Background: Investigate the safety and efficacy of preoperative atomization inhalation of indocyanine green (ICG) solution in precise lesion resection of pediatric thoracoscopic intralobar pulmonary sequestration.
Methods: 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.
Results: 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.
Conclusions: 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.
{"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}
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
{"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}
Pulmonary fibrosis (PF) is a chronic, progressive lung disease characterized by fibroblast proliferation, extensive extracellular matrix and collagen deposition, accompanied by inflammatory damage, ultimately leading to death due to respiratory failure. Endoplasmic reticulum (ER) stress in pulmonary fibrotic tissue is indeed recognized as a significant factor exacerbating PF development. Emerging evidences indicated a potential association between ER stress induced by lactate and cellular apoptosis in PF. However, the mechanisms in this process need further elucidation. In this paper, pulmonary fibrosis model was induced by bleomycin (BLM) intratracheally in mice. In the cellular model, type II epithelial cells were treated by lactate and TGF-β to detect ER stress and apoptosis markers. Lactate could promote ER stress response and apoptosis. Mechanically, lactate activated Caspase-12 via ATF4-Chop axis to induce cell apoptosis and promote fibrosis. ER stress inhibitor could effectively suppress alveolar epithelial cells apoptosis and pulmonary fibrosis. We concluded that pro-fibrotic properties of lactate are associated with alveolar epithelial cells apoptosis by causing ER stress and thus provide new potential therapeutic targets for pulmonary fibrosis.
肺纤维化(PF)是一种慢性进行性肺部疾病,其特点是成纤维细胞增殖、细胞外基质和胶原广泛沉积,并伴有炎症损伤,最终导致呼吸衰竭而死亡。肺纤维化组织中的内质网(ER)应激确实被认为是加剧肺纤维化发展的一个重要因素。新的证据表明,乳酸诱导的 ER 应激与肺纤维化中的细胞凋亡之间存在潜在联系。然而,这一过程的机制还需要进一步阐明。本文通过气管内注射博莱霉素(BLM)诱导小鼠肺纤维化模型。在细胞模型中,用乳酸盐和 TGF-β 处理 II 型上皮细胞,检测 ER 应激和细胞凋亡标志物。乳酸盐可促进ER应激反应和细胞凋亡。在机制上,乳酸盐通过ATF4-Chop轴激活Caspase-12,诱导细胞凋亡并促进纤维化。ER应激抑制剂能有效抑制肺泡上皮细胞凋亡和肺纤维化。我们的结论是,乳酸盐的促纤维化特性与肺泡上皮细胞通过引起ER应激而凋亡有关,从而为肺纤维化提供了新的潜在治疗靶点。
{"title":"Lactate activates ER stress to promote alveolar epithelial cells apoptosis in pulmonary fibrosis.","authors":"Zhiheng Sun, Wanyu He, Huiwen Meng, Zhihua Ji, Junxing Qu, Guoying Yu","doi":"10.1186/s12931-024-03016-5","DOIUrl":"10.1186/s12931-024-03016-5","url":null,"abstract":"<p><p>Pulmonary fibrosis (PF) is a chronic, progressive lung disease characterized by fibroblast proliferation, extensive extracellular matrix and collagen deposition, accompanied by inflammatory damage, ultimately leading to death due to respiratory failure. Endoplasmic reticulum (ER) stress in pulmonary fibrotic tissue is indeed recognized as a significant factor exacerbating PF development. Emerging evidences indicated a potential association between ER stress induced by lactate and cellular apoptosis in PF. However, the mechanisms in this process need further elucidation. In this paper, pulmonary fibrosis model was induced by bleomycin (BLM) intratracheally in mice. In the cellular model, type II epithelial cells were treated by lactate and TGF-β to detect ER stress and apoptosis markers. Lactate could promote ER stress response and apoptosis. Mechanically, lactate activated Caspase-12 via ATF4-Chop axis to induce cell apoptosis and promote fibrosis. ER stress inhibitor could effectively suppress alveolar epithelial cells apoptosis and pulmonary fibrosis. We concluded that pro-fibrotic properties of lactate are associated with alveolar epithelial cells apoptosis by causing ER stress and thus provide new potential therapeutic targets for pulmonary fibrosis.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"401"},"PeriodicalIF":5.8,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11550544/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631158","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}
Pub Date : 2024-11-08DOI: 10.1186/s12931-024-03027-2
Sridesh Nath, Hafiz Qurashi, Georgios D Kitsios, William Bain, Hamam Aneis, Tomeka Suber, Niall Prendergast, Matthew Hensley, Caitlin Schaefer, Yingze Zhang, Jessica Bon, Bryan J McVerry, John Evankovich, Faraaz Ali Shah
Introduction: Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung injury. The impact of pre-existing chronic obstructive pulmonary disease (COPD) or emphysema on ARDS pathogenesis is not well characterized.
Methods: Secondary analysis of ARDS patients enrolled in the Acute Lung Injury Registry and Biospecimen Repository at the University of Pittsburgh between June 2012 and September 2021. Patients were categorized into two mutually exclusive groups by the prevalence of COPD or emphysema at the time of ARDS diagnosis. The COPD/emphysema group comprised ARDS patients with radiological evidence of emphysema, chart diagnosis of COPD, or both. Demographics, lung mechanics, and clinical outcomes were obtained from the electronic medical record. Host-response biomarkers known to have validated associations with ARDS were previously measured in plasma and lower respiratory tract samples using a customized Luminex assay. Continuous and categorical variables were compared between groups with and without COPD/emphysema.
Results: 217 patients with ARDS were included in the study, 57 (27%) had COPD/emphysema. Patients with COPD/emphysema were older (median 62 [interquartile range 55-69] versus 53 [41-64] years, p < 0.01), more likely to be male (62% vs. 44%, p = 0.02) and had a higher prevalence of congestive heart failure (25% vs. 4%, p < 0.01) compared to patients without COPD/emphysema. Baseline demographics, laboratory parameters, and mechanical ventilatory characteristics were otherwise similar between the two groups. No difference in 90-day mortality was observed between groups; however, patients with COPD/emphysema had shorter duration of intensive care unit (ICU) stay (median 10 [7-18] versus 16 [9-28] days, p = 0.04) and shorter duration of mechanical ventilation (median 7 [4-16] vs. 12 [6-20] days, p = 0.01). Host response biomarkers in serum and lower respiratory tract samples did not significantly differ between groups.
Conclusion: ARDS patients with COPD or emphysema had similar respiratory mechanics, host response biomarker profiles, and mortality compared to those without COPD or emphysema but with a shorter median duration of mechanical ventilation and ICU length of stay. Future studies should address differences in clinical and biological responses by disease severity, and should investigate the impact of severity of COPD and emphysema on mechanical ventilation and targeted therapeutic strategies in ARDS.
{"title":"Clinical and biologic profiles of patients with acute respiratory distress syndrome by prevalence of chronic obstructive pulmonary disease or emphysema; a cohort study.","authors":"Sridesh Nath, Hafiz Qurashi, Georgios D Kitsios, William Bain, Hamam Aneis, Tomeka Suber, Niall Prendergast, Matthew Hensley, Caitlin Schaefer, Yingze Zhang, Jessica Bon, Bryan J McVerry, John Evankovich, Faraaz Ali Shah","doi":"10.1186/s12931-024-03027-2","DOIUrl":"10.1186/s12931-024-03027-2","url":null,"abstract":"<p><strong>Introduction: </strong>Acute respiratory distress syndrome (ARDS) is characterized by diffuse lung injury. The impact of pre-existing chronic obstructive pulmonary disease (COPD) or emphysema on ARDS pathogenesis is not well characterized.</p><p><strong>Methods: </strong>Secondary analysis of ARDS patients enrolled in the Acute Lung Injury Registry and Biospecimen Repository at the University of Pittsburgh between June 2012 and September 2021. Patients were categorized into two mutually exclusive groups by the prevalence of COPD or emphysema at the time of ARDS diagnosis. The COPD/emphysema group comprised ARDS patients with radiological evidence of emphysema, chart diagnosis of COPD, or both. Demographics, lung mechanics, and clinical outcomes were obtained from the electronic medical record. Host-response biomarkers known to have validated associations with ARDS were previously measured in plasma and lower respiratory tract samples using a customized Luminex assay. Continuous and categorical variables were compared between groups with and without COPD/emphysema.</p><p><strong>Results: </strong>217 patients with ARDS were included in the study, 57 (27%) had COPD/emphysema. Patients with COPD/emphysema were older (median 62 [interquartile range 55-69] versus 53 [41-64] years, p < 0.01), more likely to be male (62% vs. 44%, p = 0.02) and had a higher prevalence of congestive heart failure (25% vs. 4%, p < 0.01) compared to patients without COPD/emphysema. Baseline demographics, laboratory parameters, and mechanical ventilatory characteristics were otherwise similar between the two groups. No difference in 90-day mortality was observed between groups; however, patients with COPD/emphysema had shorter duration of intensive care unit (ICU) stay (median 10 [7-18] versus 16 [9-28] days, p = 0.04) and shorter duration of mechanical ventilation (median 7 [4-16] vs. 12 [6-20] days, p = 0.01). Host response biomarkers in serum and lower respiratory tract samples did not significantly differ between groups.</p><p><strong>Conclusion: </strong>ARDS patients with COPD or emphysema had similar respiratory mechanics, host response biomarker profiles, and mortality compared to those without COPD or emphysema but with a shorter median duration of mechanical ventilation and ICU length of stay. Future studies should address differences in clinical and biological responses by disease severity, and should investigate the impact of severity of COPD and emphysema on mechanical ventilation and targeted therapeutic strategies in ARDS.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"400"},"PeriodicalIF":5.8,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11549746/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631153","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}
Background and purposes: Liver X receptors (LXRs) are specialized nuclear receptors essential for maintaining cholesterol homeostasis, modulating LXR activity could have therapeutic potential in lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by impaired alveolar development, in which apoptosis of alveolar epithelial cells is a key contributing factor. The current research focuses on exploring the potential mechanism by which the LXR pathway regulating alveolar epithelial type II cell apoptosis in response to hyperoxia exposure.
Methods: BPD infants and non-BPD preterm infants were enrolled to measure serum total cholesterol (TC) levels. To further investigate the role of cholesterol metabolism in BPD, a neonatal rat model of BPD was established, and in vitro studies were conducted using mouse lung epithelial cells (MLE12). These experiments aimed to explore the impact of hyperoxia on cholesterol metabolism and assess the effects of LXR agonist intervention.
Results: Elevated serum TC levels in BPD infants were observed, accompanied by lung cholesterol overload in BPD rats. Hyperoxia exposure also led to intracellular cholesterol accumulation in MLE12 cells, which may be attributed to the downregulated LXR signaling pathway. Activation of the LXR pathway prevented apoptosis and mitochondrial dysfunction in MLE12 cell. In BPD rats, intervention with the LXR agonist restored alveolar architecture and reduced alveolar epithelial type II cell apoptosis, which was associated with decreased oxidative stress and lung cholesterol accumulation.
Conclusions: Disrupted cholesterol metabolism and impaired homeostasis in premature infants may contribute to the development of BPD. Targeting LXR signaling may provide potential therapeutic targets in BPD.
{"title":"Activation of LXR signaling ameliorates apoptosis of alveolar epithelial cells in Bronchopulmonary dysplasia.","authors":"Yizhe Ma, Yameng Wang, Anni Xie, Luchun Wang, Yuqiong Zhang, Mingyan Tao, Xianhui Deng, Zhidan Bao, Renqiang Yu","doi":"10.1186/s12931-024-03031-6","DOIUrl":"10.1186/s12931-024-03031-6","url":null,"abstract":"<p><strong>Background and purposes: </strong>Liver X receptors (LXRs) are specialized nuclear receptors essential for maintaining cholesterol homeostasis, modulating LXR activity could have therapeutic potential in lung diseases. Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by impaired alveolar development, in which apoptosis of alveolar epithelial cells is a key contributing factor. The current research focuses on exploring the potential mechanism by which the LXR pathway regulating alveolar epithelial type II cell apoptosis in response to hyperoxia exposure.</p><p><strong>Methods: </strong>BPD infants and non-BPD preterm infants were enrolled to measure serum total cholesterol (TC) levels. To further investigate the role of cholesterol metabolism in BPD, a neonatal rat model of BPD was established, and in vitro studies were conducted using mouse lung epithelial cells (MLE12). These experiments aimed to explore the impact of hyperoxia on cholesterol metabolism and assess the effects of LXR agonist intervention.</p><p><strong>Results: </strong>Elevated serum TC levels in BPD infants were observed, accompanied by lung cholesterol overload in BPD rats. Hyperoxia exposure also led to intracellular cholesterol accumulation in MLE12 cells, which may be attributed to the downregulated LXR signaling pathway. Activation of the LXR pathway prevented apoptosis and mitochondrial dysfunction in MLE12 cell. In BPD rats, intervention with the LXR agonist restored alveolar architecture and reduced alveolar epithelial type II cell apoptosis, which was associated with decreased oxidative stress and lung cholesterol accumulation.</p><p><strong>Conclusions: </strong>Disrupted cholesterol metabolism and impaired homeostasis in premature infants may contribute to the development of BPD. Targeting LXR signaling may provide potential therapeutic targets in BPD.</p><p><strong>Clinical trial number: </strong>Not applicable.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"399"},"PeriodicalIF":5.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11545640/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606933","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}
Acute lung injury (ALI) is a common critical respiratory disease in clinical practice, especially in the ICU, with a high mortality rate. The pathogenesis of ALI is relatively complex, mainly involving inflammatory response imbalance, oxidative stress, cell apoptosis, and other aspects. However, currently, the treatment measures taken based on the above mechanisms have not had significant effects. Recent research shows that mitochondrial dysfunction and pyroptosis play an important role in ALI, but there is not much analysis on the relationship between mitochondrial dysfunction and pyroptosis at present. This article reviews the situation of mitochondrial dysfunction in ALI, pyroptosis in ALI, whether mitochondrial dysfunction is related to pyroptosis in ALI, and how to do so, and further analyzes the relationship between them in ALI. This review describes how to alleviate mitochondrial dysfunction, and then suppress the associated immunological pyroptosis, providing new ideas for the clinical treatment of ALI.
急性肺损伤(ALI)是临床上常见的危重呼吸系统疾病,尤其是在重症监护病房,死亡率较高。急性肺损伤的发病机制相对复杂,主要涉及炎症反应失衡、氧化应激、细胞凋亡等方面。然而,目前基于上述机制采取的治疗措施效果并不明显。近年来的研究表明,线粒体功能障碍和热凋亡在 ALI 中起着重要作用,但目前关于线粒体功能障碍和热凋亡之间关系的分析并不多。本文综述了线粒体功能障碍在 ALI 中的情况、ALI 中的热休克、线粒体功能障碍与 ALI 中的热休克是否相关以及如何相关,并进一步分析了二者在 ALI 中的关系。这篇综述介绍了如何缓解线粒体功能障碍,进而抑制相关的免疫性脓毒血症,为 ALI 的临床治疗提供了新思路。
{"title":"Research progress of mitochondrial dysfunction induced pyroptosis in acute lung injury.","authors":"Luhan Yang, Qingyi Ren, Yaohui Wang, Yucheng Zheng, Fei Du, Fang Wang, Jie Zhou, Linxi Gui, Shengdong Chen, Xiurui Chen, Wanting Zhang, Yuhong Sun, Xiaolin Zhong, Hao Liu, Xian Jiang, Zhuo Zhang","doi":"10.1186/s12931-024-03028-1","DOIUrl":"10.1186/s12931-024-03028-1","url":null,"abstract":"<p><p>Acute lung injury (ALI) is a common critical respiratory disease in clinical practice, especially in the ICU, with a high mortality rate. The pathogenesis of ALI is relatively complex, mainly involving inflammatory response imbalance, oxidative stress, cell apoptosis, and other aspects. However, currently, the treatment measures taken based on the above mechanisms have not had significant effects. Recent research shows that mitochondrial dysfunction and pyroptosis play an important role in ALI, but there is not much analysis on the relationship between mitochondrial dysfunction and pyroptosis at present. This article reviews the situation of mitochondrial dysfunction in ALI, pyroptosis in ALI, whether mitochondrial dysfunction is related to pyroptosis in ALI, and how to do so, and further analyzes the relationship between them in ALI. This review describes how to alleviate mitochondrial dysfunction, and then suppress the associated immunological pyroptosis, providing new ideas for the clinical treatment of ALI.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"398"},"PeriodicalIF":5.8,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11545853/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606945","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}
Pub Date : 2024-11-04DOI: 10.1186/s12931-024-03029-0
Johnathan D Keith, Mikayla Murphree-Terry, Gretchen Bollar, Ashley M Oden, Ian H Doty, Susan E Birket
Background: Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.
Methods: We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung.
Results: We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection.
Conclusions: The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model.
{"title":"Ivacaftor ameliorates mucus burden, bacterial load, and inflammation in acute but not chronic P. aeruginosa infection in hG551D rats.","authors":"Johnathan D Keith, Mikayla Murphree-Terry, Gretchen Bollar, Ashley M Oden, Ian H Doty, Susan E Birket","doi":"10.1186/s12931-024-03029-0","DOIUrl":"10.1186/s12931-024-03029-0","url":null,"abstract":"<p><strong>Background: </strong>Newly approved highly effective modulation therapies (HEMT) have been life-changing for people with CF. Although these drugs have resulted in significant improvements in lung function and exacerbation rate, bacterial populations in the lung have not been eradicated. The mechanisms behind the continued colonization are not completely clear.</p><p><strong>Methods: </strong>We used a humanized rat to assess the effects of ivacaftor therapy on infection outcomes. Rats harbor an insert expressing humanized CFTR cDNA, including the G551D mutation. hG551D rats were treated with ivacaftor either during or before infection with P. aeruginosa. The response to infection was assessed by bacterial burden in the lung and mucus burden in the lung.</p><p><strong>Results: </strong>We found that hG551D rats treated with ivacaftor had reduced bacteria present in the lung in the acute phase of the infection but were not different than vehicle control in the chronic phase of the infection. Similarly, the percentage of neutrophils in the airways were reduced at the acute, but not chronic, timepoints. Overall weight data indicated that the hG551D rats had significantly better weight recovery during the course of infection when treated with ivacaftor. Potentiation of the G551D mutation with ivacaftor resultant in short-circuit current measurements equal to WT, even during the chronic phase of the infection. Despite the persistent infection, hG551D rats treated with ivacaftor had fewer airways with mucus plugs during the chronic infection.</p><p><strong>Conclusions: </strong>The data indicate that the hG551D rats have better outcomes during infection when treated with ivacaftor compared to the vehicle group. Rats have increased weight gain, increased CFTR protein function, and decreased mucus accumulation, despite the persistence of infection and inflammation. These data suggest that ivacaftor improves tolerance of infection, rather than eradication, in this rat model.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"397"},"PeriodicalIF":5.8,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11536857/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142577056","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}
Pub Date : 2024-11-01DOI: 10.1186/s12931-024-02987-9
Aiyuan Zhou, Xiyan Zhang, Xinyue Hu, Tiao Li, Wenzhong Peng, Hang Yang, Dingding Deng, Chunheng Mo, Rongli Lu, Pinhua Pan
Background: Interferon regulatory factor-1 (IRF1) is a transcription factor that plays a significant role in various biological processes, including inflammatory injury, viral infection, cell death, and immune responses, and it has been extensively studied in the context of different lung diseases. However, the mechanism underlying its involvement in lung fibrosis remains largely unknown.
Methods: Wild type (WT) mice, IRF1 global-null mice (Irf1-/-) were subjected to a bleomycin-induced lung fibrosis model to enable examination of the role of IRF1 in lung fibrosis. Proteomic analysis of lung tissue from WT and Irf1-/- mice treated with saline or bleomycin was performed to explore the mechanism of IRF1 in regulating lung fibrosis.
Results: In the bleomycin-induced fibrosis mouse model, increased expression of IRF1 was observed. Irf1 knockout mice displayed decreased lung fibrosis relative to WT mice following treatment with bleomycin. The protein expression of fibronectin, as assessed by the Western blot analysis of lung tissues, was downregulated in Irf1-/- mice. We observed a similar reduction in collagen content using hydroxyproline detection. Histologically, there was less collagen deposition in the lungs of Irf1-/- mice compared with WT mice. Proteomics data revealed that IRF1 may be involved in lung fibrosis via the regulation of ferroptosis. We determined that paraoxonase 1(PON1), a poorly characterized protein in lung fibrosis, was upregulated in Irf1-/- mice following exposure to bleomycin. In vitro experiments revealed that IRF1 could regulate the level of GSH and MDA through PON1. We also determined that PON1 levels were lower in the plasma of IPF patients compared with healthy controls.
Conclusion: Our data highlight the importance of IRF1 in the fibrotic process, and PON1 may be a potential mediator of IRF1 in the progression of lung fibrosis.
背景:干扰素调节因子-1(IRF1)是一种转录因子,在炎症损伤、病毒感染、细胞死亡和免疫反应等多种生物过程中发挥着重要作用,它在不同肺部疾病中的作用已被广泛研究。然而,它参与肺纤维化的机制在很大程度上仍然未知:方法:将野生型(WT)小鼠和IRF1全基因缺失小鼠(Irf1-/-)置于博莱霉素诱导的肺纤维化模型中,以研究IRF1在肺纤维化中的作用。对用生理盐水或博莱霉素处理的WT小鼠和Irf1-/-小鼠的肺组织进行了蛋白质组学分析,以探索IRF1调控肺纤维化的机制:结果:在博莱霉素诱导的肺纤维化小鼠模型中,观察到IRF1的表达增加。与WT小鼠相比,IRF1基因敲除小鼠在博莱霉素治疗后肺纤维化程度降低。通过对肺组织的 Western 印迹分析评估,Irf1-/-小鼠的纤维连接蛋白的蛋白表达下调。通过羟脯氨酸检测,我们观察到胶原蛋白含量也有类似的减少。从组织学角度看,与 WT 小鼠相比,Irf1-/- 小鼠肺部的胶原沉积较少。蛋白质组学数据显示,IRF1 可能通过调节铁氧化酶参与肺纤维化。我们发现,在暴露于博莱霉素后,Irf1-/-小鼠体内的对氧磷(paraoxonase)1(PON1)上调,而对氧磷(paraoxonase)1是一种在肺纤维化中特征不明显的蛋白质。体外实验显示,IRF1可通过PON1调节GSH和MDA的水平。我们还发现,与健康对照组相比,IPF 患者血浆中的 PON1 水平较低:我们的数据强调了IRF1在纤维化过程中的重要性,而PON1可能是IRF1在肺纤维化进展过程中的潜在介质。
{"title":"Loss of interferon regulatory factor-1 prevents lung fibrosis by upregulation of pon1 expression.","authors":"Aiyuan Zhou, Xiyan Zhang, Xinyue Hu, Tiao Li, Wenzhong Peng, Hang Yang, Dingding Deng, Chunheng Mo, Rongli Lu, Pinhua Pan","doi":"10.1186/s12931-024-02987-9","DOIUrl":"10.1186/s12931-024-02987-9","url":null,"abstract":"<p><strong>Background: </strong>Interferon regulatory factor-1 (IRF1) is a transcription factor that plays a significant role in various biological processes, including inflammatory injury, viral infection, cell death, and immune responses, and it has been extensively studied in the context of different lung diseases. However, the mechanism underlying its involvement in lung fibrosis remains largely unknown.</p><p><strong>Methods: </strong>Wild type (WT) mice, IRF1 global-null mice (Irf1<sup>-/-</sup>) were subjected to a bleomycin-induced lung fibrosis model to enable examination of the role of IRF1 in lung fibrosis. Proteomic analysis of lung tissue from WT and Irf1<sup>-/-</sup> mice treated with saline or bleomycin was performed to explore the mechanism of IRF1 in regulating lung fibrosis.</p><p><strong>Results: </strong>In the bleomycin-induced fibrosis mouse model, increased expression of IRF1 was observed. Irf1 knockout mice displayed decreased lung fibrosis relative to WT mice following treatment with bleomycin. The protein expression of fibronectin, as assessed by the Western blot analysis of lung tissues, was downregulated in Irf1<sup>-/-</sup> mice. We observed a similar reduction in collagen content using hydroxyproline detection. Histologically, there was less collagen deposition in the lungs of Irf1<sup>-/-</sup> mice compared with WT mice. Proteomics data revealed that IRF1 may be involved in lung fibrosis via the regulation of ferroptosis. We determined that paraoxonase 1(PON1), a poorly characterized protein in lung fibrosis, was upregulated in Irf1<sup>-/-</sup> mice following exposure to bleomycin. In vitro experiments revealed that IRF1 could regulate the level of GSH and MDA through PON1. We also determined that PON1 levels were lower in the plasma of IPF patients compared with healthy controls.</p><p><strong>Conclusion: </strong>Our data highlight the importance of IRF1 in the fibrotic process, and PON1 may be a potential mediator of IRF1 in the progression of lung fibrosis.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"394"},"PeriodicalIF":5.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529560/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565215","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}
Pub Date : 2024-11-01DOI: 10.1186/s12931-024-03013-8
Wei Bo, Xiaokai Wang, Ning Yu, Chun Wang, Chunying Liu
Background: Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Cisplatin (DDP)-based combination chemotherapy is the main treatment of NSCLC. Due to resistance to DDP, 5-year overall survival rate of NSCLC patients is very low. Shenqifuzheng injection (SQFZ) is essential for lung cancer progression. However, whether SQFZ plays a role in DDP resistance in NSCLC and its molecular mechanism remains unclear.
Methods: Levels of FOXO3, FBXO22 and p53 in NSCLC tissues and cells were assessed by RT-qPCR and Western blot. Cell proliferation and apoptosis were analyzed utilizing CCK-8, Colony formation and Flow cytometry assays. Lactate (LA) levels were tested via ELISA. ChIP and Dual luciferase reporter assays validated regulatory relationship between FOXO3 and FBXO22. Immunoprecipitation assay evaluated p53 ubiquitination levels. The subcutaneous tumor model of nude mice was constructed. TUNEL staining detected apoptosis in tissues, and IHC assessed expression of Ki67, FOXO3, FBXO22 and p53.
Results: FOXO3 was decreased, whereas LA and FBXO22 were increased in NSCLC patients. LA led to a higher DDP resistance in A549/DDP cells, while SQFZ reversed this effect by upregulating FOXO3. Furthermore, FBXO22 was a downstream effecter of FOXO3 and FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ. We next found SQFZ inhibited LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 axis. Finally, SQFZ regulated LA-mediated DDP resistance in NSCLC nude mice.
Conclusion: SQFZ influences LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 pathway, providing a promising agent for NSCLC treatment.
{"title":"Shenqifuzheng injection inhibits lactic acid-induced cisplatin resistance in NSCLC by affecting FBXO22/p53 axis through FOXO3.","authors":"Wei Bo, Xiaokai Wang, Ning Yu, Chun Wang, Chunying Liu","doi":"10.1186/s12931-024-03013-8","DOIUrl":"10.1186/s12931-024-03013-8","url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancer (NSCLC) accounts for 80% of lung cancers. Cisplatin (DDP)-based combination chemotherapy is the main treatment of NSCLC. Due to resistance to DDP, 5-year overall survival rate of NSCLC patients is very low. Shenqifuzheng injection (SQFZ) is essential for lung cancer progression. However, whether SQFZ plays a role in DDP resistance in NSCLC and its molecular mechanism remains unclear.</p><p><strong>Methods: </strong>Levels of FOXO3, FBXO22 and p53 in NSCLC tissues and cells were assessed by RT-qPCR and Western blot. Cell proliferation and apoptosis were analyzed utilizing CCK-8, Colony formation and Flow cytometry assays. Lactate (LA) levels were tested via ELISA. ChIP and Dual luciferase reporter assays validated regulatory relationship between FOXO3 and FBXO22. Immunoprecipitation assay evaluated p53 ubiquitination levels. The subcutaneous tumor model of nude mice was constructed. TUNEL staining detected apoptosis in tissues, and IHC assessed expression of Ki67, FOXO3, FBXO22 and p53.</p><p><strong>Results: </strong>FOXO3 was decreased, whereas LA and FBXO22 were increased in NSCLC patients. LA led to a higher DDP resistance in A549/DDP cells, while SQFZ reversed this effect by upregulating FOXO3. Furthermore, FBXO22 was a downstream effecter of FOXO3 and FBXO22 affected p53 ubiquitination to reverse the inhibitory effect of SQFZ. We next found SQFZ inhibited LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 axis. Finally, SQFZ regulated LA-mediated DDP resistance in NSCLC nude mice.</p><p><strong>Conclusion: </strong>SQFZ influences LA-induced DDP resistance in NSCLC via FOXO3/FBXO22/p53 pathway, providing a promising agent for NSCLC treatment.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"396"},"PeriodicalIF":5.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531113/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565222","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}
Pub Date : 2024-11-01DOI: 10.1186/s12931-024-02997-7
Delian E Hofman, Tonia Magrì, Catharina C Moor, Luca Richeldi, Marlies S Wijsenbeek, Yuko Waseda
Comprehensive care integrates individual patient needs and is highly valued for patients with pulmonary fibrosis (PF). The importance of a patient-centered care approach is rooted in the unpredictable progressiveness of the disease course in PF. The respiratory impairment associated with PF has a major impact on the quality of life for both patients and their caregivers. We believe that prioritizing patient preferences could improve the shared decision making process and may ultimately lead to better health outcomes. Despite the growing emphasis for this approach, it remains challenging to adopt it in clinical practice. In this review, we propose the comprehensive Triple A Care Model, consisting of the domains Access, Anticipate, and Act, which emphasizes core elements of patient-centered care for patients with PF. We will provide an overview of the unmet needs in care for patients with PF and elaborate on the current methods for delivering patient-centered care. The latest insights into symptom management and supportive measures and several approaches to improving access to care are discussed, in line with the most recent guidelines.
{"title":"Patient-centered care in pulmonary fibrosis: access, anticipate, and act.","authors":"Delian E Hofman, Tonia Magrì, Catharina C Moor, Luca Richeldi, Marlies S Wijsenbeek, Yuko Waseda","doi":"10.1186/s12931-024-02997-7","DOIUrl":"10.1186/s12931-024-02997-7","url":null,"abstract":"<p><p>Comprehensive care integrates individual patient needs and is highly valued for patients with pulmonary fibrosis (PF). The importance of a patient-centered care approach is rooted in the unpredictable progressiveness of the disease course in PF. The respiratory impairment associated with PF has a major impact on the quality of life for both patients and their caregivers. We believe that prioritizing patient preferences could improve the shared decision making process and may ultimately lead to better health outcomes. Despite the growing emphasis for this approach, it remains challenging to adopt it in clinical practice. In this review, we propose the comprehensive Triple A Care Model, consisting of the domains Access, Anticipate, and Act, which emphasizes core elements of patient-centered care for patients with PF. We will provide an overview of the unmet needs in care for patients with PF and elaborate on the current methods for delivering patient-centered care. The latest insights into symptom management and supportive measures and several approaches to improving access to care are discussed, in line with the most recent guidelines.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":"25 1","pages":"395"},"PeriodicalIF":5.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11531140/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142565218","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}