Epithelial IL5RA promotes epithelial-mesenchymal transition in pulmonary fibrosis via Jak2/STAT3 cascade.

Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis.

p21-activated kinase 2 binds to transcription factor SOX2 and up-regulates DEK to promote the progression of lung squamous cell carcinoma.

Lung squamous cell carcinoma (LSCC) is a prevalent and progressive subtype of lung cancer. This study aimed to substantiate the regulatory effect of the PAK2/SOX2/DEK axis on the LSCC development. LSCC tissues (n = 83) and adjacent normal tissues were collected and SOX2 expression was determined by qRT-PCR and Western blotting. Correlation between SOX2 expression and the prognosis of LSCC patients was then explored utilizing Kaplan-Meier analysis. Co-immunoprecipitation and glutathione-S-transferase pull-down assays were conducted to validate the binding of SOX2 to DEK. Gain- and loss- of function assays were then performed on LSCC cells, with CCK-8 and Transwell assays applied to detect the malignant behaviors of cells. A mouse xenograft model of LSCC was further established for in vivo validation. The expression levels of SOX2, PAK2 and DEK were up-regulated in LSCC tissues and cells. SOX2 overexpression was correlated with poor prognosis of LSCC patients. Knockdown of SOX2 weakened the viability and the migratory and invasive potential of LSCC cells. Further, PAK2 directly interacted with SOX2. PAK2 overexpression accelerated the malignant phenotypes of LSCC cells through interplay with SOX2. Moreover, SOX2 activated the expression of DEK, and silencing DEK attenuated the malignant behaviors of LSCC cells. In conclusion, PAK2 could bind to the transcription factor SOX2 and thus activate the expression of DEK, thereby driving the malignant phenotypes of LSCC cells both in vivo and in vitro.

Mesenchymal stem cell-derived extracellular vesicles suppress the fibroblast proliferation by downregulating FZD6 expression in fibroblasts via micrRNA-29b-3p in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), a progressive and fatal lung disease, usually leads to an irreversible distortion of the pulmonary structure. The functional roles of bone marrow-derived mesenchymal stem cells (BMSC)-secreted extracellular vesicles (EVs) in fibroblasts have been implicated, yet their actions in the treatment of IPF are not fully understood. This study investigated the roles of BMSC-derived EVs expressing miR-29b-3p in fibroblasts in IPF treatment. EVs derived from BMSCs were successfully isolated and could be internalized by pulmonary fibroblasts, and Cell Counting Kit-8 (CCK-8) and Transwell assay results identified that EVs inhibited the activation of fibroblast in IPF. miR-29b-3p, frizzled 6 (FZD6), α-skeletal muscle actin (α-SMA), and Collagen I expressions were examined, which revealed that miR-29b-3p was poorly expressed and FZD6, α-SMA, and Collagen I were overexpressed in pulmonary tissues. Dual-luciferase reporter assay results demonstrated that miR-29b-3p could inversely target FZD6 expression. The gain- and loss-of-function assays were conducted to determine regulatory effects of FZD6 and miR-29b-3p on IPF. CCK-8 and Transwell assays results displayed that BMSCs-derived EVs overexpressing miR-29b-3p contributed to inhibited pulmonary interstitial fibroblast proliferation, migration, invasion, and differentiation. Furthermore, the effects of BMSCs-derived EVs overexpressing miR-29b-3p on IPF progression were assessed in vivo, which confirmed the repressive effects of BMSCs-derived EVs overexpressing miR-29b-3p on IPF progression. Collectively, BMSCs-derived EVs overexpressing miR-29b-3p relieve IPF through FZD6.

MicroRNA-448 overexpression inhibits fibroblast proliferation and collagen synthesis and promotes cell apoptosis via targeting ABCC3 through the JNK signaling pathway.

Idiopathic pulmonary fibrosis (IPF) is a condition that results in the progressive deterioration of lung function with poor prognosis. The current study is aimed at exploring how microRNA-448 (miR-448) targeting ABCC3 affects fibroblast proliferation, apoptosis, and collagen synthesis of mice with IPF via the Jun N-terminal kinase (JNK) signaling pathway. Bioinformatics and dual-luciferase polymerase chain reaction were used to predict the relationship of miR-448 and ABCC3. The expression of miR-448 and ABCC3 was detected in IPF tissues. Using IPF mouse models, lung fibroblasts for the experiments were treated with miR-448 mimic, miR-448 inhibitor, si-ABCC3, or SP600125 (inhibitor of JNK) to evaluate the cell proliferation and apoptosis in response to miR-448. Reverse transcription quantitative polymerase chain reaction and western blot analysis were used to identify the expression of miR-448, ABCC3, and the activation of the JNK signaling pathway. ABCC3 was targeted and downregulated by miR-448 based on bioinformatics prediction and dual-luciferase reporter gene assay. Additionally, miR-448 was found to be highly expressed in IPF lung tissues with low expression levels of ABCC3. In response to the treatment of miR-448 mimic or si-ABCC3, lung fibroblasts exhibited decreased cell proliferation and increased apoptotic rates, whereas the miR-448 inhibitor reversed the conditions. Notably, we also found that miR-448 mimic inhibited the JNK signaling pathway. In conclusion, by using miR-448 to target and downregulate ABCC3 to block the JNK signaling pathway in mice with IPF, we found an increase in fibroblast apoptosis, inhibited cell proliferation, and decreased collagen synthesis of fibroblasts.

Sinensetin protects against pulmonary fibrosis via inhibiting Wnt/ß-Catenin signaling pathway.

Pulmonary fibrosis is a fatal lung disease characterized by progressive fibroblast proliferation and extensive extracellular matrix (ECM) deposition. Although great efforts have been placed to understand the pathogenesis and explore therapeutic strategies, the treatment options for pulmonary fibrosis are very limited and the prognosis of pulmonary fibrosis patients remains poor. Sinensetin is a polymethoxylated flavone derived from citrus fruits, and has been characterized with anti-fibrotic property. However, the underlying mechanism is still unclear. In present study, combining in vitro and in vivo models, we revealed for the first time that sinensetin can protect against pulmonary fibrosis via inhibiting glycogen synthase kinase-3ß (GSK-3ß)-mediated Wnt/ß-Catenin signaling pathway. According to our results, the activation of Wnt/ß-Catenin signaling pathway in pulmonary fibrosis is responsible for fibroblast proliferation and differentiation to form ECM-producing myofibroblasts. Sinensetin treatment dephosphorylates and activates GSK-3ß, a component of ß-Catenin destruction complex, which induces ß-Catenin degradation and deactivates Wnt/ß-Catenin-mediated fibroblast proliferation and differentiation. As a result, myofibroblasts formation and ECM production are reduced and the progression of pulmonary fibrosis is suppressed. These results not only advance our knowledge on the pharmacological activities of sinensetin, but also provide novel insights on pulmonary fibrosis treatment.

[Corrigendum] Overexpression of lncRNA EGFR­AS1 is associated with a poor prognosis and promotes chemotherapy resistance in non­small cell lung cancer.

After the publication of the article, the authors have realized that the affiliation presented for the joint co­author listed on the paper (Jian­Ren Tu) was incorrect. The correct author list (and affiliations) should therefore have been published as follows: Yu­Hua Xu1*, Jian­Ren Tu2*, Tian­Tian Zhao3, Shi­Guang Xie3 and Sheng­Bo Tang4. 1Department of Cardiovascular Medicine, Jiangxi Chest Hospital, Nanchang, Jiangxi 330006; 2Department of Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi 330029; Departments of 3Respiratory Medicine and 4Medical Oncology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 330006, P.R. China. *Contributed equally. The authors apologize for their oversight, and for any inconvenience that this has caused. [the original article was published in International Journal of Oncology 54: 295­305, 2019; DOI: 10.3892/ijo.2018.4629].

Overexpression of lncRNA EGFR­AS1 is associated with a poor prognosis and promotes chemotherapy resistance in non­small cell lung cancer.

Chemoresistance is one of the most important biological elements affecting the progression and prognosis of cancer. Long non­coding RNAs (lncRNAs) are important regulators and are aberrantly expressed in various types of cancer in humans, including non­small cell lung cancer (NSCLC). The present study aimed to investigate the effect of lncRNAs on NSCLC resistance to chemotherapy. The relative expression level of epidermal growth factor receptor antisense RNA 1 (EGFR­AS1) was quantified by reverse transcription-quantitative polymerase chain reaction analysis in NSCLC tissues, paired adjacent normal tissues, patient plasma and NSCLC cell lines, and its association with prognosis was assessed by multivariate analysis. The biological functions of EGFR­AS1 in NSCLC cells were determined in vitro. It was found that EGFR­AS1 was abnormally upregulated in NSCLC tissues compared with adjacent normal lung tissues. Furthermore, patients with NSCLC with increased expression of EGFR­AS1 had a poor prognosis. EGFR­AS1 knockdown significantly inhibited NSCLC malignancy in vitro, including cell proliferation and chemoresistance. Furthermore, the expression levels of EGFR­AS1 were increased in plasma samples from patients with cisplatin-based chemotherapy resistance. Bioinformatics analysis and a luciferase reporter assay confirmed that EGFR­AS1 mediated cell proliferation and chemoresistance through directly binding to microRNA­223. Therefore, EGFR­AS1 overexpression-induced chemoresistance can contribute to poor prognosis in NSCLC.

[Bilateral sequential whole lung lavage in the same treatment session for pulmonary alveolar proteinosis].

OBJECTIVE: To study the safety and effectiveness of bilateral sequential whole lung lavage in the same treatment session for pulmonary alveolar proteinosis. METHODS: Twelve times bilateral sequential whole lung lavage in the same treatment session were performed under general anaesthesia using a double lumen endotracheal tube for 10 cases of pulmonary alveolar proteinosis. The volume of lavage, return volume and the return rate were calculated. The efficacy was evaluated according to the improvement of symptoms, pulmonary function and arterial blood gas analysis data. RESULTS: Twelve times bilateral sequential whole lung lavage in the same treatment session were performed successfully for the 10 cases of pulmonary alveolar proteinosis. The total volume of lavage was (26,417+/-7,064) ml, the return volume was (25,962+/-7,023) ml, the time of lavage was (192+/-26) minutes. The symptoms and chest radiograph were improved immediately after the procedure for all patients. The alveolar to arterial oxygen tension difference was decreased significantly. Arterial oxygen tensions were increased but no significant difference was reached. There was no significant immediate improvement for the pulmonary function. No complications were noted but pulmonary edema in one patient. CONCLUSION: Bilateral sequential whole lung lavage in the same treatment session is a safe and effective procedure for treatment of pulmonary alveolar proteinosis.