慢性阻塞性肺疾病患者肺部丝裂原活化蛋白激酶、蛋白激酶B和缺氧诱导因子1α的表达

目的探讨丝裂原活化蛋白激酶(MAPK)、磷酸肌醇3激酶(PI3K)、缺氧诱导因子1α(HIF1α)的表达变化在缺氧性肺动脉高压(HPH)中的作用和意义。方法通过苏木精伊红(HE)染色检测慢性阻塞性肺疾病(COPD)患者和对照组患者肺小动脉形态学改变,应用免疫组化检测肺小动脉壁内磷酸化蛋白激酶B(p PKB)、磷酸化胞外信号调控激酶(p ERK)、磷酸化c Jun氨基端蛋白激酶(p JNK)、磷酸化p38(p P38)表达水平,应用原位杂交和免疫组化检测肺小动脉壁内HIF1α的表达水平。结果COPD患者管腔面积与管总面积比值(LA%,18±3)及肺小动脉中膜厚度[PAMT,(31±3)μm]均较对照组[30±5、(40±4)μm]显著增高(t=7.58、6.57,P均<0.01)。COPD患者肺小动脉壁p ERK蛋白、p PKB蛋白、HIF1α蛋白和HIF1αmRNA表达[均以吸光度(A)值表示]水平(0.164±0.012、0.113±0.009、0.232±0.008、0.154±0.013)较对照组(0.062±0.010、0.031±0.011、0.058±0.006、0.052±0.008)显著增强(t=23.18、21.03、62.14、2.44,P均<0.01),而p JNK、p P38蛋白表达(0.041±0.012、0.031±0.010)与对照组(0.048±0.013、0.028±0.007)比较差异均无统计学意义(P均>0.05)。相关分析表明HIF1α蛋白、HIF1αmRNA、p ERK蛋白和p PKB蛋白表达与COPD组LA%呈显著负相关(r=-0.920～-0.892,P均<0.05),与PAMT呈显著正相关(r=0.895～0.934,P均<0.05)。结论MAPK信号通路和PI3K信号通路以及HIF1α可能参与了COPD患者HPH的发生。

Expression of mitogen-actived protein kinase, phosphatidylinositol 3-kinase and hypoxia-inducible factor-1α in pulmonary arteries of patients with chronic obstructive pulmonary disease

OBJECTIVE: To investigate the expression of mitogen-actived protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and hypoxia-inducible factor-1alpha (HIF-1alpha) in pulmonary artery of chronic obstructive pulmonary disease (COPD), and therefore to explore the possible roles of MAPK, PI3K and HIF-1alpha in the development of hypoxia-induced pulmonary hypertension (HPH). METHODS: Small pulmonary arterial remodeling was observed by morphometric analysis in surgically removed lung tissues from COPD patients and control patients treated for lung tumors. The expression of p-ERK, p-JNK, p-P38, p-PKB and HIF-1alpha in lung tissue was examined by in situ hybridization and immunohistochemistry. RESULTS: Morphometry analysis showed that the ratio of wall area to total area (WA%) and pulmonary artery media thickness (PAMT) were increased in COPD patients [18 +/- 3, (31 +/- 3) microm] than in the control [30 +/- 5, (40 +/- 4) microm, t = 7.58, 6.57, all P < 0.01]. The expression levels of p-ERK protein, p-PKB protein, HIF-1alpha protein and HIF-1alpha mRNA level (absorbance, A) were significantly higher in pulmonary artery walls of COPD patients (0.164 +/- 0.012, 0.113 +/- 0.009, 0.232 +/- 0.008, 0.154 +/- 0.013, respectively) as compared to those of the control (0.062 +/- 0.010, 0.031 +/- 0.011, 0.058 +/- 0.006, 0.052 +/- 0.008, respectively, t = 23.18, 21.03, 62.14, 2.44, all P < 0.01), while p-JNK and p-P38 protein levels in the control group (0.048 +/- 0.013, 0.028 +/- 0.007, respectively) and COPD patients (0.041 +/- 0.012, 0.031 +/- 0.010, respectively, all P > 0.05) were barely positive. The expression of p-ERK, p-PKB and HIF-1alpha were negatively correlated with LA% (r = -0.920 - -0.892, all P < 0.05), and positively correlated with PAMT (r = 0.895 - 0.934, all P < 0.05). CONCLUSION: Differential expression of p-ERK, p-PKB and HIF-1alpha may be involved in the occurrence of HPH in COPD patients.