The Role of p38 MAPK Signaling Pathway in Macrophage Pyroptosis and Murine Acute Lung Injury

Abstract

Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is characterized by the uncontrolled progressive lung inflammation. Macrophage plays a key role in the pathogenesis of ALI/ARDS. Macrophage pyroptosis is a process of cell death with release of pro-inflammatory cytokines IL-1beta and IL-18. We hypothesize that macrophage pyroptosis may partially account for the uncontrolled lung inflammation of ALI/ARDS. In this study, we observed greater macrophage pyroptosis in the LPS-treated macrophages and ALI/ARDS mouse model. The expression of NLRP3, IL-1beta and cleavage of Caspase-1 were significantly elevated after LPS treatment, accompanied with more activation of p38 MAPK signaling in vitro and in vivo. However, blocking p38 MAPK signaling through inhibitor SB203580 significantly suppressed the acute lung injury and excessive lung inflammation in vivo, consistent with the reduced expression of NLRP3 inflammasome, IL-1beta and cleavage of Caspaase-1. SB203580 significant decreased the population of Caspase-1+propidium iodide (PI)+ pyroptotic cells and expression of NLRP3/ IL-1beta in the treated rat NR8383 macrophage cell lines. However, we observed more population of Annexin V+PIapoptotic cells after blocking p38 MAPK signaling. The results indicated that blockade of p38 MAPK signaling skewed macrophage cell death from pro-inflammatory pyroptosis towards non-inflammatory apoptosis. The effects may contribute to the attenuated acute lung injury and excessive inflammation in the SB203580-treated mice. The results provide a novel therapeutic strategy for the treatment of the uncontrolled lung inflammation among patients with ALI/ARDS