Fibrotic diseases occur in a variety of organs and lead to continuous organ injury, function decline, and even failure. Currently effective treatment options are limited. Galectin-3 (Gal-3) is a pleiotropic lectin that plays an important role in cell proliferation, adhesion, differentiation, angiogenesis, and apoptosis. Accumulating evidence indicates that Gal-3 activates a variety of profibrotic factors, promotes fibroblast proliferation and transformation, and mediates collagen production. Recent studies have defined key roles for Gal-3 in fibrogenesis in diverse organ systems, including liver, kidney, lung, and myocardial. To help set the stage for future research, we review recent advances about the role played by Gal-3 in fibrotic diseases. Herein we discuss the potential profibrotic role of Gal-3, inhibition of which may represent a promising therapeutic strategy against tissue fibrosis.

Epithelial mesenchymal transition (EMT) is a key progression that promotes pulmonary fibrosis (PF). Numb, a phosphotyrosine-binding domain (PTB) protein, is implicated with EMT. Nuclear factor erythroid 2-related factor2 (Nrf2) and its downstream proteins heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) constitute an important pathway of antioxidant defense signal for protecting against PF. It remains elusive whether Nrf2 antioxidant pathway and Numb have a potential relationship in EMT-mediated PF. Here, we observed the effects of Nrf2 pathway and Numb on bleomycin(BLM)-induced PF in Nrf2-knockout (Nrf2^−/−) and wild-type (WT) mice. Meanwhile, rat type II alveolar epithelial cells line (RLE-6TN) and human epithelial cells line (A549) were both treated with an Nrf2 activator sulforaphane (SFN), or transfected siRNAs of Nrf2 and Numb to unravel roles of Nrf2 pathway, Numb and the link between them on transforming growth factor β1 (TGF-β1)-induced EMT. We found BLM-induced lung fibrosis were more severe in Nrf2^−/− mice compared to WT mice with reduced expressions of HO-1 and NQO1. Numb was enhanced with down-regulated expressions of Nrf2 in BLM groups and further increased in Nrf2^−/− groups. In vitro, given exogenous TGF-β1 on RLE-6TN and A549 up-regulated Numb expressions, accompanied with down-regulations of Nrf2 and its target proteins HO-1 and NQO1. Transfected with Nrf2 and Numb siRNAs further aggravated and relieved the progression of EMT, respectively. Inversely, activating Nrf2 pathway by SFN reduced the expression of Numb and EMT-related protein. Moreover, Numb deficiency by siRNA relieved the protection of activating Nrf2 against EMT. In conclusion, activating Nrf2 antioxidant pathway suppresses EMT during PF via inhibiting the abnormal expression of Numb. These findings provide insight into PF pathogenesis and a basis for novel treatment approaches.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and abnormal inflammatory response. Wnt/β‐catenin and AMP‐activated protein kinase (AMPK) have been shown to modulate lung inflammatory responses and injury. However, it remains elusive whether Wnt/β‐catenin and AMPK modulate nuclear factor erythroid‐2 related factor‐2 (Nrf2)‐mediated protective responses during the development of emphysema. Here we showed that treatment with a Wnt pathway activator (LiCl) reduced elastase‐induced airspace enlargement and cigarette smoke extract (CSE)‐induced lung inflammatory responses in WT mice, which was associated with increased activation of Nrf2 pathway. Interestingly, these effects of LiCl were not observed in Nrf2^−/− mice exposed to elastase. In normal human bronchial epithelial (NHBE) cells, Wnt3a overexpression up‐regulated, whereas Wnt3a knockdown further down‐regulated the levels of Nrf2 and its target proteins heme oxygenase‐1 (HO‐1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) by CSE treatment. In contrast, Nrf2 deficiency did not have any effects on Wnt/β‐catenin pathway in mouse lungs and NHBE cells. Both elastase and CSE exposures reduced AMPK phosphorylation. A specific AMPK activator metformin increased Wnt3a, β‐catenin, Nrf2 phosphorylation and activation but reduced the levels of IL‐6 and IL‐8 in NHBE cells and mouse lungs exposed to CSE. Furthermore, Nrf2 deficiency abolished the protection of metformin against CSE‐induced increase in IL‐6 and IL‐8 in NHBE cells. In conclusion, Nrf2 mediates the protective effects of both Wnt3a/β‐catenin and AMPK on lung inflammatory responses during the development of COPD/emphysema. These findings provide potential therapeutic targets for the intervention of COPD/emphysema.

High‐mobility group box 1 (HMGB1) is originally identified as a DNA‐binding protein that functions as a structural co‐factor critical for proper transcriptional regulation in somatic cells. Recent studies indicate that HMGB1 can be passively released from necrotic cells or actively secreted into the extracellular milieu under appropriate signal stimulation. Extracellular HMGB1 is a multifunctional cytokine that contributes to the process of infection, injury, inflammation, apoptosis, and immune responses by binding to specific cell‐surface receptors. Recently, emerging studies indicate that HMGB1 is closely involved in fibrotic disorders including cystic fibrosis, liver fibrosis and pulmonary fibrosis, while HMGB1 signal inhibitions protect against the experimental models of fibrotic diseases. From a clinical perspective, HMGB1 represents a current challenge that can be exploited orchestrate reparative responses. This review focuses on the crucial role of HMGB1 in the pathogenesis of fibrotic diseases and inhibition of which may represent a promising clinical approach for treating tissue fibrosis.

Fibrosis in animal models and human diseases is associated with aberrant activation of the Wnt/β‐catenin pathway. Despite extensive research efforts, effective therapies are still not available. Myofibroblasts are major effectors, responsible for extracellular matrix deposition. Inhibiting the proliferation of the myofibroblast is crucial for treatment of fibrosis. Proliferation of myofibroblasts can have many triggering effects that result in fibrosis. In recent years, the Wnt pathway has been studied as an underlying factor as a primary contributor to fibrotic diseases. These efforts notwithstanding, the specific mechanisms by which Wnt‐mediated promotes fibrosis reaction remain obscure. The central role of the transforming growth factor‐β (TGF‐β) and myofibroblast activity in the pathogenesis of fibrosis has become generally accepted. The details of interaction between these two processes are not obvious. The present investigation was conducted to evaluate the level of sustained expression of fibrosis iconic proteins (vimentin, α‐SMA and collagen I) and the TGF‐β signalling pathway that include smad2/3 and its phosphorylated form p‐smad2/3. Detailed analysis of the possible molecular mechanisms mediated by β‐catenin revealed epithelial–mesenchymal transition and additionally demonstrated transitions of fibroblasts to myofibroblast cell forms, along with increased activity of β‐catenin in regulation of the signalling network, which acts to counteract autocrine TGF‐β/smad2/3 signalling. A major outcome of this study is improved insight into the mechanisms by which epithelial and mesenchymal cells activated by TGFβ1‐smad2/3 signalling through Wnt/β‐catenin contribute to lung fibrosis.

Epithelial-mesenchymal transition (EMT) is a phenotype conversion that plays a critical role in the development of pulmonary fibrosis (PF). It is known that snail could regulate the progression of EMT. Nuclear factor erythroid 2 related factor 2 (Nrf2), a key regulator of antioxidant defense system, protects cells against oxidative stress. However, it is not known whether Nrf2 regulates snail thereby modulating the development of PF. Here, 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 (RLE-6TN) were treated with a specific Nrf2 activator sulforaphane, or transfected with Nrf2 and snail siRNAs to determine their effects on transforming growth factor β1 (TGF-β1)-induced EMT. We found that 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 siRNA enhanced TGF-β1-induced EMT along with increased expression of snail. Interestingly, when snail was silenced by siRNA, sulforaphane treatment was unable to reduce the progression of EMT in RLE-6TN cells. These findings suggest that Nrf2 attenuates EMT and fibrosis process by regulating the expression of snail in PF.