Regulation of the NLRP3 inflammasome and macrophage pyroptosis by the p38 MAPK signaling pathway in a mouse model of acute lung injury

• Published in: Molecular medicine reports Vol. 18; no. 5; pp. 4399 - 4409
• Main Authors: Li, Dandan, Ren, Weiying, Jiang, Zhilong, Zhu, Lei
• Format: Journal Article
• Language: English
• Published: Greece Spandidos Publications 01.11.2018; Spandidos Publications UK Ltd; D.A. Spandidos
• Subjects: Acute Lung Injury - drug therapy; Acute Lung Injury - genetics; Acute Lung Injury - pathology; Animals; Annexin V; Apoptosis; Care and treatment; Caspase; Caspase-1; Caspases - genetics; Cell culture; Cell death; Cellular signal transduction; Cytokines; Diagnosis; Disease Models, Animal; Edema; Gene expression; Genetic aspects; Health aspects; Humans; Imidazoles - pharmacology; Inflammasomes; Inflammasomes - genetics; Inflammation; Inflammation - drug therapy; Inflammation - genetics; Inflammation - pathology; Interleukin 18; Interleukin-18 - genetics; Interleukin-1beta - genetics; Kinases; Laboratory animals; Leucine; Lipopolysaccharides; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung diseases; Lungs; Macrophages; Macrophages - drug effects; Macrophages - pathology; MAP kinase; Mice; Mortality; Neutrophils; NLR Family, Pyrin Domain-Containing 3 Protein - genetics; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - genetics; Pathogens; Protein kinase; Protein kinases; Proteins; Pyridines - pharmacology; Pyrin protein; Pyroptosis; Pyroptosis - genetics; Respiratory distress syndrome; Respiratory Distress Syndrome, Adult - drug therapy; Respiratory Distress Syndrome, Adult - genetics; Rodents; Signal Transduction; Studies; Tumor necrosis factor-TNF; United States > US
• ISSN: 1791-2997; 1791-3004; 1791-3004
• DOI: 10.3892/mmr.2018.9427

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)‑1β 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‑1β 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‑1β 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‑1β. 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.