Corrigendum: Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice.

[This corrects the article DOI: 10.3389/fimmu.2021.594330.].

Epithelium-derived IL17A Promotes Cigarette Smoke-induced Inflammation and Mucus Hyperproduction.

The airway epithelium is a central modulator of innate and adaptive immunity in the lung. IL17A expression was found to be increased in the airway epithelium; however, the role of epithelium-derived IL17A in chronic obstructive pulmonary disease (COPD) remains unclear. In this study, we aimed to determine whether epithelium-derived IL17A regulates inflammation and mucus hyperproduction in COPD by using a cultured human bronchial epithelial (HBE) cell line in vitro and an airway epithelium IL17A-specific knockout mouse in vivo. Increased IL17A expression was observed in the mouse airway epithelium upon cigarette smoke (CS) exposure or in a mouse model of COPD that was induced by using CS and Eln (elastin). CS extract (CSE) also triggered IL17A expression in HBE cells. Blocking IL17A or IL17RA (IL17 receptor A) effectively attenuated CSE-induced MUC5AC and the inflammatory cytokines IL6, TNF-α, and IL1ß in HBE cells, suggesting that IL17A mediates CSE-induced inflammation and mucin production in an autocrine manner. CSE activated p-JUN (phospho-JUN) and p-JNK (phospho-c-Jun N-terminal kinase), which were also reduced by IL17RA siRNA, and JUN siRNA attenuated CSE-induced IL6 and MUC5AC. In vivo, selective knockout of IL17A in the airway epithelium markedly reduced the neutrophilic infiltration in BAL fluid, peribronchial inflammation, proinflammatory mediators (CXCL1 [CXC ligand 1] and CXCL2), and mucus production in a COPD mouse model. We showed a novel function of airway epithelium-derived IL17A, which can act locally in an autocrine manner to amplify inflammation and increase mucus production in COPD pathogenesis.

Autophagy Promotes Cigarette Smoke-Initiated and Elastin-Driven Bronchitis-Like Airway Inflammation in Mice.

Cigarette smoke (CS)-induced macrophage activation and airway epithelial injury are both critical for the development of chronic obstructive pulmonary disease (COPD), while the eventual functions of autophagy in these processes remain controversial. We have recently developed a novel COPD mouse model which is based on the autoimmune response sensitized by CS and facilitated by elastin. In the current study, we therefore utilized this model to investigate the roles of autophagy in different stages of the development of bronchitis-like airway inflammation. Autophagic markers were increased in airway epithelium and lung tissues, and Becn+/- or Lc3b-/- mice exhibited reduced neutrophilic airway inflammation and mucus hyperproduction in this COPD mouse model. Moreover, treatment of an autophagic inhibitor 3-methyladenine (3-MA) either during CS-initiated sensitization or during elastin provocation significantly inhibited the bronchitis-like phenotypes in mice. Short CS exposure rapidly induced expression of matrix metallopeptidase 12 (MMP12) in alveolar macrophages, and treatment of doxycycline, a pan metalloproteinase inhibitor, during CS exposure effectively attenuated the ensuing elastin-induced airway inflammation in mice. CS extract triggered MMP12 expression in cultured macrophages, which was attenuated by autophagy impairment (Becn+/- or Lc3b-/-) or inhibition (3-MA or Spautin-1). These data, taken together, demonstrate that autophagy mediates both the CS-initiated MMP12 activation in macrophages and subsequent airway epithelial injury, eventually contributing to development COPD-like airway inflammation. This study reemphasizes that inhibition of autophagy as a novel therapeutic strategy for CS-induced COPD.

Elevated SLC6A6 expression drives tumorigenesis and affects clinical outcomes in gastric cancer.

AIM: To assess SLC6A6 expression in gastric cancer, its correlation with patients' clinicopathological features and survival, and the possible epigenetic regulation mechanism. METHODS: Expression profiles and methylation data were obtained from the Gene Expression Omnibus database and the Cancer Genome Atlas. The SLC6A6's protein level were obtained from the Human Protein Atlas. Correlations between SLC6A6 expression and clinicopathological features were assessed using the χ2 test, and survival by the Kaplan-Meier analysis. By analyzing methylation data, the mechanisms of SLC6A6 dysregulation were investigated. RESULTS: SLC6A6 expression was higher in gastric cancer, and indicated poor prognosis. Low-methylation levels were significantly related to high SLC6A6 expression. CONCLUSION: SLC6A6 may be a potential prognostic marker and therapeutic target. Hypomethylation contributes to SLC6A6 upregulation in gastric cancer.

Comparison of Outcomes following Mitral Valve Repair versus Replacement for Chronic Ischemic Mitral Regurgitation: A Meta-Analysis.

Background The selection of mitral valve surgery, including mitral valve repair and mitral valve replacement, is still an important dilemma for patients with chronic ischemic mitral regurgitation. We carry out a meta-analysis to evaluate the effectiveness and safety of mitral valve repair versus replacement for ischemic mitral regurgitation. Methods We searched PubMed, Embase, the Cochrane Library, and Web of Science to identify studies from their inception to July 2015. A meta-analysis was performed using RevMan 5.3 software (Cochrane Collaboration, Oxford, United Kingdom). A random-effect model was used and sensitivity analysis was performed on studies reporting on operation after 2000, high-quality studies, and those studies reporting on more than 150 patients. Result A total of 2,324 patients were identified from 10 retrospective studies. Mitral valve repair was associated with a trend toward lower operative mortality (odds ratio [OR] = 0.45; 95% confidence interval [CI]: 0.31-0.65; p < 0.0001) and higher recurrence of mitral regurgitation (OR = 5.89; 95% CI: 3.34-10.39; p < 0.00001). Five-year survival rate was similar between the two groups (OR = 1.20; 95% CI: 0.88-1.65; p = 0.25). No differences in reoperation, the incidence of acute renal failure and acute respiratory failure, the length of ICU stay, and the length of hospital stay were found. Conclusion Mitral valve repair was associated with lower operative mortality but a higher recurrence of mitral regurgitation compared with mitral valve replacement. Owing to the limited quantity and quality of the included studies, this conclusion still needs to be further confirmed by conducting more high-quality, multicenter randomized controlled trials with large sample size.

MicroRNA-320a acts as a tumor suppressor by targeting BCR/ABL oncogene in chronic myeloid leukemia.

Accumulating evidences demonstrated that the induction of epithelial-mesenchymal transition (EMT) and aberrant expression of microRNAs (miRNAs) are associated with tumorigenesis, tumor progression, metastasis and relapse in cancers, including chronic myeloid leukemia (CML). We found that miR-320a expression was reduced in K562 and in CML cancer stem cells. Moreover, we found that miR-320a inhibited K562 cell migration, invasion, proliferation and promoted apoptosis by targeting BCR/ABL oncogene. As an upstream regulator of BCR/ABL, miR-320a directly targets BCR/ABL. The enhanced expression of miR-320a inhibited the phosphorylation of PI3K, AKT and NF-κB; however, the expression of phosphorylated PI3K, AKT and NF-κB were restored by the overexpression of BCR/ABL. In K562, infected with miR-320a or transfected with SiBCR/ABL, the protein levels of fibronectin, vimentin, and N-cadherin were decreased, but the expression of E-cadherin was increased. The expression of mesenchymal markers in miR-320a-expressing cells was restored to normal levels by the restoration of BCR/ABL expression. Generally speaking, miR-320a acts as a novel tumor suppressor gene in CML and miR-320a can decrease migratory, invasive, proliferative and apoptotic behaviors, as well as CML EMT, by attenuating the expression of BCR/ABL oncogene.