Polystyrene microplastics induce pulmonary fibrosis by promoting alveolar epithelial cell ferroptosis through cGAS/STING signaling.

Polystyrene microplastics (PS-MPs) are new types of environmental pollutant that have garnered significant attention in recent years since they were found to cause damage to the human respiratory system when they are inhaled. The pulmonary fibrosis is one of the serious consequences of PS-MPs inhalation. However, the impact and underlying mechanisms of PS-MPs on pulmonary fibrosis are not clear. In this study, we studied the potential lung toxicity and PS-MPs-developed pulmonary fibrosis by long-term intranasal inhalation of PS-MPs. The results showed that after exposing to the PS-MPs, the lungs of model mouse had different levels of damage and fibrosis. Meanwhile, exposing to the PS-MPs resulted in a markedly decrease in glutathione (GSH), an increase in malondialdehyde (MDA), and iron overload in the lung tissue of mice and alveolar epithelial cells (AECs). These findings suggested the occurrence of PS-MP-induced ferroptosis. Inhibitor of ferroptosis (Fer-1) had alleviated the PS-MPs-induced ferroptosis. Mechanically, PS-MPs triggered cell ferroptosis and promoted the development of pulmonary fibrosis via activating the cGAS/STING signaling pathway. Inhibition of cGAS/STING with G150/H151 attenuated pulmonary fibrosis after PS-MPs exposure. Together, these data provided novel mechanistic insights of PS-MPs-induced pulmonary fibrosis and a potential therapeutic paradigm.

IL-17A promotes tumorigenesis and upregulates PD-L1 expression in non-small cell lung cancer.

BACKGROUND: The tumor microenvironment plays a key role in non-small cell lung cancer (NSCLC) development and also influences the effective response to immunotherapy. The pro-inflammatory factor interleukin-17A mediates important immune responses in the tumor microenvironment. In this study, the potential role and mechanisms of IL-17A in NSCLC were investigated. METHODS: We detected IL-17A by immunohistochemistry (IHC) in 39 NSCLC patients. Its expression was correlated with the programmed cell death-ligand1 (PD-L1). IL-17A knockdown and overexpression in A549 and SPC-A-1 cell models were constructed. The function of IL-17A was examined in vitro by wound healing, migration, invasion, plate colony formation and T cell killing assay. Western blot analysis, immunofluorescence assay and IHC were performed to investigate the regulation effects of IL-17A on autophagy in A549 and SPC-A-1. The effect of IL-17A on ROS/Nrf2/p62 signaling pathway was detected. Subcutaneous tumor models were established to examine the tumor-promoting effect of IL-17A in vivo and its effect on immunotherapy. RESULTS: We found a prevalent expression of IL-17A in NSCLC tumor tissues and it was positively correlated with PD-L1 expression (r = 0.6121, p < 0.0001). In vitro, IL-17A promotes lung cancer cell migration, invasion and colony formation ability. Moreover, IL-17A upregulated N-cadherin, Twist, and Snail, and downregulated E-cadherin in NSCLC cells. IL-17A enhanced cell survival in the T cell killing assay. Mechanistically, IL-17A induced ROS production and increased Nrf2 and p62 expression, thereby inhibiting autophagy and reducing PD-L1 degradation. In vivo experiments, anti-IL-17A monoclonal antibody alone slowed the growth of subcutaneous tumors in mice. When combined with anti-PD-L1 monoclonal antibody, tumor tissue expression of PD-L1 was reduced and the therapeutic effect was diminished. CONCLUSION: We found that IL-17A promoted NSCLC progression and inhibited autophagy through the ROS/Nrf2/p62 pathway leading to increased PD-L1 expression in cancer cells. Modulation of IL-17A may affect the therapeutic efficacy of immunotherapy.

Risk factors and prognostic value of osteoporosis in hospitalized patients with bronchiectasis.

BACKGROUND: The risk factors for osteoporosis and its prognostic value in patients with bronchiectasis is not well characterized. We explored the risk factors for osteoporosis and its prognostic impact in hospitalized non-cystic fibrosis bronchiectasis (NCFB) patients in Southeast China. METHODS: This observational cohort study consecutively enrolled 179 hospitalized patients with NCFB bronchiectasis between 2017 and 2021. The risk factors and the impact of osteoporosis on all-cause mortality were assessed. RESULTS: 21.2% (38/179) of hospitalized NCFB patients were diagnosed with osteoporosis. Patients with osteoporosis had more severe symptoms (assessed by chronic airway assessment test, CAT, median 22 vs. 17, P = 0.017), poorer quality of life (assessed by St. George Respiratory Questionnaires, SQRC, median 42 vs. 27, P = 0.007), more severe disease stage (assessed by bronchiectasis severity index, BSI, median 14 vs. 11, P = 0.02), more comorbidities (assessed by Bronchiectasis Aetiology Comorbidity Index, BACI, median 5 vs. 4, P = 0.021) than patients without. Age, female sex, anemia, post-infection, and history of regular inhaled corticosteroid treatment were independent risk factors for osteoporosis in those patients. 21 patients (11.7%) died over a median follow-up period of 32 months. The all-cause mortality in NCFB patients with osteoporosis [28.94% (11/38)] was significantly higher than those without osteoporosis [7.09% (10/141)] [hazard ratio (HR) 5.34, 95% confidence interval (CI) 2.26-12.67, P < 0.001]. After adjusting for BSI and other confounding factors, osteoporosis was still independently associated with all-cause mortality in hospitalized NCFB patients (HR 4.29, 95% CI 1.75-10.49, P < 0.001). CONCLUSIONS: Osteoporosis had an independent effect on all-cause mortality in hospitalized NCFB patients. Management of comorbidities, including bone health, is a critical aspect of treating NCFB patients.

TM4SF19-AS1 facilitates the proliferation of lung squamous cell carcinoma by recruiting WDR5 to mediate TM4SF19.

BACKGROUND: As reported, long non-coding RNAs are a pivotal player in lung squamous cell carcinoma (LSCC) progression. We noticed the remarkably upregulated transmembrane-4-l-six-family-19 antisense RNA 1 (TM4SF19-AS1) in LSCC and further demonstrated the function it played in LSCC and the possible molecular mechanism. METHODS: Via bioinformatics approach, we evaluated TM4SF19-AS1 and TM4SF19 levels in LSCC tissue, and real-time quantitative polymerase chain reaction (qRT-PCR) and Western blot revealed their mRNA and protein levels in LSCC cells. Cell Counting Kit-8 and colony formation assays analyzed the proliferation ability of LSCC cells, and cell adhesion ability was detected via cell adhesion assay. RNA immunoprecipitation and chromatin immunoprecipitation analyzed the underlying mechanism of TM4SF19-AS1 regulating its target, while methylation-specific PCR indicated the methylation level of TM4SF19-AS1. RESULTS: TM4SF19-AS1 was markedly upregulated in LSCC. Functional assays revealed that TM4SF19-AS1 could facilitate the proliferation and adhesion of LSCC. Besides, we revealed the mechanism of TM4SF19-AS1 regulation that it directly bound to WD repeat-containing protein 5 (WDR5), and was then recruited to TM4SF19 promoter region, which activated DNA demethylation, thereby suppressing malignant LSCC progression. CONCLUSION: Our research demonstrated that TM4SF19-AS1 affected LSCC cell proliferation by recruiting WDR5 to manipulate transmembrane-4-lsix-family-member-19 (TM4SF19), which offers a new observation on LSCC pathogenesis, indicating that TM4SF19-AS1 is able to be a promising target for LSCC treatment.

Risk Factors Associated with Impairment in Pulmonary Diffusing Capacity among Patients with Noncystic Fibrosis Bronchiectasis.

This study aims to investigate the risk factors associated with impaired pulmonary diffusing capacity among patients with noncystic fibrosis bronchiectasis (NCFB) and compare the predictive value of several scoring systems for the impairment in these patients. Between July 2019 and June 2021, patients who were admitted to the hospital and diagnosed with NCFB were included in this study. Clinical data were collected and analyzed retrospectively. A total of 175 NCFB patients were included in the analysis. Multivariate logistic regression analysis revealed that impaired pulmonary diffusing capacity diagnosed by carbon monoxide diffusing capacity (DLCO) <80% prediction was associated with age, Reiff score, body mass index (BMI), comorbid chronic obstructive pulmonary disease (COPD), and interstitial lung disease (ILD). Disease duration, frequency of exacerbation, hemoglobin level, and COPD were independent risk factors for impaired pulmonary diffusing capacity diagnosed by DLCO/alveolar volume (VA) <80% prediction. Age, Reiff score, and smoking status were independent risk factors for decreased VA diagnosed by VA <80% prediction. The areas under the curve (AUC) for discrimination of DLCO <80% prediction were 0.822 (0.760-0.885) for Bronchiectasis Severity Index (BSI), 0.787 (0.718-0.856) for FACED, 0.795 (0.729-0.863) for E-FACED, and 0.767 (0.694-0.839) for modified Medical Research Council (mMRC) scores; the AUC for discrimination of DLCO/VA <80% prediction was 0.803 (0.727-0.880) for BSI, 0.752 (0.669-0.835) for FACED, 0.757 (0.676-0.839) for E-FACED, and 0.762 (0.679-0.845) for mMRC, respectively. The BSI had the largest AUC, but the differences between those scoring systems had no statistical significance (P=0.181 for DLCO <80% prediction and P=0.105 for DLCO/VA <80% prediction). The mMRC score (up to 2 grades) showed a high specificity for discriminating diffusing dysfunction (88.3% for DLCO <80% prediction and 76.1% for DLCO/VA <80% prediction). In NCFB patients, several factors such as age, Reiff score, BMI, exacerbation frequency, disease duration, and comorbid COPD and ILD were associated with impaired pulmonary diffusing capacity, which requires more attention in managing those patients. In addition, several scoring methods, including a simple index of mMRC, showed a comparable and moderate performance for predicting pulmonary diffusing impairment and would facilitate the systematic evaluation of the diffusing capacity of NCFB patients.