Lysophosphatidylcholine 14:0 Alleviates Lipopolysaccharide-Induced Acute Lung Injury via Protecting Alveolar Epithelial Barrier by Activation of Nrf2/HO-1 Pathway

Background: Acute lung injury (ALI) is characterized by diffuse alveolar injury and acute non-cardiac pulmonary edema, with high morbidity and mortality. Lysophosphatidylcholine 14:0 (LPC14:0) has anti-inflammatory and anti-oxidative effects in sepsis and bacteremia. We hypothesized that LPC14:0 could be a potential treatment for ALI. Therefore, the effects of LPC14:0 on lung epithelial cells and the underlying mechanism on ALI were investigated.

Methods: Lipopolysaccharide (LPS) was instilled intratracheally in vivo while the Murine Lung Epithelial-12 was stimulated by tert-butyl hydroperoxide (t-BHP) in vitro to induce the ALI model. In vivo, lung injury was evaluated by histopathological changes and pulmonary edema was assessed by wet/dry ratio. Evans blue infiltration in lung tissue, total protein content, total cell counts and inflammatory factors in bronchoalveolar lavage fluid were evaluated for alveolar permeability. In vitro, cell viability and cell death rate were assessed by cell counting kit-8 and Calcein-AM/PI stain respectively. The expression of ZO-1, Occludin, Nrf2, and HO-1 was evaluated by Western blot.

Results: LPC14:0 attenuated the LPS-stimulated lung injury and oxidative stress in vivo, and alleviated the t-BHP-induced cell damage in vitro. Moreover, LPC14:0 significantly inhibited the degradation of the tight junction proteins and activated the Nrf2/HO-1 signaling pathway both in vivo and in vitro. Mechanistically, ML385, the Nrf2 inhibitor, inhibited the protective effects of LPC14:0 on barrier function in vitro.

Conclusion: This study first demonstrated that LPC14:0 mitigated LPS-induced ALI and the destruction of tight junctions, at least in part through up-regulation of the Nrf2/HO-1 pathway.

ALI; Nrf2; acute lung injury; alveolar epithelial barrier; lysophosphatidylcholine 14:0; tight junction.