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 PTX-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-β(1), 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-β(1) (pg/g) (1452.4 ± 465.7 vs. 818.9 ± 202.8 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 ± 2.4 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-β(1) 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 D(1) 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-β(1), implying that activation of Wnt/β-catenin signaling may be involved in the pathogenesis of pulmonary fibrosis.