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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。
Objective To investigate the role of MAPK, PI3K and HIF1α expression in hypoxic pulmonary hypertension (HPH). Methods Morphological changes of pulmonary arterioles were detected by hematoxylin and eosin (HE) staining in patients with chronic obstructive pulmonary disease (COPD) and control group. The expression of phospho-PKB (p PKB ), Phosphorylated extracellular signal-regulated kinase (p ERK), phosphorylated c-Jun N-terminal protein kinase (p JNK) and phosphorylated p38 (p P38) were detected by immunohistochemistry and in situ hybridization The level of HIF1α expression. Results The ratio of luminal area to total tube area (LA%, 18 ± 3) and pulmonary arteriole membrane thickness [PAMT, (31 ± 3) μm] in COPD patients were significantly higher than those in control subjects [30 ± 5, μm] was significantly higher (t = 7.58,6.57, P <0.01). The levels of p ERK protein, p PKB protein, HIF1α protein and HIF1α mRNA expression in pulmonary arteriole wall in COPD patients (both expressed as absorbance (A)] were significantly higher than those in control group (0.164 ± 0.012,0.113 ± 0.009,0.232 ± 0.008,0.154 ± 0.013) (0.062 ± 0.010,0.031 ± 0.011,0.058 ± 0.006,0.052 ± 0.008) (P <0.01), while the expression of p JNK and p P38 protein (0.041 ± 0.012,0.031 ± 0.010) compared with the control group (0.048 ± 0.013,0.028 ± 0.007), there was no significant difference (all P> 0.05). Correlation analysis showed that the expression of HIF1α protein, HIF1αmRNA, p ERK protein and p PKB protein were negatively correlated with LA% of COPD group (r = -0.920-0.892, P <0.05), and positively correlated with PAMT (r = 0.895 ~ 0.934, P <0.05). Conclusion MAPK signaling pathway, PI3K signaling pathway and HIF1α may be involved in the pathogenesis of HPH in COPD patients.