Respiratory Research最新文献

{"title":"Therapeutic effects of melatonin on the lungs of rats exposed to passive smoking.","authors":"Juanjuan Xiong, Li Xie, YiRan Huang, JiaHui Zhu, ZhiYan Hong, HaoYun Qian, Jingjing Liu","doi":"10.1186/s12931-024-03042-3","DOIUrl":"https://doi.org/10.1186/s12931-024-03042-3","url":null,"abstract":"<p><strong>Background: </strong>Passive smoke has a significant impact on lung function and constitutes a critical public health issue, as smoking generates free radicals that damage the lungs and other tissues. Currently, limited research exists on whether the antioxidant melatonin can mitigate lung damage caused by smoking. This study aims to investigate the mechanisms through which melatonin alleviates acute lung disease induced by passive smoking.</p><p><strong>Methods: </strong>Rats were divided into five groups (n = 6): a control group and three groups exposed to low, medium, and high concentrations of smoke, and a melatonin treatment group.</p><p><strong>Results: </strong>Data indicated that in the high concentration passive smoking group, the alveolar structure of the lung tissue was destroyed, and the total antioxidant capacity in lung tissue diminished as the concentration of smoke increased. The expressions of TNF-α, IL-6, and IL-1β exhibited similar results. The anti-apoptotic factors Bcl-2 and Bcl-xL mRNA level significantly decreased in the high concentration smoking group, while no significant changes were observed in the medium and low concentration groups. Conversely, the high concentration passive smoking increased the pro-apoptotic factors Bax and Caspase-3 mRNA levels. Additionally, endogenous melatonin levels in lung tissue gradually decreased following exposure to smoke, whereas the exogenous melatonin alleviated the changes in inflammatory factors and apoptosis-related factors in lung tissue. Furthermore, at high smoking concentrations, the mRNA levels of lung cancer-related genes vascular endothelial growth factor (VEGF), cytochromeP450 1A1 (CYP1A1), and cytochrome P450 1B1 (CYP1B1) were significantly increased, while exogenous melatonin reduced the expression of these genes in lung tissue.</p><p><strong>Conclusions: </strong>These findings suggest that melatonin can diminish lung tissue damage, apoptosis, and inflammatory responses induced by passive smoking, as well as decrease the expression of lung cancer-related genes. Further experimental investigations involving exogenous melatonin treatments will be needed.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"411"},"PeriodicalIF":5.8,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142677573","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prognostic risk prediction model for patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD): a systematic review and meta-analysis.","authors":"Zihan Xu, Fan Li, You Xin, Ye Wang, Yuping Wang","doi":"10.1186/s12931-024-03033-4","DOIUrl":"10.1186/s12931-024-03033-4","url":null,"abstract":"<p><strong>Background: </strong>Chronic obstructive pulmonary disease (COPD) is a prevalent respiratory condition and a leading cause of mortality, with acute exacerbations (AECOPD) significantly complicating its management and prognosis. Despite the development of various prognostic prediction models for patients with AECOPD, their performance and clinical applicability remain unclear, necessitating a systematic review to evaluate these models and provide guidance for their future improvement and clinical use.</p><p><strong>Method: </strong>PubMed, Web of Science, CINAHL, Scopus, EMBASE, and Medline were searched for studies published from their inception until February 5, 2024. Data extraction and evaluation were conducted using the Checklist for Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS). The Prediction model Risk Of Bias Assessment Tool (PROBAST) was employed to assess the risk of bias and applicability of the models.</p><p><strong>Results: </strong>After deduplication and screening 5942 retrieved articles, 46 studies comprising 53 models were included. Of these, 17 (37.0%) studies developed from studies conducted in China. All models were based on cohort studies. Mortality was the predicted outcome in 27 (50.9%) models. Logistic regression was used in 41 (77.4%) models, while machine learning methods were employed in 9 (17.0%) models. The median (minimum, maximum) sample size for model development was 672 (106, 150,035). The median (minimum, maximum) number of predictors per model was 5 (2, 42). Frequently used predictors included age (n = 28), dyspnea severity scores (n = 12), and PaCO2 (n = 11). The pooled AUC was 0.80 for mortality prediction models and 0.84 for hospitalization-related outcomes. 52 models have a high overall risk of bias, and all models were judged to have low concern regarding applicability. Major sources of bias included insufficient sample sizes (83.0%), reliance on univariate analysis for predictor selection (73.6%), inappropriate internal and external validation methods (54.7%), inappropriate inclusion and exclusion criteria for study subjects (50.9%) and so on. The only model with low bias was the PEARL score.</p><p><strong>Conclusion: </strong>Current prognostic risk prediction models for patients with AECOPD generally exhibit high bias. Future efforts should standardize model development and validation methods, and develop widely usable clinical models.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"410"},"PeriodicalIF":5.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11566839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631168","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":"Letter to the editor: Incidence rate of occult lymph node metastasis in clinical T1 - 2N0M0 small cell lung cancer patients and radiomic prediction based on contrast-enhanced CT imaging: a multicenter study.","authors":"Zhe Hu, Zhikang Tian, Xi Wei, Yueqin Chen","doi":"10.1186/s12931-024-02940-w","DOIUrl":"10.1186/s12931-024-02940-w","url":null,"abstract":"","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"408"},"PeriodicalIF":5.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631161","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":"Mortality after treatment of malignant pleural effusions with indwelling pleural catheters versus chemical pleurodesis: a population-based study.","authors":"Chanel Kwok, Kednapa Thavorn, Kayvan Amjadi, Shawn D Aaron, Tetyana Kendzerska","doi":"10.1186/s12931-024-03023-6","DOIUrl":"10.1186/s12931-024-03023-6","url":null,"abstract":"<p><strong>Background: </strong>Little is known about patient outcomes following treatment of malignant pleural effusions (MPE) in the real-world setting.</p><p><strong>Research question: </strong>We aimed to compare post-procedure all-cause mortality between individuals who received indwelling pleural catheter (IPC) insertion versus chemical pleurodesis for managing MPEs.</p><p><strong>Study design and methods: </strong>We performed a retrospective population-based study using provincial health administrative data (Ontario, Canada) of adults with a MPE who underwent IPC insertion or chemical pleurodesis between 2015 and 2019. Individuals were followed until death or March 31, 2021. Difference in post-procedure mortality was calculated using inverse probability of treatment weighting (IPTW)-adjusted Cox proportional hazard regression analysis to balance potential confounders at baseline.</p><p><strong>Results: </strong>We identified 4,790 (77.3%) individuals who received an IPC and 1,407 (22.7%) who had chemical pleurodesis for MPE. IPC insertions are increasing and chemical pleurodesis procedures are decreasing. The majority of IPCs were inserted in outpatients (61%), by pulmonologists (64.2%) and at sites with higher annual IPC volume, while chemical pleurodesis procedures were generally done by thoracic surgeons (74%) and at sites with higher annual pleurodesis volumes. In unadjusted comparison median time from initial cancer diagnosis to intervention was significantly longer in the IPC group (244 days, interquartile range [IQR]:33-903) compared to pleurodesis group (81 days, IQR:10-737; p < 0.0001). Unadjusted median time from index procedure to death was significantly longer in the pleurodesis group (165[IQR:48-457] days vs. 81[IQR:29-256] days, p < 0.0001), however the difference between groups became insignificant after the IPTW was applied (HR 1.27, 95%CI 0.95-1.69). 35% of IPCs were removed prior to death or end of follow-up.</p><p><strong>Interpretation: </strong>After adjusting for differences in baseline characteristics there was no difference in post-procedure mortality between IPC and chemical pleurodesis groups. In the real world, there are significant differences in the characteristics of patients who receive these two procedures and notable regional practice variation between procedure use. Future research should evaluate these variations in care and their effect on patient outcomes.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"409"},"PeriodicalIF":5.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562646/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631164","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":"Euphorbium compositum SN improves the innate defenses of the airway mucosal barrier network during rhinovirus infection.","authors":"Charu Rajput, Haleh Ganjian, Ganesh Muruganandam, Kathrin Weyer, Julia Dannenmaier, Bernd Seilheimer, Umadevi Sajjan","doi":"10.1186/s12931-024-03030-7","DOIUrl":"10.1186/s12931-024-03030-7","url":null,"abstract":"<p><strong>Background: </strong>Rhinoviruses (RV) are the major cause of common colds in healthy individuals and are associated with acute exacerbations in patients with chronic lung diseases. Yet, no vaccines or effective treatment against RV are available. This study investigated the effect of Euphorbium compositum SN (ECSN6), a multicomponent, multitarget medication made from natural ingredients, on the mucosal barrier network during RV infection.</p><p><strong>Methods: </strong>Mucociliary-differentiated airway epithelial cell cultures were infected with RV or sham, and treated with 20% ECSN6 or placebo twice daily. Barrier integrity was assessed by measuring transepithelial resistance (TER), permeability to inulin, and expression and localization of intercellular junctions proteins (IJ). Ciliary beat frequency (CBF), expression of pro-inflammatory cytokines, antiviral interferons and mucins, and viral load were also measured. C57BL/6 mice were infected intranasally with RV or sham and treated with 40% ECSN6 or placebo twice daily. Inflammation of sinunasal mucosa, localization of E-cadherin, viral load and mucin gene expression were determined.</p><p><strong>Results: </strong>ECSN6-treated, uninfected cell cultures showed small, but significant increase in TER over placebo, which was associated with enhanced localization of E-cadherin and ZO-1 to IJ. In RV-infected cultures, treatment with ECSN6, but not placebo prevented RV-induced (1) reduction in TER, (2) dissociation of E-cadherin and ZO-1 from the IJ, (3) mucin expression, and (4) CBF attenuation. ECSN6 also decreased RV-stimulated expression of pro-inflammatory cytokines and permeability to inulin. Although ECSN6 significantly increased the expression of some antiviral type I and type III interferons, it did not alter viral load. In vivo, ECSN6 reduced RV-A1-induced moderate inflammation of nasal mucosa, beneficially affected RV-A1-induced cytokine responses and Muc5ac mRNA expression and prevented RV-caused dissociation of E-cadherin from the IJ of nasal mucosa without an effect on viral clearance.</p><p><strong>Conclusions: </strong>ECSN6 prevents RV-induced airway mucosal barrier dysfunction and improves the immunological and mucociliary barrier function. ECSN6 may maintain integrity of barrier function by promoting localization of tight and adherence junction proteins to the IJ. This in turn may lead to the observed decrease in RV-induced pro-inflammatory responses in vitro. By improving the innate defenses of the airway mucosal barrier network, ECSN6 may alleviate respiratory symptoms caused by RV infections.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"407"},"PeriodicalIF":5.8,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11562495/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631156","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 soluble isoform of receptor for advanced glycation end product is a predictive biomarker for acute exacerbation of idiopathic pulmonary fibrosis: a German and Japanese cohort study.","authors":"Erika Kitadai, Kakuhiro Yamaguchi, Shinichiro Ohshimo, Hiroshi Iwamoto, Shinjiro Sakamoto, Yasushi Horimasu, Takeshi Masuda, Taku Nakashima, Hironobu Hamada, Francesco Bonella, Josune Guzman, Ulrich Costabel, Noboru Hattori","doi":"10.1186/s12931-024-03014-7","DOIUrl":"10.1186/s12931-024-03014-7","url":null,"abstract":"<p><strong>Background: </strong>The receptor for advanced glycation end product (RAGE) is a transmembrane receptor accelerating a pro-inflammatory signal. RAGE signalling is promoted by decreased soluble isoform of RAGE (sRAGE), which is a decoy receptor for RAGE ligands, and RAGE SNP rs2070600 minor allele. In Caucasian and Japanese cohorts, low circulatory sRAGE levels and presence of the minor allele are associated with poor survival of idiopathic pulmonary fibrosis (IPF) and increased disease susceptibility to interstitial lung disease, respectively. However, whether sRAGE and RAGE SNP rs2070600 are associated with acute exacerbation of IPF (AE-IPF) is unclear.</p><p><strong>Methods: </strong>This retrospective cohort study evaluated the association between the onset of AE-IPF and serum sRAGE levels in 69 German and 102 Japanese patients with IPF. The association of AE-IPF with RAGE SNP rs2070600 in 51 German and 84 Japanese patients, whose DNA samples were stored, was also investigated.</p><p><strong>Results: </strong>In each cohort, the incidence of AE-IPF was significantly and reproducibly higher in the patients with sRAGE < 467.1 pg/mL. In a pooled exploratory analysis, the incidence of AE-IPF was lowest in the patients with higher sRAGE levels and rs2070600 minor allele, although no significant difference in the incidence was observed between the patients with and without the rs2070600 minor allele.</p><p><strong>Conclusions: </strong>Low sRAGE levels were associated with increased incidence of AE-IPF in two independent cohorts of different ethnicities. The combination of rs2070600 and sRAGE levels may stratify patients with IPF for the risk of AE.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"405"},"PeriodicalIF":5.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631175","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":"Beyond diagnosis: maximizing the role of medical thoracoscopy in pleural disease treatment.","authors":"Kaige Wang, Ling Zuo, Panwen Tian, Fen Tan, Weimin Li","doi":"10.1186/s12931-024-03001-y","DOIUrl":"10.1186/s12931-024-03001-y","url":null,"abstract":"<p><p>Medical thoracoscopy has been extensively utilized in the diagnosis of pleural disease, yet its potential therapeutic applications remain underutilized. This article presents a comprehensive overview of the various uses of medical thoracoscopy in managing pleural diseases. It has been employed to facilitate thoracic drainage and reduce hospitalization duration of patients with complicated parapneumonic effusions and empyema. Additionally, medical thoracoscopic occlusion therapy can be used for bronchoscopic closure and refractory pneumothorax. However, there is currently a lack of standardized protocols for utilizing medical thoracoscopy to reduce the volume of giant emphysematous bullae. Furthermore, medical thoracoscopy allows for pleurodesis or photodynamic therapy in patients with malignant pleural effusion. Nevertheless, further high-quality clinical research is needed to validate these findings.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"406"},"PeriodicalIF":5.8,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11555924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631152","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":"Computed tomography morphological assessments of central airways in interstitial lung abnormalities and idiopathic pulmonary fibrosis.","authors":"Tomoki Maetani, Naoya Tanabe, Kiminobu Tanizawa, Ryo Sakamoto, Yusuke Shiraishi, Yusuke Hayashi, Michihiro Uyama, Atsushi Matsunashi, Susumu Sato, Katsuhiro Suzuki, Izuru Masuda, Motonari Fukui, Shizuo Kaji, Tomohiro Handa, Toyohiro Hirai","doi":"10.1186/s12931-024-03032-5","DOIUrl":"10.1186/s12931-024-03032-5","url":null,"abstract":"<p><strong>Background: </strong>Little is known about whether central airway morphological changes beyond traction bronchiectasis develop and affect clinical outcomes in patients with idiopathic pulmonary fibrosis (IPF). This study aimed to compare central airway structure comprehensively between patients with IPF, subjects with interstitial lung abnormality (ILA), and those without ILA (control) using computed tomography (CT). We further examined the prognostic impact of IPF-specific CT airway parameters in patients with IPF.</p><p><strong>Methods: </strong>This retrospective study included male patients with IPF, and male health checkup subjects divided into those with ILA and control based on lung cancer screening CT. Using an artificial intelligence-based segmentation technique, the extent of fibrotic regions in the lung was quantified. After airway tree segmentation, CT parameters for central airway morphology, including the lumen area of the extrapulmonary airways (LA^extra), wall and lumen area of the segmental/subsegmental intrapulmonary airways (WA^intra and LA^intra), tracheal distortion (tortuosity and curvature) and bifurcation angle of the main carina, were calculated.</p><p><strong>Results: </strong>There were 106 patients with IPF, 53 subjects with ILA, and 1295 controls. Multivariable models adjusted for age, height and smoking history revealed that LA^intra and WA^intra were larger in both ILA and IPF, and that tracheal tortuosity and curvature were higher in IPF, but not in ILA, than in the control, whereas the bifurcation angle did not differ between the 3 groups. According to multivariable Cox proportional hazards models including only patients with IPF, increased WA^intra was significantly associated with greater mortality (standardized hazard ratio [95% confidence interval] = 1.58 [1.17, 2.14]), independent of the volume of fibrotic regions, normal-appearing regions, or the whole airway tree in the lung.</p><p><strong>Conclusion: </strong>Increased lumen area and wall thickening of the central airways may be involved in the pathogenesis of ILA and IPF, and wall thickening may affect the prognosis of patients with IPF.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"404"},"PeriodicalIF":5.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631154","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":"Atomized inhalation of indocyanine green in thoracoscopic surgery for intralobar pulmonary sequestration: a multicenter study.","authors":"Ye Yin, Guofeng Zhang, Wei Li, Didi Zhuansun, Xiaofeng Xiong, Yanan Li, Yin He, Wenjing Wang, Tianqi Zhu, Jiexiong Feng","doi":"10.1186/s12931-024-03024-5","DOIUrl":"10.1186/s12931-024-03024-5","url":null,"abstract":"<p><strong>Background: </strong>Investigate the safety and efficacy of preoperative atomization inhalation of indocyanine green (ICG) solution in precise lesion resection of pediatric thoracoscopic intralobar pulmonary sequestration.</p><p><strong>Methods: </strong>A multicenter 1:1 matched case-control study was adopted, to compare the safety and efficacy of the ICG group (preoperative atomization inhalation of 0.5 mg/kg ICG solution) with traditional group (no preoperative atomization inhalation of ICG solution). The baseline, intraoperative, and postoperative recovery conditions of the two groups were observed. Outpatient follow-up visits were conducted 3 to 6 months after surgery, including lung CT scans and pulmonary ventilation function tests.</p><p><strong>Results: </strong>134 patients were included in the study. The ICG group included 67 patients, and the traditional surgery group included 67 patients matched at a ratio of 1:1 according to age and lesion location. There were no reports of deaths or adverse reactions. The postoperative chest drainage tube indwelling time [(53.19 ± 8.15) hours vs. (73.25 ± 15.51) hours, P < 0.001] and postoperative hospital stay [(4.81 ± 1.84) days vs. (6.72 ± 1.31) days, P < 0.001] were shorter in the ICG group than in the traditional group. More importantly, the postoperative pulmonary function in the ICG group was better than that in the traditional group. No residual lesions were found in the postoperative CT examination of both groups.</p><p><strong>Conclusions: </strong>The innovative application of atomization inhalation of ICG provides the possibility for precise localization and lesion resection of pediatric thoracoscopic intralobar pulmonary sequestration. This maximizes the preservation of normal lung parenchyma, better improves postoperative pulmonary function, and shortens postoperative recovery time.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"403"},"PeriodicalIF":5.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550537/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631151","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":"Repeated inhalation of GM-CSF by nonhuman primates induces bronchus-associated lymphoid tissue along the lower respiratory tract.","authors":"Ryushi Tazawa, Riuko Ohashi, Nobutaka Kitamura, Takahiro Tanaka, Kazuhide Nakagaki, Sachiko Yuki, Atsushi Fujiwara, Koh Nakata","doi":"10.1186/s12931-024-03003-w","DOIUrl":"10.1186/s12931-024-03003-w","url":null,"abstract":"<p><strong>Background: </strong>Repeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear.</p><p><strong>Methods: </strong>In this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2-3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim.</p><p><strong>Results: </strong>All the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab-producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro.</p><p><strong>Conclusion: </strong>Long-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"402"},"PeriodicalIF":5.8,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550524/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631172","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}