Connexin 43 Mediated Interaction Between Alveolar Macrophages and Type 2 Epithelial Progenitors Protects Against Bleomycin Induced Acute Lung Injury 3901

Abstract Description Acute respiratory distress syndrome (ARDS) remains among the most common complications of critical illness. ARDS involves the death of type I alveolar epithelial cells, which are then repopulated by a progenitor subset of type II alveolar epithelial cell progenitors (AEP). All alveolar epithelial cell populations are in continuous contact with alveolar macrophages (AM), but the mechanistic role of AM in ARDS is undefined. We hypothesized that AM protect against ARDS through communication with AEPs. We generated mice with selective depletion of alveolar macrophages by deleting core-binding factor-β in the myeloid compartment (LysM-Cre+/- CBFβ-fl/fl). These animals were healthy at baseline but, in contrast to littermate controls, displayed progressive lung injury, inflammation, hypoxia, and death after bleomycin challenge. Mice with deletion of connexin-43 (Cx43) hemichannels in CD11c-expressing cells (CD11c-Cre+/- Cx43-fl/fl) displayed a similar susceptibility. AM expression of Cx43 was necessary to the susceptibility, because the phenotype was rescued by intrapulmonary adoptive transfer of wildtype AM but not the transfer of AM with deletion of Cx43 (from CD11c-Cre+/- Cx43-fl/fl donors). Finally, the phenotype was recapitulated in in mice deficient in Cx43 in AEP expressing Grainyhead transcription factor cellular promoter 2-like 1 (Tfc2l1-Cre+/- Cx43-fl/fl). In conclusion, AM protect against lung injury via a mechanism involving the Cx43 hemichannels on both AM and AEP. Funding Sources Supported by: NIH R01AI135128 and U01EB024501 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)