Respiratory Research最新文献

{"title":"Loss of PTPN21 disrupted mitochondrial metabolic homeostasis and aggravated experimental pulmonary fibrosis.","authors":"Hui Lian, Kai Xu, Airu Chang, Yaxuan Wang, Shuaichen Ma, Lianhui Cheng, Wenyu Zhao, Cong Xia, Lan Wang, Guoying Yu","doi":"10.1186/s12931-024-03041-4","DOIUrl":"10.1186/s12931-024-03041-4","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is a high-mortality lung disease with unclear pathogenesis. Convincing evidence suggests that an imbalance in mitochondrial homeostasis resulting from repeated injury to alveolar epithelial type 2 cells (AEC2) underlies IPF. Non-receptor protein tyrosine phosphatase 21 (PTPN21) performs various functions in cancer; however, its role in IPF has not been studied. This study aimed to investigate the role of PTPN21 in lung fibrosis. The experimental results showed that loss of PTPN21 exacerbated lung fibrosis by increasing cell numbers in bronchoalveolar lavage fluid, lung hydroxyproline content, and extracellular matrix protein expression of fibronectin and α-smooth muscle actin (α-SMA) in bleomycin-challenged mouse lungs. In A549 cells (AEC2), knockdown of PTPN21 suppressed focal adhesion and migration, reduced mitochondrial fission and increased fusion, increased the level of mitochondrial superoxide, decreased mitochondrial membrane potential and ATP levels. Simultaneously, knockdown of PTPN21 impaired autophagy, and increased intracellular reactive oxygen species levels. Treatment of fibroblasts (MRC-5) and primary human lung fibroblasts (PHLF)) with the supernatant from PTPN21-knockdown A549 cells increased the expression of fibronectin, collagen 1 and α-SMA. Conversely, overexpression of PTPN21 in A549 cells produced opposite effects. However, treatment of MRC-5 and PHLF with the supernatant from PTPN21-overexpressing A549 cells only slightly reduced the expression of fibronectin, collagen 1 in MRC-5 cells, but did not change the expression of α-SMA. In summary, this study revealed that the loss of PTPN21 in epithelial cells disrupted mitochondrial metabolic homeostasis, leading to epithelial cell inactivation and increased the deposition of extracellular matrix proteins in fibroblasts, thereby exacerbating experimental pulmonary fibrosis.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"426"},"PeriodicalIF":5.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781627","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-33-experienced group 2 innate lymphoid cells in the lung are poised to enhance type 2 inflammation selectively in adult female mice.","authors":"Haya Aldossary, Rami Karkout, Katalina Couto, Lydia Labrie, Elizabeth D Fixman","doi":"10.1186/s12931-024-03043-2","DOIUrl":"10.1186/s12931-024-03043-2","url":null,"abstract":"<p><p>While Th2 adaptive immunity has long been considered to orchestrate type 2 inflammation in the allergic lung, group 2 innate lymphoid cells (ILC2s), with the ability to produce a similar profile of type 2 cytokines, likely participate in lung inflammation in allergic asthma. ILC2s are also implicated in sex disparities in asthma, supported by data from murine models showing they are inhibited by male sex hormones. Moreover, larger numbers of ILC2s are present in the lungs of female mice and are correlated with greater type 2 inflammation. Lung ILC2s exhibit intriguing memory-like responses, though whether these differ in males and females does not appear to have been addressed. We have examined type 2 lung inflammation in adult male and female Balb/c mice following delivery of IL-33 to the lung. While the number of ILC2s was elevated equally in males and females four weeks after exposure to IL-33, ILC2s from female mice expressed higher levels of ST2, the IL-33 cognate receptor subunit, and a larger proportion of ILC2s from females expressed the IL-25 receptor (IL-25R), which has previously been linked to memory-like ILC2 responses in mice. Our data show that the subset of ILC2s expressing IL-25R, upon activation, was more likely to produce IL-5 and IL-13. Moreover, STAT6 was absolutely required for enhanced responsiveness in this model system. Altogether, our data show that enhanced type 2 inflammation in females is linked to durable changes in ILC2 subsets with the ability to respond more robustly, in a STAT6-dependent manner, upon secondary activation by innate epithelial-derived cytokines.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"427"},"PeriodicalIF":5.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"T follicular helper cell is essential for M2 macrophage polarization and pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension.","authors":"Cheng Li, Pingping Liu, Hao Zhu, Huan Yang, Jun Zha, Huiling Yao, Shaoze Zhang, Jin Huang, Guang Li, Gang Jiang, Yongliang Jiang, Aiguo Dai","doi":"10.1186/s12931-024-03058-9","DOIUrl":"10.1186/s12931-024-03058-9","url":null,"abstract":"<p><strong>Background: </strong>Hypoxia-induced pulmonary hypertension (HPH) is a subgroup of type 3 pulmonary hypertension that may cause early right ventricular failure and eventual cardiac failure, which lacks potential therapeutic targets. Our previous research demonstrated that T follicular helper (T_FH) cells that produce IL-21 were involved in HPH. However, the molecular mechanisms of T_FH/IL-21-mediated pathogenesis of HPH have been elusive. Here we investigate the role of T_FH cells and IL-21 in HPH.</p><p><strong>Methods: </strong>Studies were performed in C57BL/6 mice or IL-21 knockout mice exposed to chronic hypoxia to induce PH, and examined by hemodynamics. Molecular and cellular studies were performed in mouse lung and pulmonary arterial smooth muscle cells (PASMCs). M2 signature gene (Fizz1), M1 signature genes (iNos, IL-12β and MMP9), GC B cell and its marker GL-7, caspase-1, M2 macrophages, T_FH cells, Bcl-6 and IL-21 level were measured. Proliferation rate of PASMCs was measured by EdU. Pyroptosis was assessed using Hoechst 33,342/PI double fluorescent staining.</p><p><strong>Results: </strong>In response to chronic hypoxia exposure-induced pulmonary hypertension, IL-21^-/- mice or downregulation of T_FH cells in WT mice developed blunted pulmonary hypertension, attenuated pulmonary vascular remodelling. Furthermore, chronic hypoxia exposure significantly increased the germinal center (GC) B cell responses, which were not present in IL-21^-/- mice or downregulation of T_FH cells in WT mice. Importantly, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Consistently, significantly enhanced expression of M2 macrophage marker Fizz1 were detected in the bronchoalveolar lavage fluid of HPH mice. Moreover, alveolar macrophages that had been cultivated with IL-21 promoted PASMCs proliferation and pyroptosis in vitro, while a selective CX3CR1 antagonist, AZD8797 (AZD), significantly attenuated the proliferation and pyroptosis of the PASMCs. Finally, ECM1 knockdown promoted IL-2-STAT5 signaling and inhibited Bcl-6 signaling to inhibit T_FH differentiation in HPH.</p><p><strong>Conclusions: </strong>T_FH/IL-21 axis amplified pulmonary vascular remodelling in HPH. This involved M2 macrophage polarization, PASMCs proliferation and pyroptosis. These data suggested that T_FH/IL-21 axis may be a novel therapeutic target for the treatment of HPH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"428"},"PeriodicalIF":5.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619207/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human adenovirus type 7 (HAdV-7) infection induces pulmonary vascular endothelial injury through the activation of endothelial autophagy.","authors":"Zhihe Chen, Zhongying Yang, Lifen Rao, Changgen Li, Na Zang, Enmei Liu","doi":"10.1186/s12931-024-03025-4","DOIUrl":"10.1186/s12931-024-03025-4","url":null,"abstract":"<p><strong>Background: </strong>HAdV-7 is a prevalent pathogen that can cause severe pneumonia in children. Previous studies have shown a significant increase in serum levels of vascular permeability factor (VPF/VEGF) and viral load in pediatric patients with fatal HAdV-7 infection, suggesting potential damage to the pulmonary vascular endothelium. Further research is necessary to elucidate the underlying mechanism.</p><p><strong>Methods: </strong>The human lung microvascular endothelial cell line-5a and human CD46 mice were used for in vitro and in vivo experiments, respectively. RNA-seq was employed for correlative omics analysis. Viral infection and copy status were examined using transmission electron microscopy to observe virus particles, immunofluorescence to detect the viral protein Hexon, and qPCR to assess HAdV-7 fiber gene copies. Various methods, including ELISAs for VEGF and other injury markers, the CCK8 assay for cell viability, and flow cytometry for endothelium numbers, were employed to evaluate endothelial damage. Acute lung injury severity was evaluated by scoring pathological inflammation and measuring pulmonary vascular permeability. Autophagy activation was assessed by observing autophagosomes and validating marker proteins.</p><p><strong>Results: </strong>GSEA analysis showed significant enrichment of gene sets related to endothelial functions (barrier, defense, and regeneration) and ALI in the HAdV-7-infected group. GO analysis indicated an enrichment of autophagy-related pathways linked to cell death. Subsequently, successful signs of HAdV-7 infection and replication were observed in the endothelium, including cytopathic effects, intracellular virions, and increased HAdV-7 fiber gene copies. Endothelial injury, including mitochondrial damage, decreased endothelium, and elevated levels of endothelial injury markers such as VEGF, sICAM-1, sVCAM-1, E-selectin, ESM1, MCP1, and IL1β were observed after HAdV-7 infection. Additionally, evidence of leaky lung blood vessels and ALI was observed, including progressive weight loss, elevated pulmonary vascular permeability, and severe lung consolidation. Furthermore, HAdV-7 infection induced autophagosome formation in the endothelium and triggered complete cell autophagy. Importantly, inhibiting autophagic flux reduced VEGF levels and other endothelial injury markers, decreased viral load, improved cell survival rate, alleviated pulmonary vessel leakage, and mitigated lung inflammation.</p><p><strong>Conclusions: </strong>HAdV-7 successfully infects pulmonary vascular endothelium and replicates effectively, causing injury to the endothelium, high VEGF expression and viral load in the serum, as well as ALI/ARDS. Autophagy inhibitors can alleviate endothelial injury, inhibit viral replication, relieve leakage from the vasculature, and reduce lung inflammation.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"425"},"PeriodicalIF":5.8,"publicationDate":"2024-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11619570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142781623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between humidity and respiratory health: the 2016-2018 Korea National Health and Nutrition Examination Survey.","authors":"Jinwoo Seok, Bo Young Lee, Hee-Young Yoon","doi":"10.1186/s12931-024-03054-z","DOIUrl":"10.1186/s12931-024-03054-z","url":null,"abstract":"<p><strong>Background: </strong>Ambient humidity has a significant impact on respiratory health and influences disease and symptoms. However, large-scale studies are required to clarify its specific effects on lung function and respiratory symptoms. We examined the relationship between relative humidity (RH), lung function, and respiratory symptoms using data from the Korea National Health and Nutrition Examination Survey (KNHANES).</p><p><strong>Methods: </strong>In this cross-sectional study, we analyzed data from KNHANES participants aged ≥ 40 years, collected between 2016 and 2018. Pulmonary function tests (PFTs) and health questionnaires were used to assess lung function and respiratory symptoms. Individual environmental data, including RH, were obtained from the Community Multiscale Air Quality model and linked to the participants' addresses. Short-term (0-14 days), mid-term (30-180 days), and long-term (1-5 years) RH exposures were examined. Linear regression models were used to evaluate the associations between RH and PFTs. Univariate and multivariable logistic regression models were applied to assess the risk of lung function abnormalities and respiratory symptoms.</p><p><strong>Results: </strong>In total, 10,396 participants were included (mean age: 58.3 years, male: 43.6%). In multiple regression analysis, higher RH was negatively associated with the forced expiratory volume in one second (FEV₁)/forced vital capacity (FVC) ratio across various time lags, while FVC was positively correlated with long-term RH exposure. In multiple logistic analysis adjusted for clinical and environmental covariates, long-term higher RH exposure was associated with a lower risk of restrictive lung disease (odds ratio [OR] at 4-year moving average [MA]: 0.978, 95% confidence interval [CI]: 0.959-0.997), while mid-term RH exposure decreased the risk of chronic cough (OR at 90-day MA: 0.968, 95% CI: 0.948-0.987) and sputum production (OR at 90-day MA: 0.985, 95% CI: 0.969-1.001).</p><p><strong>Conclusions: </strong>Higher RH was negatively associated with lung function and increased the risk of obstructive lung disease, whereas mid-term RH exposure reduced the risk of chronic cough and sputum production.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"424"},"PeriodicalIF":5.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Palmitoleic acid inhibits Pseudomonas aeruginosa quorum sensing activation and protects lungs from infectious injury.","authors":"Lei Han, Jie Ren, Yishu Xue, Guogang Xie, Jianwei Gao, Qiang Fu, Ping Shao, Hui Zhu, Min Zhang, Fengming Ding","doi":"10.1186/s12931-024-03035-2","DOIUrl":"10.1186/s12931-024-03035-2","url":null,"abstract":"<p><strong>Background: </strong>Unsaturated fatty acids targeting quorum sensing (QS) system have shown potential application in reducing bacterial virulence. We aim to investigate the effect of palmitoleic acid (PMA) on P. aeruginosa QS activation, and its impact on infection-induced lung injury.</p><p><strong>Methods: </strong>The influence of PMA on QS signaling molecule (3OC12-HSL and C4-HSL) concentrations, pyocyanin production, and QS gene transcription levels were examined in wildtype PAO1 culture. The roles of PMA in reducing infection-induced injury were assessed in human bronchial epithelial BEAS-2B cells and mouse lung infection models, respectively. PMA levels and QS signaling molecule concentrations were tested in the bronchoalveolar lavage fluid (BALF) of bronchiectasis patients with first-time detection of P. aeruginosa infection.</p><p><strong>Results: </strong>PMA administration dose-dependently suppressed the expression of QS signaling molecules, pyocyanin, and QS genes during the logarithmic stage of bacterial growth. In BEAS-2B cells, PMA-treated PAO1 filtrates significantly reduced cell apoptosis and expression of IL-8 and IL-6. In mouse lung infection models, prophylactically oral administration of PMA significantly downregulated the expression of P. aeruginosa QS signals and QS genes (lasR, rhlR, rhlI, lasB, rhlA, phzA1, phnA) in lungs, and relieved neutrophilic airway inflammation. Finally, PMA levels were negatively correlated with the concentrations of both 3OC12-HSL and C4-HSL in BALF of bronchiectasis patients, and positively correlated with their forced vital capacity (FVC) and forced expiratory volume in the first second (FEV_1.0).</p><p><strong>Conclusion: </strong>Our findings show that PMA inhibits P. aeruginosa QS activation and protects lungs from injury caused by bacterial virulence. Hence, PMA may serve as a potential anti-QS agent against P. aeruginosa infection and would help to alleviate lung injury in bronchiectasis patients.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"423"},"PeriodicalIF":5.8,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11613874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774049","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An optimized QIAzol-based protocol for simultaneous miRNA, RNA, and protein isolation from precision-cut lung slices (PCLS).","authors":"Wojciech Langwiński, Joanna Nowakowska, Kosma Sakrajda, Kamil Ziarniak, Zuzanna Stachowiak, Maria Kachel, Beata Narożna, Aleksandra Szczepankiewicz","doi":"10.1186/s12931-024-03026-3","DOIUrl":"https://doi.org/10.1186/s12931-024-03026-3","url":null,"abstract":"<p><strong>Background: </strong>Precision-cut lung slices (PCLS) are ex vivo models with preserved lung cell populations and maintained tissue architecture. PCLS are, therefore, a powerful tool in respiratory research to study molecular mechanisms that closely reflect whole tissue biology. High-quality RNA and protein extraction from PCLS is, however, challenging as agarose significantly interferes with the yield and purity of extracted material. The present study aimed to optimize QIAzol-based isolation protocol for high-yield and quality RNA, miRNA, and protein extraction from PCLS.</p><p><strong>Materials and methods: </strong>PCLS were prepared from 10 to 15-week-old Wistar rats and cultured for 7 days in Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 (DMEM/F-12) supplemented with 0.1% FBS, penicillin, and streptomycin. LDH release to PCLS culture media was measured to determine cellular cytotoxicity. To select the optimal miRNA/RNA isolation protocol, we tested two different times (10 min, 2 h) and temperatures (room temperature, 4 °C, and -20 °C) of precipitation with isopropanol. Finally, we also assessed isolation with GHCL (guanidinium hydrochloride) extraction buffer. To select the optimal protein isolation protocol, we tested protein precipitation for 10 min at room temperatures (21 ± 1 °C) with 1.5 volumes of isopropanol and 3 volumes of acetone per 1 volume of phenol-ethanol supernatant. Additionally, we also tested protein precipitation for 3 h at -20 °C with 3, 5, and 7 acetone volumes per 1 volume of phenol-ethanol supernatant. We also validated protein precipitation with back extraction buffer instead of 100% ethanol. To measure the general efficiency of the optimized QIAZ-4 protocol, we used native rat lungs. PCLS for the ex vivo model of allergic inflammation were treated with IL-13 at a concentration of 80 ng/ml.</p><p><strong>Results: </strong>Standard QIAzol isolation protocol provided RNA, miRNA, and protein with low yield and poor quality. We found that 2-h isopropanol precipitation at 4 °C with a high concentration of salts significantly increased the yield and quality of extracted RNA and miRNA and provided acceptable qPCR efficiency (between 90 and 110%). Surprisingly, 2-h isopropanol precipitation at -20 °C significantly increased qPCR efficiency above the acceptable range (average efficiency: 120.4%). As for protein extraction, we found that 3-h acetone precipitation at -20 °C provided the highest yield with linear protein detection on Westen Blot. Optimized QIAZ-4 provided significantly higher miRNA and RNA yield compared to standard QIAzol protocols. We also found a significantly increased expression of Eotaxin-1 in PCLS treated with IL-13 as compared to the untreated controls.</p><p><strong>Conclusions: </strong>In our study, we described a simple QIAzol-based method for the simultaneous isolation of RNA, miRNA, and protein from PCLS.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"422"},"PeriodicalIF":5.8,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11608482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142774046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between alcohol consumption and risk of developing tuberculosis in patients with diabetes: a nationwide retrospective cohort study.","authors":"Chiwook Chung, Kyu Na Lee, Kyungdo Han, Junhee Park, Dong Wook Shin, Sei Won Lee","doi":"10.1186/s12931-024-03047-y","DOIUrl":"10.1186/s12931-024-03047-y","url":null,"abstract":"<p><strong>Background: </strong>Diabetes mellitus (DM) and alcohol consumption are risk factors for tuberculosis (TB). We investigated the association between alcohol consumption and TB development in individuals with type 2 DM (T2DM).</p><p><strong>Methods: </strong>Individuals who underwent the national health examination during 2009-2012 were screened using the Korean National Health Information Database. In total, 2,437,443 eligible individuals with T2DM were followed up until December 2018. We identified 21,275 individuals with newly developed TB. Alcohol consumption was evaluated based on the health examination questionnaire, and individuals were categorized into none (0 g/day), mild-to-moderate (1-29.9 g/day), and heavy (≥ 30 g/day) drinkers. Multivariate Cox proportional hazard models were used to estimate the adjusted hazard ratio (aHR) of risk factors for TB.</p><p><strong>Results: </strong>Mild-to-moderate alcohol drinkers had a lower risk of developing TB (aHR 0.92, 95% confidence interval [CI] 0.89-0.96), and heavy alcohol drinkers had a higher risk of developing TB (aHR 1.21, 95% CI 1.16-1.27) than nonalcohol drinkers. When categorized by an alcohol intake of 5 g/day, alcohol drinkers of < 5 g/day had the lowest risk (aHR 0.85, 95% CI 0.81-0.90). The risk increased with alcohol intake, resulting in ≥ 20 g/day as the threshold (20-25 g/day, aHR 1.09, 95% CI 1.02-1.16). Stratified analysis revealed that current smokers had an increased risk of developing TB even among mild-to-moderate drinkers.</p><p><strong>Conclusions: </strong>Heavy alcohol consumption has been linked to an increased risk of developing TB in patients with T2DM. In contrast, mild-to-moderate alcohol consumption was associated with a reduced risk of TB, except in current smokers, where it led to a higher risk of TB. The risk of TB substantially increased with alcohol intake of 20 g/day or more, following a J-shaped curve.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"420"},"PeriodicalIF":5.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607905/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toll-like receptor activation induces airway obstruction and hyperresponsiveness in guinea pigs.","authors":"Yujiao Xiang, Jielu Liu, Mu Nie, Gunnar Nilsson, Jesper Säfholm, Mikael Adner","doi":"10.1186/s12931-024-03050-3","DOIUrl":"10.1186/s12931-024-03050-3","url":null,"abstract":"<p><strong>Background: </strong>Microbial infections, particularly those caused by rhinovirus (RV) and respiratory syncytial virus (RSV), are major triggers for asthma exacerbations. These viruses activate toll-like receptors (TLRs), initiating an innate immune response. To better understand microbial-induced asthma exacerbations, animal models that closely mimic human lung characteristics are essential. This study aimed to assess airway responses in guinea pigs exposed to TLR agonists, simulating microbial infections.</p><p><strong>Methods: </strong>The agonists poly(I: C) (TLR3), lipopolysaccharide (LPS; TLR4) and imiquimod (TLR7), or the combination of poly(I: C) and imiquimod (P/I) were administered intranasally once a day over four consecutive days. The latter group received daily intraperitoneal injections of dexamethasone starting one day before the TLR agonists challenge. Respiratory functions were measured by whole-body plethysmography and forced oscillatory technique. Bronchoalveolar lavage fluid (BALF) cells and lungs were collected for analysis.</p><p><strong>Results: </strong>The intranasal exposure of LPS and P/I caused an increase in enhanced pause (Penh) after challenge, whereas neither poly(I: C) nor imiquimod alone showed any effect. After the challenges of LPS, poly(I: C) or P/I, but not imiquimod alone, induced an increase of both Rrs (resistance of the respiratory system) and Ers (elastance of the respiratory system). LPS exposure caused an increase of neutrophils in BALF, whereas none of the other exposures affected the composition of cells in BALF. Exposure to LPS, poly (I: C), imiquimod, and P/I all caused a marked infiltration of inflammatory cells and an increase of mast cells around the small airways. For the expression of inflammatory mediators, LPS increased CXCL8, poly(I: C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ. Imiquimod increased CXCL8 and IL-6, whereas P/I decreased IL-5, and increased IL-6 and IFNγ. The increases in Rrs, Ers, and airway inflammation, but not the altered expression of inflammatory cytokines, were attenuated by dexamethasone.</p><p><strong>Conclusions: </strong>TLR agonists promote acute airway inflammation and induce airway obstruction and hyperresponsiveness in guinea pigs. The severity of these effects varies depending on the specific agonists used. Notably, dexamethasone reversed pulmonary functional changes and mitigated bronchial inflammation caused by the combined treatment of P/I. However, it had no impact on the expression of inflammatory mediators.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"421"},"PeriodicalIF":5.8,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142755644","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum proteome profiling reveals HGFA as a candidate biomarker for pulmonary arterial hypertension.","authors":"Meng Zhang, Haobo Li, Shuangshuang Ma, Xincheng Li, Linfeng Xi, Yishan Li, Zhu Zhang, Shuai Zhang, Qian Gao, Qiang Huang, Jun Wan, Wanmu Xie, Jifeng Li, Peiran Yang, Yunxia Zhang, Zhenguo Zhai","doi":"10.1186/s12931-024-03036-1","DOIUrl":"10.1186/s12931-024-03036-1","url":null,"abstract":"<p><strong>Background: </strong>Identification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process.</p><p><strong>Methods: </strong>We used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR).</p><p><strong>Results: </strong>We identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure.</p><p><strong>Conclusion: </strong>The study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"418"},"PeriodicalIF":5.8,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142752062","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}