Background Previous discovery that long-term administration of pentoxifylline （PTX） to mice chronically exposed to smoke led to the development of pulmonary fibrosis rather than emphysema initiated our curiosity on ...Background Previous discovery that long-term administration of pentoxifylline （PTX） to mice chronically exposed to smoke led to the development of pulmonary fibrosis rather than emphysema initiated our curiosity on whether the Wnt/β-catenin pathway, a set of signaling proteins essential to organ development and lung morphogenesis in particular were activated in the pathogenesis of pulmonary fibrosis. Methods Male BALB/c mice were randomized into four study groups： Group Sm, smoke exposure and taken regular forage; Group PTX, no smoke but taken PTX-rich forage; Group Sm＋PTX, smoke exposure and taken PrX-rich forage; Group control： shamed smoke exposure and taken regular forage. Animals were sacrificed at day 120. Morphometry of the lung sections and the expressions of TGF-β1, hydroxyproline, β-catenin, cyclin D1, T cell factor 1 （Tcf-1） and lymphoid enhancer factor 1 （Lef-1） mRNA, etc, in the lung homogenate or in situ were qualitatively or quantitatively analyzed. Results As expected, smoke exposure along with PTX administration for 120 days, lungs of the mice progressed to be a fibrosis-like phenotype, with elevated fibrosis score （3.9±1.1 vs. 1.7±0.6 in Group Sm, P 〈0.05）. TGF-β1（pg/g） （1452.4±465.7 VS. 818.9±2.02.8 in Group Sm, P 〈0.05） and hydroxyproline （mg/g） （5.6±0.6, vs. 2.4±0.1 in Group Sm, P 〈0.05） were also consistently increased. The upregulation of β-catenin measured either by counting the cell with positive staining in microscopic field （17.4±7.9 vs. 9.9±2.9 in Group Sm, P 〈0.05） or by estimation of the proportion of blue-stained area by Masson＇s trichrome （11.8±5.6 vs. 4.7±4 in Group Sm） in Group SM＋PTX was much more noticeable as than those in Group Sm. The expression of β-catenin measured by positive cell counts was correlated to TGF-β1 concentration in lung tissue （r=0.758, P 〈0.001）. PTX per se caused neither fibrosis nor emphysema though expression of β-catenin and downstream gene cyclin D1 may also be altered by this medication. Conclusions PTX mediated transformation of pulmonary emphysema into pulmonary fibrosis under chronic cigarette smoke exposure is associated with upregulation of β-catenin and elevation of TGF-β1, implying that activation of Wnt/β-catenin signaling may be involved in the pathogenesis of pulmonary fibrosis.展开更多
基金This study was supported by a grant from Natural Science Foundation of Hubei Province, China （No. 2008cdb153）.Acknowledgements： We are grateful to Prof. NIE Xiu in the Department of Pathology of this hospital for her valuable advices and devoting efforts on pathological analysis in this study.
文摘Background Previous discovery that long-term administration of pentoxifylline （PTX） to mice chronically exposed to smoke led to the development of pulmonary fibrosis rather than emphysema initiated our curiosity on whether the Wnt/β-catenin pathway, a set of signaling proteins essential to organ development and lung morphogenesis in particular were activated in the pathogenesis of pulmonary fibrosis. Methods Male BALB/c mice were randomized into four study groups： Group Sm, smoke exposure and taken regular forage; Group PTX, no smoke but taken PTX-rich forage; Group Sm＋PTX, smoke exposure and taken PrX-rich forage; Group control： shamed smoke exposure and taken regular forage. Animals were sacrificed at day 120. Morphometry of the lung sections and the expressions of TGF-β1, hydroxyproline, β-catenin, cyclin D1, T cell factor 1 （Tcf-1） and lymphoid enhancer factor 1 （Lef-1） mRNA, etc, in the lung homogenate or in situ were qualitatively or quantitatively analyzed. Results As expected, smoke exposure along with PTX administration for 120 days, lungs of the mice progressed to be a fibrosis-like phenotype, with elevated fibrosis score （3.9±1.1 vs. 1.7±0.6 in Group Sm, P 〈0.05）. TGF-β1（pg/g） （1452.4±465.7 VS. 818.9±2.02.8 in Group Sm, P 〈0.05） and hydroxyproline （mg/g） （5.6±0.6, vs. 2.4±0.1 in Group Sm, P 〈0.05） were also consistently increased. The upregulation of β-catenin measured either by counting the cell with positive staining in microscopic field （17.4±7.9 vs. 9.9±2.9 in Group Sm, P 〈0.05） or by estimation of the proportion of blue-stained area by Masson＇s trichrome （11.8±5.6 vs. 4.7±4 in Group Sm） in Group SM＋PTX was much more noticeable as than those in Group Sm. The expression of β-catenin measured by positive cell counts was correlated to TGF-β1 concentration in lung tissue （r=0.758, P 〈0.001）. PTX per se caused neither fibrosis nor emphysema though expression of β-catenin and downstream gene cyclin D1 may also be altered by this medication. Conclusions PTX mediated transformation of pulmonary emphysema into pulmonary fibrosis under chronic cigarette smoke exposure is associated with upregulation of β-catenin and elevation of TGF-β1, implying that activation of Wnt/β-catenin signaling may be involved in the pathogenesis of pulmonary fibrosis.
