15-Lipoxygenase expressing neutrophils promote Acute Lung Injury resolution 2306687

Abstract

Abstract Introduction The acute respiratory distress syndrome (ARDS) is a major cause of respiratory failure among critical ill patients with limited available therapeutic options. Dysregulated unresolving inflammation and extensive lung injury are main features of ARDS. There is a urgent need for a better understanding of the biochemical and immunological events in ARDS that inform novel treatment strategies. Methods We used a mouse model of self-limited acid-induced ALI by selectively instilling hydrochloric acid to the left lung of adult mice. The time-course of lung disease was evaluated by consolidation by micro-computed tomography (mCT) and total protein in bronchoalveolar lavage (BAL), while inflammation was assessed by histology and flow cytometry. Results Neutrophils, that were rapidly recruited into the lungs, decreased over time during resolution while macrophage numbers, significantly reduced during initial stages, increased. Immunophenotyping of leukocytes recruited to the lungs during the resolution of injury uncovered a neutrophils’ subset that was expressing sialic acid—binding, Ig-like lectin F (SiglecF) and Alox15 (15-lipoxygenase). These cells were distinct from eosinophils and transcriptionally, phenotypically, and functionally different from the SiglecF-negative neutrophils. The roles for SiglecF-positive neutrophils were further assessed by in vitro functional studies and adoptive transfer experiments. Depletion of neutrophils impaired epithelial repair, while the adoptive transfer of SiglecF-positive neutrophils accelerated epithelial cell restitution. Among the mechanisms associated with the SiglecF-positive neutrophils in lung repair was the production of Alox15-derived specialized pro-resolving mediators and CSF1. In patients with respiratory failure, ALOX15+ neutrophils were present in the BAL and their frequency correlated with improved oxygenation. Conclusion In summary, we identified protective roles for a distinct subset of tissue neutrophils during the resolution of lung injury. Funding Source Pew Charitable Trusts, grant Latin American Fellowship 00034105 ; and American Lung Association, Catalyst Award CA- 1420662. Topic Categories Cellular Adhesion, Migration, and Inflammation (CAM)