过氧化物酶体增殖活化受体γ激动剂对呼吸机相关肺损伤大鼠肺胶原合成的影响及机制

Effect and mechanism of 15-deoxy-△^(12,14)-prostaglandin J_2 on expression of collagen synthesis in rats with ventilator-induced lung injury

目的探讨过氧化物酶体增殖活化受体(PPAR)γ激动剂[15-去氧-△^(12,14-)前列腺素(PG)J_2 (15d—PGJ_2)]对呼吸机相关肺损伤大鼠肺胶原合成的影响及机制。方法普通级雄性SD大鼠24只,随机分为3组(正常对照组、Ⅰ组、Ⅱ组),每组8只。Ⅰ和Ⅱ组呼吸机条件相同(VT16ml/kg,PEEP为5cmH_2O,吸呼比为2：1,FiO_2为1．0),其中药物干预组(Ⅱ组)通气前1h腹腔注射15d-PGJ_2(1mg/kg),分别通气4h。通气结束后测定肺组织湿/干重(W/D)、肺组织光镜病理、Ⅰ型前胶原肽(PINP)和Ⅲ型前胶原肽(PⅢNP)浓度、Ⅰ型和Ⅲ型前胶原mRNA表达、以及PPARγ和核因子(NF)-kB活性。结果①Ⅰ组肺组织W/ D显著高于正常对照组和Ⅱ组(P＜0．05)。肺组织W/D在正常对照组和Ⅱ组之间无显著差异。②Ⅰ组肺组织Ⅰ型前胶原mRNA表达显著高于正常对照组和Ⅱ组(P均＜0．05)。Ⅱ组与正常对照组肺组织Ⅰ型前胶原mRNA表达无显著差异。③与Ⅰ组比较,正常对照组和Ⅱ组Ⅲ型前胶原mRNA表达均显著降低(P均＜0．05)。与正常组比较,Ⅱ组Ⅲ型前胶原mRNA表达无显著改变。④与正常对照组比较,Ⅰ组和Ⅱ组NF-kB活性均显著增高(P均＜0．05)。Ⅰ组与Ⅱ组NF-kB活性比较,无显著差异。⑤Ⅰ组PPARγ活性显著低于正常对照组(P＜0．05)。与Ⅰ组比较,Ⅱ组PPAγ活性显著增高(P＜0．05)。结论15d- PGJ_2下调呼吸机相关肺损伤大鼠肺组织Ⅰ型和Ⅲ型前胶原mRNA表达,其机制可能与激活PPARγ有关。

Objective To evaluate the effect and mechanism of 15-deoxy-△^12,14 prostaglandin J2 （15d- PGJ2 ） on the collagen synthesis in the rats with ventilator-induced lung injury. Methods Twenty-four male Sprague-Dawley rats were randomized into three groups with eight animals in each group [control group, ventilation（ Ⅰ ） group,and ventilation plus drug（ Ⅱ ） group]. The condition of ventilator is same（ Ⅰ , PEEP 5cmH20）. Ⅱ group was intraperitoneal injected with a bolus of 15d-PGJ2 （1mg/kg） one hour before the consequently treatments. The rats of Ⅰ group and Ⅱ group were individually ventilated for 4h. The severity of lung injury was evaluated by wet weight and dry weight ratios （W/D）. The concentration of procollagen propeptide type Ⅰ and type Ⅲ in lung homogenates was assessed by enzyme-linked immunosorbent assay （ELISA）, the expression of their mRNA was detected by reverse transcription polymerase chain reaction （RT-PCR） ,and NF-kB and PPART DNA-binding activity was detected by electrophoretic mobility gel shift assay （EMSA）. Results The level of W/D of the lung in Ⅰ group was significantly higher than that in control group （ P 〈0.05）. That in Ⅱ group decreased significantly compared with Ⅰ group （ P d0.05） and there was no difference between Ⅱ group and control group. The expression of procollagen type I mRNA in Ⅰ groap was higher than that in control group （ P （0.05）. The level of procollagen type I mRNA in Ⅱ group was lower than that in Ⅰ group （ P〈0.05）. Compared with control group,there was no difference in the expression of procollagen type Ⅰ mRNA in Ⅱ group. The expression of procollagen type Ⅲ mRNA in Ⅰ group was higher than that in control group （ P 〈0.05） ,but the level of procollagen type Ⅲ mRNA in Ⅱ group was lower than that in Ⅰ group （ P 〈0.05）,as well as no difference between II group and control group. NF-kB DNA-binding activity increased significantly in Ⅰ group and Ⅱ group, as compared with control group （all P〈0.05） ,and there was no significant difference between Ⅰ group and Ⅱ group. PPARγ DNA-binding activity was lower in Ⅰ group than that in control group and in Ⅱ group （all P 〈0.05）. No difference was found between Ⅱ group and control group in PPARγ DNA-binding activity. Conclusions Procollagen synthesis could be inhibited by 15d-PGJ2 in the rats with ventilator-induced lung injury and it may do its work throngh the activation of PPARγ.