创伤作为一种强的生物因子刺激信号，激活p38 MAPK信号传导通路，其对组织修复和创伤愈合有重要作用。p38途径控制多种转录因子的基因表达活性，如：ATH1/2、CHOP/GADD153、ELK1、转录调节因子(ETS1)、MAX、主动外排转运体基因2A(MEF2A)、MEF2C、核转录因子κB (NFκB)、热休克转录因子1(HSF1)、血清淀粉样P成分1(SAP1)等[17]。其中,有些转录因子是p38直接底物，而有些是p38间接底物。p38 MAPK调节细胞增殖和分化，调控上皮细胞、内皮细胞、平滑肌细胞及成纤维细胞等多种细胞的运动，并能参与细胞骨架蛋白的合成，如微管蛋白、放线蛋白、HSP、中间丝蛋白等，从而参加完成伤口的愈合过程。Saika等[24]在角膜组织培养实验中发现磷酸化p38 MAPK早在创伤后1h即出现于创伤角膜上皮中。p38 MAPK的激活依赖于TGFβ，激活的p38 MAPK在角膜创伤愈合过程中加速上皮细胞迁移同时抑制细胞过度增殖，从而促进创口的快速覆盖及表层角膜的再铺和愈合。特异性p38 MAPK抑制物SB202190和SB203580加入培养基后，对上皮细胞的迁移覆盖具有明显的抑制效应，成纤维细胞、胶原酶Ⅰ和胶原酶Ⅲ也被抑制，明显延缓了角膜上皮的修复和再生。p38 MAPK调节多种细胞因子的产生，参与炎症反应。Dennis 等[25]实验发现，用p38 MAPK特异性抑制剂SB203580抑制p38 MAPK的磷酸化可减轻甚至可完全阻断巨噬细胞内TNFα的产生，说明炎症反应中TNFα的产生与p38 MAPK的激活密切相关。而用LPS刺激大鼠巨噬细胞后可致巨噬细胞内p38 MAPK的激活，能促进单核巨噬细胞产生IL1、IL4、IL6、IL8、IL12等炎性因子和介导中性粒细胞的活化[26]。此外，p38还能诱导产生能调控结缔组织病理性重构的COX2酶[27]，及与氧化损伤相关的细胞内酶类如iNOS[28]等，因此p38通路与炎症反应的发生密切相关。
Sharma等[29]还通过实验发现p38和ERK1/2在角膜创伤愈合过程中具有协同调节角膜上皮细胞迁移和增殖的作用。他们发现两种旁分泌性生长因子，肝细胞生长因子（HGF）和表皮细胞生长因子（KGF），可诱导p38和ERK1/2快速明显激活，激活的p38和ERK1/2并迅速地聚集在细胞核内。若向培养基中加入p38和ERK1/2各自的特异性抑制剂SB203580和PD98059处理后再使用HGF或KGF进行刺激，则发现p38和ERK1/2的激活和核内聚集现象均受到明显抑制。实验还发现抑制p38和ERK1/2两种酶其中之一即诱导另一种酶的交叉激活。单独使用p38特异性抑制剂SB203580几乎完全阻断上皮细胞的迁移，相比之下，ERK1/2特异性抑制剂PD98059仅通过伴随的p38的激活对细胞迁移有微弱抑制作用；同时，抑制ERK1/2可阻断上皮细胞增殖而p38对上皮细胞的增殖几乎无影响。单独抑制p38或ERK1/2将延缓角膜创伤愈合过程，而当两条通路同时被阻断时角膜创伤愈合过程受到明显抑制。这些实验发现充分表明p38和ERK1/2协同调节角膜创伤愈合的动力学过程：p38的激活诱导细胞迁移同时ERK1/2的激活诱导细胞增殖。另外，在伤口愈合过程中，当部分细胞需替换时，一些不需要的细胞将发生凋亡，其中部分凋亡即是通过ERK/p38通路实现的[30,31]。
5展望
角膜创伤愈合是一个复杂的过程，这个复杂过程离不开多种生物因子，细胞外基质蛋白及酶的参与。因为与修复相关的生物因子和酶数量众多，因此传统的临床前和临床研究中仅针对其中某一种或几种进行干预，往往达不到预期目的。但现在发现，虽然生物因子数量众多，但进入细胞内的信息通道却为数较少，如能对其中关键的信号通路进行有效阻断和调节，这对于角膜创伤的组织修复和愈合具有目标明确、效果明显的优势。p38 MAPK通路是参与角膜创伤愈合和炎症反应调控的重要信号系统，若能运用特异性药物，在信号通路水平有效地调控p38 MAPK的表达和活性，将为临床角膜创伤和炎症的防治及合理用药提供新的理论依据。
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