The deleterious effects of hypercapnia on the lungs

描述（由申请方提供）：高碳酸血症（高pCO 2）见于肺部疾病患者，如慢性阻塞性肺病（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”的通气策略通常用于患有急性呼吸窘迫综合征（ARDS）的机械通气患者。来自我们小组和其他人的数据挑战了现有的范式，表明高碳酸血症对ARDS患者有益。相反，我们已经报道了CO2水平升高对肺泡上皮功能和宿主免疫力有直接的有害影响。我们已发表的报告和初步研究的数据支持我们的假设，即高水平的CO2减少肺泡上皮细胞迁移和增殖在受伤的肺，从而损害肺损伤修复。此外，我们推测，高碳酸血症促进泛素-蛋白酶体介导的肌纤维降解，并损害其再生所需的肌肉卫星细胞的功能。因此，在本申请中，我们提出确定高碳酸血症导致肺损伤恢复受损的机制以及高CO2对膈肌退化和再生受损的影响。我们将在三个相互关联的目标中测试这些假设：在与特定目标1相关的实验中，我们将确定高碳酸血症介导的GEFs-Rac 1抑制是否导致细胞迁移受损;在与特定目标2相关的实验中，我们将确定高CO2是否通过miR-183/96/182簇在体外损害肺泡上皮细胞迁移和在体内损害肺损伤修复;在与具体目标#3相关的研究中，我们将确定高碳酸血症是否导致横膈膜功能障碍，其通过泛素/蛋白酶体途径引起肌肉退化和受损的肌肉再生。我们已经为每个具体目标进行了初步实验，这些目标支持这项拨款建议的可行性。拟议的实验将产生新的信息的机制，暴露于高碳酸血症损害肺泡上皮细胞和隔膜功能，这是具有临床意义的患者与ARDS谁需要机械通气和慢性肺部疾病和高碳酸血症的患者。

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.