Journal
MOLECULAR MEDICINE REPORTS
Volume 18, Issue 5, Pages 4399-4409Publisher
SPANDIDOS PUBL LTD
DOI: 10.3892/mmr.2018.9427
Keywords
acute lung injury and acute respiratory distress syndrome; alveolar macrophages; p38 mitogen-activated protein kinase signaling pathway; pyroptosis; nucleotide-binding domain; leucine-rich-containing family; pyrin domain-containing-3 inflammasome
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Funding
- National Natural Science Foundation of China
- Shanghai Three-Year Plan of the Key Subjects Construction in Public Health-Infectious Diseases and Pathogenic Microorganism [81270137, 81300054]
- Zhongshan Hospital, Fudan University in China [A654116001]
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Acute lung injury and acute respiratory distress syndrome (ALI/ARDS) is characterized by uncontrolled progressive lung inflammation. Macrophages serve a key role in the pathogenesis of ALI/ARDS. Macrophage pyroptosis is a process of cell death releasing the proinflammatory cytokines interleukin (IL)-1 beta and IL-18. It was hypothesized that macrophage pyroptosis may partially account for the uncontrolled lung inflammation of ALI/ARDS. In the present study, greater macrophage pyroptosis in lipopolysaccharide (LPS)-treated macrophages and the ALI/ARDS mouse model was observed. The expression of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP)3 and IL-1 beta and cleavage of caspase-1 were significantly elevated following LPS treatment accompanied by greater activation of p38 mitogen-activated protein kinase (MAPK) signaling in vitro and in vivo. However, blocking p38 MAPK signaling through the inhibitor SB203580 significantly suppressed the acute lung injury and excessive lung inflammation in vivo, consistent with the reduced expression of the NLRP3 inflammasome and IL-1 beta and cleavage of caspase-1. Pretreatment of the rat NR8383 macrophage cell line with SB203580 significantly decreased the population of caspase-1+PI+ pyroptotic cells and expression of NLRP3/IL-1 beta. However, a larger population of Annexin V+PI- apoptotic cells was observed following blocking of the p38 MAPK signaling pathway. The results indicated that blockage of p38 MAPK signaling pathway skewed macrophage cell death from proinflammatory pyroptosis towards non-inflammatory apoptosis. These effects may contribute to attenuated acute lung injury and excessive inflammation in the SB203580-treated mice. The results may provide a novel therapeutic strategy for the treatment of uncontrolled lung inflammation in patients with ALI/ARDS.
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