Proton-Sensing Tdag8 Exhibits the Protective Role in Lipopolysaccharide-Induced Acute Lung Injury

Introduction: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are characterized by the infiltration of neutrophils in the alveolar space and the subsequence impairment of lung function. The pH of the interstitium and the bronchoalveolar space has been shown to fall in inflammatory diseases, such as ALI and ARDS. Proton-sensing T-cell death-associated gene 8 (TDAG8) is mainly expressed in hematopoietic cells such as macrophages. Here, we explored the role of TDAG8 in lung injury as induced by lipopolysaccharide (LPS). Methods: ALI was induced intratracheal administration of LPS in female C57BL/6 wild type (WT) or TDAG8-KO mice. After administration, we measured cell numbers, proteins, cytokines and chemokines in bronchoalveolar lavage fluids (BALF) and mRNAs of the lungs. Histological analysis of lung sections was performed. Results: LPS treatment increased TDAG8 expression in the lungs and neutrophil accumulation without appreciable change in the alveolar macrophages, which were associated with the penetration of the blood proteins into BALF and damage of the alveolar architecture. LPS also increased several mRNA and protein expressions of inflammatory cytokines and chemokines in the lungs or BALF. The LPS-induced neutrophil accumulation, associated lung damage, and inflammatory mediator production were enhanced in TDAG8-KO mice as compared with those in WT mice. Conclusion: Our results suggest that TDAG8 is negative regulator for lung neutrophilic inflammation and injury, in part, through the inhibition of chemokine production.