High CO2 Levels Impair Lung Wound Healing.

Delayed lung repair leads to alveolo-pleural fistulae which are a major cause of morbidity following 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 due to inhibition of epithelial cell migration. Cell migration and airway epithelial wound closure was dependent on Rac1-GTPase activation which was suppressed by hypercapnia directly, through the upregulation of AMP-kinase, and indirectly, through inhibition of injury-induced NFkB-mediated CXCL12 release, respectively. Both these pathways were independently suppressed since dominant negative AMP-kinase rescued the effects of hypercapnia on Rac1-GTPase in uninjured resting cells while proteasomal inhibition reversed the NFkB-mediated CXCL12 release during injury. Constitutive over-expression 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 alveolo-pleural 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.