Nick J A, Young S K, Brown K K, Avdi N J, Arndt P G, Suratt B T, Janes M S, Henson P M, Worthen G S
Department of Medicine, National Jewish Medical and Research Center, Denver, CO 80206, USA.
J Immunol. 2000 Feb 15;164(4):2151-9. doi: 10.4049/jimmunol.164.4.2151.
Early inflammatory events include cytokine release, activation, and rapid accumulation of neutrophils, with subsequent recruitment of mononuclear cells. The p38 mitogen-activated protein kinase (MAPK) intracellular signaling pathway plays a central role in regulating a wide range of inflammatory responses in many different cells. A murine model of mild LPS-induced lung inflammation was developed to investigate the role of the p38 MAPK pathway in the initiation of pulmonary inflammation. A novel p38 MAPK inhibitor, M39, was used to determine the functional consequences of p38 MAPK activation. In vitro exposure to M39 inhibited p38 MAPK activity in LPS-stimulated murine and human neutrophils and macrophages, blocked TNF-alpha and macrophage inflammatory protein-2 (MIP-2) release, and eliminated migration of murine neutrophils toward the chemokines MIP-2 and KC. In contrast, alveolar macrophages required a 1000-fold greater concentration of M39 to block release of TNF-alpha and MIP-2. Systemic inhibition of p38 MAPK resulted in significant decreases in the release of TNF-alpha and neutrophil accumulation in the airspaces following intratracheal administration of LPS. Recovery of MIP-2 and KC from the airspaces was not affected by inhibition of p38 MAPK, and accumulation of mononuclear cells was not significantly reduced. When KC was instilled as a proinflammatory stimulus, neutrophil accumulation was significantly decreased by p38 MAPK inhibition independent of TNF-alpha or LPS. Together, these results demonstrate a much greater dependence on the p38 MAPK cascade in the neutrophil when compared with other leukocytes, and suggest a means of selectively studying and potentially modulating early inflammation in the lung.
早期炎症事件包括细胞因子释放、中性粒细胞活化和快速聚集，随后是单核细胞的募集。p38丝裂原活化蛋白激酶（MAPK）细胞内信号通路在调节许多不同细胞的广泛炎症反应中起核心作用。建立了轻度脂多糖诱导的小鼠肺部炎症模型，以研究p38 MAPK通路在肺部炎症起始中的作用。一种新型的p38 MAPK抑制剂M39被用于确定p38 MAPK激活的功能后果。体外暴露于M39可抑制脂多糖刺激的小鼠和人类中性粒细胞及巨噬细胞中的p38 MAPK活性，阻断肿瘤坏死因子-α（TNF-α）和巨噬细胞炎性蛋白-2（MIP-2）的释放，并消除小鼠中性粒细胞向趋化因子MIP-2和KC的迁移。相比之下，肺泡巨噬细胞需要浓度高1000倍的M39才能阻断TNF-α和MIP-2的释放。气管内给予脂多糖后，全身抑制p38 MAPK可导致TNF-α释放和中性粒细胞在气腔中的积聚显著减少。气腔中MIP-2和KC的恢复不受p38 MAPK抑制的影响，单核细胞的积聚也没有显著减少。当注入KC作为促炎刺激物时，p38 MAPK抑制可显著减少中性粒细胞的积聚，而与TNF-α或脂多糖无关。总之，这些结果表明，与其他白细胞相比，中性粒细胞对p38 MAPK级联的依赖性更强，并提示了一种选择性研究和潜在调节肺部早期炎症的方法。
