Nrf2 inhibits epithelial-mesenchymal transition by suppressing snail expression during pulmonary fibrosis

OBJECTIVE Epithelial-mesenchymal transition(EMT)is a phenotype conversion that plays a critical role in the development of pulmonary fibrosis(PF).It is known that a transcription factor snail could regulate the progression of EMT.Nuclear factor erythroid 2 related factor 2(Nrf2),a key regulator of antioxidant defense system,protects cells and tissues against oxidative stress.However,it is not known whether Nrf2 regulates snail thereby modulating the development of PF.MEHODS Bleomycin(BLM)was intratracheally injected into both Nrf2-knockout(Nrf2-/-)and wild-type mice to compare the development of PF.Rat type II alveolar epithelial cells(AECs)RLE-6TN were treated with a specific Nrf2activator sulforaphane,or transfected with Nrf2 and snail si RNAs to determine their effects on transforming growth factorβ1(TGF-β1)-induced EMT.RESULTS BLM-induced EMT and lung fibrosis were more severe in Nrf2-/-mice compared to wild-type mice.In vitro,sulforaphane treatment attenuated TGF-β1-induced EMT,accompanied by the down-regulation of snail.Inversely,silencing Nrf2 by si RNA enhanced TGF-β1-induced EMT along with the expression of snail.Interestingly,silencing snail by si RNA reduced TGF-β1-induced EMT even in the presence of sulforaphane in RLE-6TN cells.CONCLUSION These findings suggested that Nrf2 may attenuate EMT and fibrosis process through regulating the expression of snail in PF.

Pathogenesis of idiopathic pulmonary fibrosis： from initial apoptosis of epithelial cells to lung remodeling？

Idiopathic pulmonary fibrosis （IPF） is a progressive and often fatal form of interstitial lung disease. Despite extensive efforts in research during recent years, the mechanisms of the disease remain poorly understood. Evidence of an inflammatory mechanism, both supportive and contrary, is briefly reviewed in this paper. However, growing evidence has indicated that the apoptosis of alveolar epithelial cells （AECs） may be the early driving force of progression, with subsequent disrupted integrity of the alveolar-capillary basement membrane leading to an abnormal wound healing pathway. Thus, this paper will focus on outlining a process of pathogenesis of IPF from initial apoptosis of AECs to end

Effects of pentoxifylline on Wnt/β-catenin signaling in mice chronically exposed to cigarette smoke

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.