诱导型一氧化氮合酶对肺纤维化形成的促进作用

The augmentative effect of inducible nitric oxide synthase on pulmonary fibrosis progression

目的 :研究纤维化肺内诱导型一氧化氮合酶上调及其与肺纤维化形成的关系。方法 :气管内滴注平阳霉素 (BLMA55mL/kg) ,观察注后 7、14、30d肺组织诱导型一氧化氮合酶 (iNOS)阳性细胞数和Ⅰ、Ⅲ型胶原纤维的变化 ;用氨基胍 (AG)阻断iNOS合成NO后 ,观察出肺血中NO-2 /NO-3 和肺组织中羟脯氨酸含量以及肺组织形态结构的变化。结果 :①注BLMA57d、14d和 30d组大鼠肺间质iNOS阳性细胞数明显多于对照组 (P <0 .0 1) ,并且 ,BLMA57d组和BLMA514d组还多于BLMA530d组 (P <0 .0 1)。BLMA514d和 30d组大鼠肺间质胶原纤维的出现多于对照组 ,BLMA514d组以Ⅲ型胶原纤维增多为主 ,BLMA530d组以Ⅰ型胶原纤维增多为主。②AG缓解出肺血NO-2 /NO-3和肺组织中羟脯氨酸含量的升高 ;AG还阻止肺间质或纤维细胞和巨噬细胞的增多。结论 :在肺纤维化形成过程中 ,肺内iNOS上调 ,大量生成NO ,有促肺纤维化的作用。

AIM: To study the up-regulation of inducible nitric oxide synthase (iNOS) in lung of pulmonary fibrosis and its relationship with fibrosis. METHODS: The changes of amount of iNOS positive stain cells and type Ⅰ?Ⅲ collagen were examined on the day 7, 14 and 30 after intratracheal administration of bleomycin A_5. The contents of NO-_2/NO-_3 (nitrite/nitrate) in out-flowing pulmonary blood (OPB), hydroxyproline in lung and the histological changes were detected after iNOS was blocked by aminoguanidine (AG). RESULTS: (1) The number of iNOS-positive stain cells increased significantly in BLMA_5 7 d, 14 d and 30 d groups compared with that in control group (P<0.01). Furthermore, the increment of the number of iNOS-positive stain cells in BLMA_5 7 d, 14 d groups was more than that in BLMA_5 30 d group. There was an increment of collagen in BLMA_5 14 d group and in BLMA_5 30 d group , with an increase in type Ⅲ collagen in BLMA_5 14 d group and an increase in type Ⅰcollagen in BLMA_5 30 d group. (2) The high level of NO-_2/NO-_3 in OPB and hydroxyproline level in lung could be reversed by AG, a selective inhibitor of iNOS. Large amount of fibroblasts and macrophages were also abated by AG. CONCLUSION: In the development of pulmonary fibrosis, the expression of iNOS is up-regulated, which induces nitric oxide (NO) production and promotes propagation of pulmonary fibrosis.