Sawatzky Deborah A, Willoughby Derek A, Colville-Nash Paul R, Rossi Adriano G
MRC Centre for Inflammation Research, The Queen's Medical Research Institute, University of Edinburgh Medical School, 47 Little France Crescent, Edinburgh, Scotland, UK EH16 4TJ.
Am J Pathol. 2006 Jan;168(1):33-41. doi: 10.2353/ajpath.2006.050058.
Inflammatory cell recruitment, activation, and apoptosis are highly regulated processes involving several checkpoints controlling the resolution of inflammation. We investigated the role of the mitogen-activated protein kinase (MAPK) signaling pathway (ie, ERK1/2) and apoptosis-regulating Bcl-2 family members (ie, Bcl-x(L) and Bax) in the resolution of a rat carrageenan-induced pleurisy model. The specific ERK1/2 inhibitor PD98059 enhanced the resolution of inflammation, whereas the MEK1/2 inhibitor U0126 had no effect and the flavonoid apigenin, a nonspecific inhibitor of ERK1/2 and COX-2, augmented inflammation. Specifically, PD98059 significantly decreased the total number of macrophages and neutrophils in the pleural cavity, mainly by increasing the rate of neutrophil apoptosis, as measured by Annexin V labeling and morphological analysis. Conversely, a specific inhibitor of proapoptotic Bax (V5) increased inflammation, indicating that by preventing apoptosis in vivo, resolution of inflammation is delayed. This was associated with a decrease in neutrophil apoptosis and an increase in macrophage and neutrophil numbers perpetuating the inflammatory response. In conclusion, this study shows that ERK1/2, Bax, and Bcl-x(L) play important functional roles in the resolution phase of the acute inflammatory response in vivo by influencing apoptosis. Importantly, these data may provide novel therapeutic targets for the treatment of inflammatory diseases.
炎症细胞的募集、激活和凋亡是高度受调控的过程，涉及多个控制炎症消退的检查点。我们研究了丝裂原活化蛋白激酶（MAPK）信号通路（即ERK1/2）和凋亡调节Bcl-2家族成员（即Bcl-x(L)和Bax）在大鼠角叉菜胶诱导的胸膜炎模型炎症消退中的作用。特异性ERK1/2抑制剂PD98059增强了炎症的消退，而MEK1/2抑制剂U0126没有效果，并且黄酮类芹菜素（一种ERK1/2和COX-2的非特异性抑制剂）加剧了炎症。具体而言，PD98059显著降低了胸腔中巨噬细胞和中性粒细胞的总数，主要是通过增加中性粒细胞凋亡率，这通过膜联蛋白V标记和形态学分析来测量。相反，促凋亡Bax的特异性抑制剂（V5）加剧了炎症，表明通过在体内阻止凋亡，炎症的消退被延迟。这与中性粒细胞凋亡减少以及巨噬细胞和中性粒细胞数量增加有关，从而使炎症反应持续存在。总之，本研究表明ERK1/2、Bax和Bcl-x(L)通过影响凋亡在体内急性炎症反应的消退阶段发挥重要的功能作用。重要的是，这些数据可能为炎症性疾病的治疗提供新的治疗靶点。
