MAP2K2 Delays Recovery in Murine Models of Acute Lung Injury and Associates with ARDS Outcome.

Acute Respiratory Distress Syndrome (ARDS) remains a significant problem in need of new pharmaceutical approaches to improve its resolution. Studies comparing gene expression signatures in rodents and humans with lung injury reveal conserved pathways, including MAPK/ERK activation. In preclinical acute lung injury (ALI) models, inhibition of MAP2K1/MAP2K2 improves measures of ALI. Myeloid cell deletion of MAP2K1 results in sustained MAP2K2 activation and non-resolving ALI, suggesting that MAP2K2 deactivation may be a key driver of ALI resolution. We used human genomic data from the iSPAAR consortium to assess genetic variants in MAP2K1 and MAP2K2 for association with mortality from ARDS. To determine the role of MAP2K2 in ALI recovery, we studied mice deficient in Map2k2 (Mek2-/-) and their wild-type controls (WT) in ALI models. We identified a MAP2K2 variant that was associated with death in ARDS and MAP2K2 expression. In Pseudomonas aeruginosa ALI, Mek2-/- mice had similar early alveolar neutrophilic recruitment but faster resolution of alveolar neutrophilia and vascular leak. Gene expression analysis revealed a role for MAP2K2 in promoting and sustaining select pro-inflammatory pathway activation in ALI. Bone marrow chimera studies indicate that leukocyte MAP2K2 is the key regulator of ALI duration. These studies implicate a role for MAP2K2 in ALI duration via transcriptional regulation of inflammatory programming with potential relevance to ARDS. Targeting leukocyte MAP2K2 may be an effective strategy to promote ALI resolution.