己酮可可碱诱导吸烟肺纤维化的机制

目的： 观察己酮可可碱 (PTX) 长期干预对慢性吸烟动物肺组织病理表型的影响并探讨其可能的机制。方法: 将BALB/c小鼠随机分为单纯吸烟组、假吸烟组、吸烟加服PTX组和假吸烟加服PTX组。第16周末处死动物，观察各组动物肺组织的病理改变，测定小鼠肺组织羟脯氨酸含量、支气管肺泡灌洗液(BALF)中IL-4和IFN-γ因子水平。结果: 单纯吸烟组小鼠表现为肺气肿样病理表型；而吸烟加服PTX组小鼠肺组织表现为肺纤维化样病理表型；假吸烟组和假吸烟加 PTX组动物既无明显肺气肿也无明显肺纤维化。吸烟加服PTX组小鼠肺纤维化评分和肺组织羟脯氨酸含量明显高于其它实验组。单纯吸烟组与吸烟加服PTX组小鼠BALF中Th2细胞因子IL-4与Th1细胞因子 IFN-γ比值分别为20.3±25.5和70.7±59.9，表明PTX导致吸烟性炎症向Th2极化转化。 结论：PTX长期干预可导致慢性吸烟性肺纤维化形成，Th1/Th2炎症极化趋势的变化可能是导致这种变化的重要机制。

Mechanism responsible for pulmonary fibrosis induced by concomitant chronic smoke exposure and pentoxifylline administration

AIM: To investigate the impact of long-term administration of pentoxifylline (PTX) on morphology and inflammation of the lung in mouse models with chronic exposure of cigarette smoke. METHODS: Male BALB/c mice were randomized into the following four study groups: smoke-exposure only, shamed smoke-exposure, smoke-exposure and PTX administration, shamed smoke-exposure and PTX administration. Animals assigned to smoke-exposure were put inside a chamber twice a day for cigarette smoke exposure. The oral dose of PTX allocated to each mouse was about 20 mg·kg-1·d-1. Animals were sacrificed anaesthetically at day 120. Slices of lung were stained with H&;E for pathological analysis. Modified ashcroft pulmonary fibrosis score (mAPFS) was estimated, and IFN-γ (a Th1 cytokine), IL-4 (a Th2 cytokine) in broncho-alveolar lavage fluid (BALF) and hydroxyproline in mouse lung tissue were measured by commercial kits of ELISA assay. RESULTS: Lungs in smoke-exposure only group exhibited emphysema-like morphology, low mAPFS (median 1.50, 95%CI 1.25-3.75), lowest hydroxyproline (2.43±0.11) mg/L and lowest ratio of IL-4 to IFN-γ (20.3±25.5), whereas lungs in smoke-exposure and PTX interference group exhibited interstitial fibrosis-like morphology, highest mAPFS (4.75, 4.09-5.71), highest hydroxyproline (5.57±0.55) mg/L and highest ratio of IL-4 to IFN-γ (70.7±59.9) among the four study groups (P<0.01). CONCLUSION: Interference of pulmonary inflammation induced by chronic smoke-exposure with PTX leads to the development of pulmonary fibrosis, which may relate to the turnover of Th1 polarized inflammation into Th2 polarized inflammation of the lungs.