Delayed lung repair leads to alveolopleural fistulae, which are a major cause of morbidity after lung resections. We have reported that intrapleural hypercapnia is associated with delayed lung repair after lung resection. Here, we provide new evidence that hypercapnia delays wound closure of both large airway and alveolar epithelial cell monolayers because of inhibition of epithelial cell migration. Cell migration and airway epithelial wound closure were dependent on Rac1-GTPase activation, which was suppressed by hypercapnia directly through the upregulation of AMP kinase and indirectly through inhibition of injury-induced NF-κB–mediated CXCL12 (pleural CXC motif chemokine 12) release, respectively. Both these pathways were independently suppressed, because dominant negative AMP kinase rescued the effects of hypercapnia on Rac1-GTPase in uninjured resting cells, whereas proteasomal inhibition reversed the NF-κB–mediated CXCL12 release during injury. Constitutive overexpression of Rac1-GTPase rescued the effects of hypercapnia on both pathways as well as on wound healing. Similarly, exogenous recombinant CXCL12 reversed the effects of hypercapnia through Rac1-GTPase activation by its receptor, CXCR4. Moreover, CXCL12 transgenic murine recipients of orthotopic tracheal transplantation were protected from hypercapnia-induced inhibition of tracheal epithelial cell migration and wound repair. In patients undergoing lobectomy, we found inverse correlation between intrapleural carbon dioxide and pleural CXCL12 levels as well as between CXCL12 levels and alveolopleural leak. Accordingly, we provide first evidence that high carbon dioxide levels impair lung repair by inhibiting epithelial cell migration through two distinct pathways, which can be restored by recombinant CXCL12.

延迟肺修复导致肺泡胸膜瘘，这是肺切除术后发病的主要原因。我们已经报道了胸腔内高碳酸血症与肺切除术后延迟肺修复有关。在这里，我们提供了新的证据，表明高碳酸血症由于抑制上皮细胞迁移而延迟了大气道和肺泡上皮细胞单层的伤口闭合。细胞迁移和气道上皮伤口闭合取决于 Rac1-GTPase 的激活，高碳酸血症通过 AMP 激酶的上调直接抑制，并通过抑制损伤诱导的 NF-κB 介导的 CXCL12（胸膜 CXC 基序趋化因子 12）释放间接抑制，分别。这两条通路都被独立抑制，因为显性负性 AMP 激酶挽救了高碳酸血症对未受伤静息细胞中 Rac1-GTPase 的影响，而蛋白酶体抑制逆转了损伤期间 NF-κB 介导的 CXCL12 释放。Rac1-GTPase 的组成型过度表达挽救了高碳酸血症对两种途径以及伤口愈合的影响。同样，外源性重组 CXCL12 通过其受体 CXCR4 激活 Rac1-GTPase 来逆转高碳酸血症的影响。而且，CXCL12转基因小鼠原位气管移植受者免受高碳酸血症诱导的气管上皮细胞迁移和伤口修复抑制。在接受肺叶切除术的患者中，我们发现胸膜内二氧化碳与胸膜 CXCL12 水平以及 CXCL12 水平与肺泡胸膜漏之间呈负相关。因此，我们提供了第一个证据，证明高二氧化碳水平通过抑制上皮细胞迁移通过两种不同的途径损害肺修复，这可以通过重组 CXCL12 恢复。