HIF1α Dependent CXCR4/SDF1 Signaling Promotes Alveolar Type II Cell Spreading and the Restitution of Epithelial Barrier Integrity After Lung Injury

Abstract

Rationale. Alveolar type (AT) II cell spreading is a critical mechanism for the restitution of epithelial barrier integrity after ATI cell sloughing during lung injury. We hypothesized that Hypoxia Inducible Factor (HIF) 1α signaling promotes ATII cell spreading and the restoration of barrier function. Results. HIF was activated in ATII cells in ODD-Luc (HIF reporter) mice treated with intratracheal (i.t.) LPS, keratinocyte chemokine (KC), or hydrochloric acid (HCl), as shown by costaining for proSPC and luciferase or glucose transporter (GLUT) 1. To elucidate whether HIF1α promotes barrier restoration via cell spreading, we treated mice with i.t. KC, which causes ATI cell sloughing followed by rapid resolution of epithelial permeability associated with ATII cell spreading but independent of proliferation. The resolution of epithelial permeability was delayed in Sftpc-rtTA;tetOCre;HIF1αf/f mice but accelerated by HIF stabilization with i.p. dimethyloxalylglycine (DMOG). In cultured MLE-12 and/or primary rat ATII cells, DMOG accelerated whereas HIF1α shRNA delayed repair of a scratch wound, an assay of cell spreading. A microarray on rat ATII cells after adenoviral overexpression of HIF1α revealed upregulation of both CXCR4 and its ligand SDF1. CXCR4 and SDF1 were upregulated in ATII cells in lung injury in vivo. Finally, scratch wound repair was accelerated by rSDF1 and delayed by the CXCR4 inhibitor AMD3100. Conclusions HIF1α promotes ATII cell spreading and the restitution of epithelial integrity after lung injury. The reparative role of HIF1α may be mediated by autocrine CXCR4/SDF1 signaling.