No abstract

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.

IFNg is conventionally recognized as an inflammatory cytokine that plays a central role in antitumor immunity. Although it has been used clinically to treat a variety of malignancies, low levels of IFNg in the tumor microenvironment (TME) increase the risk of tumor metastasis during immunotherapy. Accumulating evidence suggests that IFNg can induce cancer progression, yet the mechanisms underlying the controversial role of IFNg in tumor development remain unclear. Here, we reveal a dose-dependent effect of IFNg in inducing tumor stemness to accelerate cancer progression in patients with a variety of cancer types. Low levels of IFNg endowed cancer stem-like properties via the intercellular adhesion molecule-1 (ICAM1)-PI3K-Akt-Notch1 axis, whereas high levels of IFNg activated the JAK1-STAT1-caspase pathway to induce apoptosis in non-small cell lung cancer (NSCLC). Inhibition of ICAM1 abrogated the stemlike properties of NSCLC cells induced by the low dose of IFNg both in vitro and in vivo. This study unveils the role of low levels of IFNg in conferring tumor stemness and elucidates the distinct signaling pathways activated by IFNg in a dose-dependent manner, thus providing new insights into cancer treatment, particularly for patients with low expression of IFNg in the TME. Significance: These findings reveal the dose-dependent effect of IFNg in inducing tumor stemness and elucidate the distinct molecular mechanisms activated by IFNg in a dosedependent manner.

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.

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Chronic obstructive pulmonary disease (COPD) is a chronic lung disease with progressive airflow limitation and functional decline. The pathogenic mechanisms for this disease include oxidative stress, inflammatory responses, disturbed protease/antiprotease equilibrium, apoptosis/proliferation imbalance, senescence, autophagy, metabolic reprogramming, and mitochondrial dysfunction. The Wnt signaling pathway is an evolutionarily conserved signaling pathway that is abnormal in COPD, including chronic bronchitis and pulmonary emphysema. Furthermore, Wnt signaling has been shown to modulate aforementioned cellular processes involved in COPD. From this perspective, we provide an updated understanding of the crosstalk between Wnt signal and these cellular processes, and highlight the crucial role of the Wnt signal during the development of COPD. We also discuss the potential for targeting the Wnt signal in future translational and pharmacological therapeutics aimed at prevention and treatment of this disease.

Epithelial–mesenchymal transition (EMT) is considered to be the key event in the formation of pulmonary fibrosis (PF). High‐mobility group box 1 (HMGB1) is a novel mediator of EMT. Nuclear factor erythroid 2‐related factor 2 (Nrf2) is a critical transcription factor for protecting against PF. However, it is unknown the relationship between Nrf2 and HMGB1 in EMT‐mediated PF. Bleomycin (BLM)‐induced PF in Nrf2‐knockout (Nrf2−/−) and wild‐type (WT) mice and transforming growth factor β1 (TGF‐β1)‐induced EMT in rat type II alveolar epithelial cell line (RLE‐6TN) and human alveolar epithelial cell line (A549) were established to observe the relationship among Nrf2, HMGB1, and EMT by western blot and immunohistochemistry. BLM‐induced EMT was more severe and the expression of HMGB1 was more increased in Nrf2 −/− mice compared with WT mice. In vitro, Nrf2 activation attenuated TGF‐β1‐induced EMT and ROS production accompanied by the downregulation of HMGB1. In contrast, silencing Nrf2 enhanced TGF‐β1‐induced EMT and ROS production along with increased the protein expression and the release of HMGB1. Moreover, HMGB1 activation aggravated TGF‐β1‐induced EMT and HMGB1 deficiency alleviated TGF‐β1‐induced EMT. Furthermore, HMGB1 silence attenuated the protective effect of Nrf2 on EMT. These findings suggest downregulation of HMGB1, which is required for the protective role of Nrf2 in EMT‐mediated PF and provide an important therapeutic target for PF.