碳减少了受损肺组织中肺泡上皮细胞的迁移和增殖，从而损害了肺损伤修复。此外，我们假设，高碳酸血症促进泛素-蛋白酶体介导的横隔肌纤维的降解，并损害其再生所需的肌肉卫星细胞的功能。因此，在这项应用中，我们建议确定高碳酸血症导致肺损伤恢复受损的机制，以及高二氧化碳对横隔肌降解和再生受损的影响。我们将在三个相互关联的目标中检验这些假设：在与特定目标#1有关的实验中，我们将确定高碳酸血症是否介导的GEFS-rac1抑制导致细胞迁移受损；在与特定目标#2相关的实验中，我们将确定通过miR-183/96/182簇的高二氧化碳是否会在体外损害肺泡上皮细胞的迁移和在体内的肺损伤修复；在与特定目标#3有关的研究中，我们将确定高碳酸血症是否导致隔膜功能障碍，从而通过泛素/蛋白酶体途径导致肌肉降解和肌肉再生受损。我们已经就每个具体目标进行了初步实验，以支持这项拨款建议的可行性。这些实验将产生关于高二氧化碳暴露损害肺泡上皮和横隔膜功能的新信息，这对需要机械通气的ARDS患者和慢性肺部疾病和高碳酸血症患者具有临床意义。

DESCRIPTION (provided by applicant): Hypercapnia (high pCO2) is observed in patients with lung diseases such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, broncho-pulmonary dysplasia and advanced neuromuscular diseases. Also, a ventilation strategy that includes "permissive hypercapnia" is commonly used in mechanically ventilated patients with the acute respiratory distress syndrome (ARDS). Data from our group and others have challenged the existing paradigm suggesting that hypercapnia is beneficial for patients with ARDS. Instead, we have reported that elevated levels of CO2 have direct, deleterious effects on alveolar epithelial function and host immunity. Our published reports and data from preliminary studies in preparation for this proposal support our hypothesis that high levels of CO2 decrease alveolar epithelial cell migration and proliferation in the injured lung, thus, impairing lung injuy repair. Furthermore, we hypothesize that hypercapnia promotes the ubiquitin-proteasome mediated degradation of diaphragmatic myofibers and impairs the function of muscle satellite cells required for its regeneration. As such, in this application we propose to determine the mechanisms by which hypercapnia leads to impaired recovery from lung injury and the effect of high CO2 on diaphragm muscle degradation and impaired regeneration. We will test these hypotheses in three interrelated aims: in experiments pertaining to specific aim # 1, we will determine whether hypercapnia-mediated inhibition of GEFs-Rac1 leads to impaired cell migration; in experiments pertaining to specific aim #2, we will determine whether high CO2 via the miR-183/96/182 cluster impairs alveolar epithelial cell migration in vitro and lung injury repar in vivo; and in studies pertaining to specific aim # 3, we will determine whether hypercapnia leads to diaphragm dysfunction causing muscle degradation via the ubiquitin/proteasomal pathway and impaired muscle regeneration. We have conducted preliminary experiments for each of the specific aims which support the feasibility of this grant proposal. The proposed experiments will generate novel information on the mechanisms by which exposure to hypercapnia impairs alveolar epithelial and diaphragm function, which is of clinical significance for patients with ARDS who require mechanical ventilation and patients with chronic lung diseases and hypercapnia.