Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
Department of Gerontology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
Mol Med Rep. 2018 Nov;18(5):4399-4409. doi: 10.3892/mmr.2018.9427. Epub 2018 Aug 24.
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.
急性肺损伤和急性呼吸窘迫综合征（ALI/ARDS）的特征是不受控制的进行性肺炎症。巨噬细胞在 ALI/ARDS 的发病机制中起关键作用。巨噬细胞细胞焦亡是一种细胞死亡的过程，会释放促炎细胞因子白细胞介素（IL）-1β和 IL-18。研究假设巨噬细胞细胞焦亡可能部分解释了 ALI/ARDS 的不受控制的肺炎症。在本研究中，观察到脂多糖（LPS）处理的巨噬细胞和 ALI/ARDS 小鼠模型中巨噬细胞细胞焦亡增加。LPS 处理后，体外和体内的核苷酸结合域、富含亮氨酸重复序列、富含亮氨酸重复序列的pyrin 结构域（NLRP）3 和 IL-1β的表达以及半胱天冬酶-1 的裂解均显著升高，同时 p38 丝裂原活化蛋白激酶（MAPK）信号通路也被激活。然而，通过抑制剂 SB203580 阻断 p38 MAPK 信号通路可显著抑制体内急性肺损伤和过度肺炎症，这与 NLRP3 炎性体和 IL-1β的表达以及半胱天冬酶-1 的裂解减少一致。用 SB203580 预处理大鼠 NR8383 巨噬细胞系可显著减少 caspase-1+PI+细胞焦亡细胞的数量和 NLRP3/IL-1β的表达。然而，在阻断 p38 MAPK 信号通路后，观察到更大比例的 Annexin V+PI-凋亡细胞。这些结果表明，阻断 p38 MAPK 信号通路使巨噬细胞死亡从促炎的细胞焦亡偏向非炎症性的凋亡。这些作用可能有助于减轻 SB203580 处理的小鼠急性肺损伤和过度炎症。这些结果可能为治疗 ALI/ARDS 患者不受控制的肺炎症提供新的治疗策略。
