Pub Date : 2024-09-28DOI: 10.1186/s12931-024-02973-1
Gabriela Gonzales, Ronit Malka, Lisa M Marinelli, Christine M Lee, Stacy Cook, Solaleh Miar, Gregory R Dion, Teja Guda
Background: Laryngeal injury associated with traumatic or prolonged intubation may lead to voice, swallow, and airway complications. The interplay between inflammation and microbial population shifts induced by intubation may relate to clinical outcomes. The objective of this study was to investigate laryngeal mechanics, tissue inflammatory response, and local microbiome changes with laryngotracheal injury and localized delivery of therapeutics via drug-eluting endotracheal tube.
Methods: A simulated traumatic intubation injury was created in Yorkshire crossbreed swine under direct laryngoscopy. Endotracheal tubes electrospun with roxadustat or valacyclovir- loaded polycaprolactone (PCL) fibers were placed in the injured airway for 3, 7, or 14 days (n = 3 per group/time and ETT type). Vocal fold stiffness was then evaluated with normal indentation and laryngeal tissue sections were histologically examined. Immunohistochemistry and inflammatory marker profiling were conducted to evaluate the inflammatory response associated with injury and ETT placement. Additionally, ETT biofilm formation was visualized using scanning electron microscopy and micro-computed tomography, while changes in the airway microbiome were profiled through 16S rRNA sequencing.
Results: Laryngeal tissue with roxadustat ETT placement had increasing localized stiffness outcomes over time and histological assessment indicated minimal epithelial ulceration and fibrosis, while inflammation remained severe across all timepoints. In contrast, vocal fold tissue with valacyclovir ETT placement showed no significant changes in stiffness over time; histological analysis presented a reduction in epithelial ulceration and inflammation scores along with increased fibrosis observed at 14 days. Immunohistochemistry revealed a decline in M1 and M2 macrophage markers over time for both ETT types. Among the cytokines, IL-8 levels differed significantly between the roxadustat and valacyclovir ETT groups, while no other cytokines showed statistically significant differences. Additionally, increased biofilm formation was observed in the coated ETTs with notable alterations in microbiota distinctive to each ETT type and across time.
Conclusion: The injured and intubated airway resulted in increased laryngeal stiffness. Local inflammation and the type of therapeutic administered impacted the bacterial composition within the upper respiratory microbiome, which in turn mediated local tissue healing and recovery.
背景:与创伤性或长时间插管相关的喉损伤可能会导致嗓音、吞咽和气道并发症。插管引起的炎症和微生物群变化之间的相互作用可能与临床结果有关。本研究的目的是调查喉力学、组织炎症反应以及喉气管损伤和通过药物洗脱气管导管局部给药引起的局部微生物群变化:方法:在直接喉镜检查下,对约克郡杂交猪进行模拟创伤性插管损伤。将电纺有罗沙司他(roxadustat)或伐昔洛韦(valacyclovir- loaded polycaprolactone (PCL))纤维的气管导管置于受伤气道中 3、7 或 14 天(每组/时间和 ETT 类型 n = 3)。然后用正常压痕法评估声带僵硬度,并对喉组织切片进行组织学检查。免疫组化和炎症标记物分析用于评估与损伤和 ETT 置入相关的炎症反应。此外,还使用扫描电子显微镜和微型计算机断层扫描观察了 ETT 生物膜的形成,并通过 16S rRNA 测序分析了气道微生物组的变化:结果:放置了罗沙司他 ETT 的喉组织的局部僵硬度随时间推移而增加,组织学评估显示上皮溃疡和纤维化极少,而炎症在所有时间点上都很严重。与此相反,放置了伐昔洛韦 ETT 的声带组织的僵硬度没有随着时间的推移而发生显著变化;组织学分析表明,上皮溃疡和炎症评分降低,14 天后观察到纤维化增加。免疫组化显示,两种 ETT 的 M1 和 M2 巨噬细胞标记物均随时间推移而下降。在细胞因子中,罗沙司他和伐昔洛韦 ETT 组的 IL-8 水平差异显著,而其他细胞因子则没有统计学意义上的显著差异。此外,在有涂层的 ETT 中观察到生物膜形成增加,每种 ETT 类型和不同时间段的微生物群发生了明显变化:结论:受伤和插管气道导致喉部僵硬度增加。局部炎症和治疗类型影响了上呼吸道微生物群中的细菌组成,进而促进了局部组织的愈合和恢复。
{"title":"Localized delivery of therapeutics impact laryngeal mechanics, local inflammatory response, and respiratory microbiome following upper airway intubation injury in swine.","authors":"Gabriela Gonzales, Ronit Malka, Lisa M Marinelli, Christine M Lee, Stacy Cook, Solaleh Miar, Gregory R Dion, Teja Guda","doi":"10.1186/s12931-024-02973-1","DOIUrl":"https://doi.org/10.1186/s12931-024-02973-1","url":null,"abstract":"<p><strong>Background: </strong>Laryngeal injury associated with traumatic or prolonged intubation may lead to voice, swallow, and airway complications. The interplay between inflammation and microbial population shifts induced by intubation may relate to clinical outcomes. The objective of this study was to investigate laryngeal mechanics, tissue inflammatory response, and local microbiome changes with laryngotracheal injury and localized delivery of therapeutics via drug-eluting endotracheal tube.</p><p><strong>Methods: </strong>A simulated traumatic intubation injury was created in Yorkshire crossbreed swine under direct laryngoscopy. Endotracheal tubes electrospun with roxadustat or valacyclovir- loaded polycaprolactone (PCL) fibers were placed in the injured airway for 3, 7, or 14 days (n = 3 per group/time and ETT type). Vocal fold stiffness was then evaluated with normal indentation and laryngeal tissue sections were histologically examined. Immunohistochemistry and inflammatory marker profiling were conducted to evaluate the inflammatory response associated with injury and ETT placement. Additionally, ETT biofilm formation was visualized using scanning electron microscopy and micro-computed tomography, while changes in the airway microbiome were profiled through 16S rRNA sequencing.</p><p><strong>Results: </strong>Laryngeal tissue with roxadustat ETT placement had increasing localized stiffness outcomes over time and histological assessment indicated minimal epithelial ulceration and fibrosis, while inflammation remained severe across all timepoints. In contrast, vocal fold tissue with valacyclovir ETT placement showed no significant changes in stiffness over time; histological analysis presented a reduction in epithelial ulceration and inflammation scores along with increased fibrosis observed at 14 days. Immunohistochemistry revealed a decline in M1 and M2 macrophage markers over time for both ETT types. Among the cytokines, IL-8 levels differed significantly between the roxadustat and valacyclovir ETT groups, while no other cytokines showed statistically significant differences. Additionally, increased biofilm formation was observed in the coated ETTs with notable alterations in microbiota distinctive to each ETT type and across time.</p><p><strong>Conclusion: </strong>The injured and intubated airway resulted in increased laryngeal stiffness. Local inflammation and the type of therapeutic administered impacted the bacterial composition within the upper respiratory microbiome, which in turn mediated local tissue healing and recovery.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439253/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330804","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 : 2024-09-28DOI: 10.1186/s12931-024-02969-x
Jianxia Sun, Xinyun Jia, Zhiqiang Zhang, Yang Yang, Chuntao Zhai, Baosheng Zhao, Yuzhen Liu
Background: Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice.
Methods: Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH.
Results: CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited.
Conclusions: Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer.
背景:以慢性间歇性缺氧(CIH)为特征的阻塞性睡眠呼吸暂停(OSA)是一种普遍存在的疾病,与各种形式的癌症有关。尽管一些临床研究表明 OSA 与肺癌之间存在潜在联系,但这种联系仍不确定,其潜在机制也不完全清楚。本研究探讨了儿茶酚胺-β-肾上腺素能受体(βAR)和NLRP3炎性体在介导CIH对小鼠肺癌进展的影响中的作用:雄性 C57BL/6 N 小鼠接受为期四周的 CIH 治疗,并在皮下播种 Lewis 肺癌细胞。在此期间给予普萘洛尔(一种βAR阻断剂)或奈皮司他(一种儿茶酚胺分泌抑制剂)。监测肿瘤体积和尾动脉血压。免疫组化染色和免疫荧光染色用于评估肿瘤组织中 Ki-67、CD31、VEGFR2、PD-1、PD-L1 和 ASC斑点的蛋白表达。ELISA 检测儿茶酚胺和各种细胞因子,Western 印迹评估细胞周期蛋白 D1、caspase-1 和 IL-1β 的表达。体外血管形成试验研究血管生成。用 NLRP3 基因敲除小鼠来确定 NLRP3 在 CIH 中的作用机制:结果:CIH导致儿茶酚胺增加。结果:CIH导致儿茶酚胺增加,儿茶酚胺-βAR抑制剂药物阻止了CIH引起的血压升高。值得注意的是,这些药物抑制了 CIH 诱导的小鼠肺肿瘤的生长,肿瘤中 Ki-67、细胞周期蛋白 D1、CD31、血管内皮生长因子受体 2、PD-1 和 PD-L1 的表达均有所下降。在体外,普萘洛尔能抑制 CIH 小鼠血清诱导的管形成。此外,CIH导致外周血中TNF-α、IL-6、IL-1β、IFN-γ和sPD-L1水平升高,IL-10水平降低,并伴随着肿瘤中NLRP3炎性体的激活,但这些效应也被药物所阻止。在NLRP3基因敲除的小鼠中,CIH诱导的肿瘤中PD-1/PD-L1的上调受到抑制:我们的研究强调了β肾上腺素能信号传导和NLRP3炎性体对CIH诱导的肺癌进展的重要作用。这些通路是减轻 OSA 对肺癌影响的潜在治疗靶点。
{"title":"Role of β-adrenergic signaling and the NLRP3 inflammasome in chronic intermittent hypoxia-induced murine lung cancer progression.","authors":"Jianxia Sun, Xinyun Jia, Zhiqiang Zhang, Yang Yang, Chuntao Zhai, Baosheng Zhao, Yuzhen Liu","doi":"10.1186/s12931-024-02969-x","DOIUrl":"10.1186/s12931-024-02969-x","url":null,"abstract":"<p><strong>Background: </strong>Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a prevalent condition that has been associated with various forms of cancer. Although some clinical studies suggest a potential link between OSA and lung cancer, this association remains uncertain, and the underlying mechanisms are not fully understood. This study investigated the role of the catecholamine-β-adrenergic receptor (βAR) and the NLRP3 inflammasome in mediating the effects of CIH on lung cancer progression in mice.</p><p><strong>Methods: </strong>Male C57BL/6 N mice were subjected to CIH for four weeks, with Lewis lung carcinoma cells seeded subcutaneously. Propranolol (a βAR blocker) or nepicastat (an inhibitor of catecholamine production) was administered during this period. Tumor volume and tail artery blood pressure were monitored. Immunohistochemical staining and immunofluorescence staining were employed to assess protein expression of Ki-67, CD31, VEGFR2, PD-1, PD-L1, and ASC specks in tumor tissues. ELISA was used to detect catecholamine and various cytokines, while western blot assessed the expression of cyclin D1, caspase-1, and IL-1β. In vitro tube formation assay investigated angiogenesis. NLRP3 knockout mice were used to determine the mechanism of NLRP3 in CIH.</p><p><strong>Results: </strong>CIH led to an increase in catecholamine. Catecholamine-βAR inhibitor drugs prevented the increase in blood pressure caused by CIH. Notably, the drugs inhibited CIH-induced murine lung tumor growth, and the expression of Ki-67, cyclin D1, CD31, VEGFR2, PD-1 and PD-L1 in tumor decreased. In vitro, propranolol inhibits tube formation induced by CIH mouse serum. Moreover, CIH led to an increase in TNF-α, IL-6, IL-1β, IFN-γ and sPD-L1 levels and a decrease in IL-10 in peripheral blood, accompanied by activation of NLRP3 inflammasomes in tumor, but these effects were also stopped by drugs. In NLRP3-knockout mice, CIH-induced upregulation of PD-1/PD-L1 in tumor was inhibited.</p><p><strong>Conclusions: </strong>Our study underscores the significant contribution of β-adrenergic signaling and the NLRP3 inflammasome to CIH-induced lung cancer progression. These pathways represent potential therapeutic targets for mitigating the impact of OSA on lung cancer.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439201/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330814","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 : 2024-09-23DOI: 10.1186/s12931-024-02935-7
Eistine Boateng, Rocio Bonilla-Martinez, Barbara Ahlemeyer, Vannuruswamy Garikapati, Mohammad Rashedul Alam, Omelyan Trompak, Gani Oruqaj, Natalia El-Merhie, Michael Seimetz, Clemens Ruppert, Andreas Günther, Bernhard Spengler, Srikanth Karnati, Eveline Baumgart-Vogt
Background: Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-β)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-β/δ, and PPAR-γ, are known to interact in a complex crosstalk.
Methods: To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-β1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-β1 treatment and the effects of the PPAR ligands were investigated.
Results: TGF-β1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-β1-induced fibrosis even when given 24 h after TGF-β1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-β/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-β/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-β/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-β/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive.
Conclusion: Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-β/δ and PPAR-γ.
{"title":"It takes two peroxisome proliferator-activated receptors (PPAR-β/δ and PPAR-γ) to tango idiopathic pulmonary fibrosis.","authors":"Eistine Boateng, Rocio Bonilla-Martinez, Barbara Ahlemeyer, Vannuruswamy Garikapati, Mohammad Rashedul Alam, Omelyan Trompak, Gani Oruqaj, Natalia El-Merhie, Michael Seimetz, Clemens Ruppert, Andreas Günther, Bernhard Spengler, Srikanth Karnati, Eveline Baumgart-Vogt","doi":"10.1186/s12931-024-02935-7","DOIUrl":"10.1186/s12931-024-02935-7","url":null,"abstract":"<p><strong>Background: </strong>Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant lung epithelial phenotypes, fibroblast activation, and increased extracellular matrix deposition. Transforming growth factor-beta (TGF-β)1-induced Smad signaling and downregulation of peroxisomal genes are involved in the pathogenesis and can be inhibited by peroxisome proliferator-activated receptor (PPAR)-α activation. However, the three PPARs, that is PPAR-α, PPAR-β/δ, and PPAR-γ, are known to interact in a complex crosstalk.</p><p><strong>Methods: </strong>To mimic the pathogenesis of lung fibrosis, primary lung fibroblasts from control and IPF patients with comparable levels of all three PPARs were treated with TGF-β1 for 24 h, followed by the addition of PPAR ligands either alone or in combination for another 24 h. Fibrosis markers (intra- and extracellular collagen levels, expression and activity of matrix metalloproteinases) and peroxisomal biogenesis and metabolism (gene expression of peroxisomal biogenesis and matrix proteins, protein levels of PEX13 and catalase, targeted and untargeted lipidomic profiles) were analyzed after TGF-β1 treatment and the effects of the PPAR ligands were investigated.</p><p><strong>Results: </strong>TGF-β1 induced the expected phenotype; e.g. it increased the intra- and extracellular collagen levels and decreased peroxisomal biogenesis and metabolism. Agonists of different PPARs reversed TGF-β1-induced fibrosis even when given 24 h after TGF-β1. The effects included the reversals of (1) the increase in collagen production by repressing COL1A2 promoter activity (through PPAR-β/δ activation); (2) the reduced activity of matrix metalloproteinases (through PPAR-β/δ activation); (3) the decrease in peroxisomal biogenesis and lipid metabolism (through PPAR-γ activation); and (4) the decrease in catalase protein levels in control (through PPAR-γ activation) and IPF (through a combined activation of PPAR-β/δ and PPAR-γ) fibroblasts. Further experiments to explore the role of catalase showed that an overexpression of catalase protein reduced collagen production. Additionally, the beneficial effect of PPAR-γ but not of PPAR-β/δ activation on collagen synthesis depended on catalase activity and was thus redox-sensitive.</p><p><strong>Conclusion: </strong>Our data provide evidence that IPF patients may benefit from a combined activation of PPAR-β/δ and PPAR-γ.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11421181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308884","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 : 2024-09-19DOI: 10.1186/s12931-024-02967-z
Asmae El Abd, Harika Dasari, Philippe Dodin, Helen Trottier, Francine M Ducharme
Background: Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma.
Methods: A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies.
Results: We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (β (95% CI)= - 0.33 (-0.65 to - 0.01); I2 = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D.
Conclusion: Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations.
{"title":"Associations between vitamin D status and biomarkers linked with inflammation in patients with asthma: a systematic review and meta-analysis of interventional and observational studies.","authors":"Asmae El Abd, Harika Dasari, Philippe Dodin, Helen Trottier, Francine M Ducharme","doi":"10.1186/s12931-024-02967-z","DOIUrl":"10.1186/s12931-024-02967-z","url":null,"abstract":"<p><strong>Background: </strong>Numerous studies indicate an association between vitamin D status and inflammatory biomarkers in patients with asthma, but findings are inconsistent. This review aims to summarize the relationship between serum vitamin D status, assessed by 25-hydroxyvitamin D (25(OH)D) level, and inflammatory biomarkers in children and adults with asthma.</p><p><strong>Methods: </strong>A literature search of interventional and observational studies on 25(OH)D up to November 2022 was conducted across six electronic databases. Outcomes of interest included a range of inflammatory biomarkers classified in four categories: T helper 2 (Th2) pro-inflammatory, non-Th2 pro-inflammatory, anti-inflammatory, and non-specific biomarkers. Study characteristics were extracted and risk of bias was evaluated using the American Academy of Nutrition and Dietetics tool. Meta-analysis was conducted on studies with a low risk of bias, while narrative reporting was used to present the direction of associations (positive, no association, or negative) for each biomarker, overall and within the low-risk studies.</p><p><strong>Results: </strong>We included 71 studies (3 interventional, 68 observational) involving asthma patients. These studies investigated the association between serum 25(OH)D and Th2 pro-inflammatory biomarkers (N = 58), non-Th2 pro-inflammatory biomarkers (N = 18), anti-inflammatory biomarkers (N = 16), and non-specific biomarkers (N = 10). Thirteen (18.3%) studies, 50 (70.4%), and 8 (11.3%) were at high, moderate, and low risk of bias, respectively. In all studies, irrespective of risk of bias, the most frequently reported finding was no significant association, followed by a negative association between 25(OH)D and pro-inflammatory biomarkers and a positive association with anti-inflammatory biomarkers. In low-risk studies, one biomarker could be meta-analysed. The pooled estimate for 25(OH)D and serum IgE showed a negative association (β (95% CI)= - 0.33 (-0.65 to - 0.01); I<sup>2</sup> = 88%; N = 4 studies). A negative association between 25(OH)D and blood eosinophils was also observed in the largest of three studies, as well as with cathelicidin (LL-37) in the only study reporting it. For other biomarkers, most low-risk studies revealed no significant association with 25(OH)D.</p><p><strong>Conclusion: </strong>Serum 25(OH)D is negatively associated with serum IgE and possibly with blood eosinophils and LL-37, supporting an in vivo immunomodulatory effect of 25(OH)D. Future research should employ rigorous methodologies and standardized reporting for meta-analysis aggregation to further elucidate these associations.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11423515/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330798","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: Over the past three decades, our understanding of sleep apnea in women has advanced, revealing disparities in pathophysiology, diagnosis, and treatment compared to men. However, no real-life study to date has explored the relationship between mask-related side effects (MRSEs) and gender in the context of long-term CPAP.
Methods: The InterfaceVent-CPAP study is a prospective real-life cross-sectional study conducted in an apneic adult cohort undergoing at least 3 months of CPAP with unrestricted mask-access (34 different masks, no gender specific mask series). MRSE were assessed by the patient using visual analog scales (VAS). CPAP-non-adherence was defined as a mean CPAP-usage of less than 4 h per day. The primary objective of this ancillary study was to investigate the impact of gender on the prevalence of MRSEs reported by the patient. Secondary analyses assessed the impact of MRSEs on CPAP-usage and CPAP-non-adherence depending on the gender.
Results: A total of 1484 patients treated for a median duration of 4.4 years (IQ25-75: 2.0-9.7) were included in the cohort, with women accounting for 27.8%. The prevalence of patient-reported mask injury, defined as a VAS score ≥ 5 (p = 0.021), was higher in women than in men (9.6% versus 5.3%). For nasal pillow masks, the median MRSE VAS score for dry mouth was higher in women (p = 0.039). For oronasal masks, the median MRSE VAS score for runny nose was higher in men (p = 0.039). Multivariable regression analyses revealed that, for both women and men, dry mouth was independently and negatively associated with CPAP-usage, and positively associated with CPAP-non-adherence.
Conclusion: In real-life patients treated with long-term CPAP, there are gender differences in patient reported MRSEs. In the context of personalized medicine, these results suggest that the design of future masks should consider these gender differences if masks specifically for women are developed. However, only dry mouth, a side effect not related to mask design, impacts CPAP-usage and non-adherence.
Trial registration: INTERFACEVENT IS REGISTERED WITH CLINICALTRIALS.GOV (NCT03013283).FIRST REGISTRATION DATE IS 2016-12-23.
{"title":"Mask side-effects are related to gender in long-term CPAP: results from the InterfaceVent real-life study.","authors":"Celia Vidal, Fanny Bertelli, Jean-Pierre Mallet, Raphael Gilson, Jean-Christian Borel, Frédéric Gagnadoux, Arnaud Bourdin, Nicolas Molinari, Dany Jaffuel","doi":"10.1186/s12931-024-02965-1","DOIUrl":"10.1186/s12931-024-02965-1","url":null,"abstract":"<p><strong>Background: </strong>Over the past three decades, our understanding of sleep apnea in women has advanced, revealing disparities in pathophysiology, diagnosis, and treatment compared to men. However, no real-life study to date has explored the relationship between mask-related side effects (MRSEs) and gender in the context of long-term CPAP.</p><p><strong>Methods: </strong>The InterfaceVent-CPAP study is a prospective real-life cross-sectional study conducted in an apneic adult cohort undergoing at least 3 months of CPAP with unrestricted mask-access (34 different masks, no gender specific mask series). MRSE were assessed by the patient using visual analog scales (VAS). CPAP-non-adherence was defined as a mean CPAP-usage of less than 4 h per day. The primary objective of this ancillary study was to investigate the impact of gender on the prevalence of MRSEs reported by the patient. Secondary analyses assessed the impact of MRSEs on CPAP-usage and CPAP-non-adherence depending on the gender.</p><p><strong>Results: </strong>A total of 1484 patients treated for a median duration of 4.4 years (IQ<sub>25-75</sub>: 2.0-9.7) were included in the cohort, with women accounting for 27.8%. The prevalence of patient-reported mask injury, defined as a VAS score ≥ 5 (p = 0.021), was higher in women than in men (9.6% versus 5.3%). For nasal pillow masks, the median MRSE VAS score for dry mouth was higher in women (p = 0.039). For oronasal masks, the median MRSE VAS score for runny nose was higher in men (p = 0.039). Multivariable regression analyses revealed that, for both women and men, dry mouth was independently and negatively associated with CPAP-usage, and positively associated with CPAP-non-adherence.</p><p><strong>Conclusion: </strong>In real-life patients treated with long-term CPAP, there are gender differences in patient reported MRSEs. In the context of personalized medicine, these results suggest that the design of future masks should consider these gender differences if masks specifically for women are developed. However, only dry mouth, a side effect not related to mask design, impacts CPAP-usage and non-adherence.</p><p><strong>Trial registration: </strong>INTERFACEVENT IS REGISTERED WITH CLINICALTRIALS.GOV (NCT03013283).FIRST REGISTRATION DATE IS 2016-12-23.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11380403/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142146654","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: Vascular endothelial damage is involved in the development and exacerbation of ventilator-induced lung injury (VILI). Pulmonary endothelial glycocalyx and neutrophil extracellular traps (NETs) are endothelial protective and damaging factors, respectively; however, their dynamics in VILI and the effects of recombinant thrombomodulin and antithrombin on these dynamics remain unclear. We hypothesized that glycocalyx degradation and NETs are induced by VILI and suppressed by recombinant thrombomodulin, recombinant antithrombin, or their combination.
Methods: VILI was induced in male C57BL/6J mice by intraperitoneal lipopolysaccharide injection (20 mg/kg) and high tidal volume ventilation (20 mL/kg). In the intervention groups, recombinant thrombomodulin, recombinant antithrombin, or their combination was administered at the start of mechanical ventilation. Glycocalyx degradation was quantified by measuring serum syndecan-1, fluorescence-labeled lectin intensity, and glycocalyx-occupied area in the pulmonary vascular lumen. Double-stranded DNA in the bronchoalveolar fluid and fluorescent areas of citrullinated histone H3 and myeloperoxidase were quantified as NET formation.
Results: Serum syndecan-1 increased, and lectin fluorescence intensity decreased in VILI. Electron microscopy revealed decreases in glycocalyx-occupied areas within pulmonary microvessels in VILI. Double-stranded DNA levels in the bronchoalveolar lavage fluid and the fluorescent area of citrullinated histone H3 and myeloperoxidase in lung tissues increased in VILI. Recombinant thrombomodulin, recombinant antithrombin, and their combination reduced glycocalyx injury and NET marker levels. There was little difference in glycocalyx injury and NET makers between the intervention groups.
Conclusion: VILI induced glycocalyx degradation and NET formation. Recombinant thrombomodulin and recombinant antithrombin attenuated glycocalyx degradation and NETs in our VILI model. The effect of their combination did not differ from that of either drug alone. Recombinant thrombomodulin and antithrombin have the potential to be therapeutic agents for biotrauma in VILI.
背景:血管内皮损伤参与了呼吸机诱发肺损伤(VILI)的发生和加重。肺内皮糖萼和中性粒细胞胞外捕获物(NET)分别是内皮保护因子和损伤因子;然而,它们在 VILI 中的动态变化以及重组凝血酶原和抗凝血酶对这些动态变化的影响仍不清楚。我们假设,VILI 会诱导糖萼降解和 NET,而重组凝血酶原、重组抗凝血酶或它们的组合会抑制糖萼降解和 NET:方法:通过腹腔注射脂多糖(20 毫克/千克)和高潮气量通气(20 毫升/千克)诱导雄性 C57BL/6J 小鼠 VILI。在干预组中,机械通气开始时给予重组血栓调节蛋白、重组抗凝血酶或它们的组合。通过测量血清辛迪加-1、荧光标记凝集素强度和肺血管腔内糖萼占位面积来量化糖萼降解情况。支气管肺泡液中的双链DNA以及瓜氨酸组蛋白H3和髓过氧化物酶的荧光区域被量化为NET的形成:结果:VILI患者血清辛迪加-1增加,凝集素荧光强度降低。电子显微镜显示,VILI 患者肺微血管中糖萼占据的区域减少。VILI 患者支气管肺泡灌洗液中的双链 DNA 含量以及肺组织中瓜氨酸化组蛋白 H3 和髓过氧化物酶的荧光面积均有所增加。重组血栓调节蛋白、重组抗凝血酶和它们的组合可减少糖萼损伤和 NET 标记物水平。干预组之间的糖萼损伤和NET标记物差异不大:结论:VILI诱导糖萼降解和NET形成。在我们的 VILI 模型中,重组血栓调节蛋白和重组抗凝血酶减轻了糖萼降解和 NET 的形成。这两种药物联合使用的效果与单独使用两种药物的效果没有区别。重组血栓调节蛋白和抗凝血酶有可能成为治疗 VILI 生物创伤的药物。
{"title":"Recombinant thrombomodulin and recombinant antithrombin attenuate pulmonary endothelial glycocalyx degradation and neutrophil extracellular trap formation in ventilator-induced lung injury in the context of endotoxemia.","authors":"Kenichiro Kikuchi, Satoshi Kazuma, Michiaki Yamakage","doi":"10.1186/s12931-024-02958-0","DOIUrl":"10.1186/s12931-024-02958-0","url":null,"abstract":"<p><strong>Background: </strong>Vascular endothelial damage is involved in the development and exacerbation of ventilator-induced lung injury (VILI). Pulmonary endothelial glycocalyx and neutrophil extracellular traps (NETs) are endothelial protective and damaging factors, respectively; however, their dynamics in VILI and the effects of recombinant thrombomodulin and antithrombin on these dynamics remain unclear. We hypothesized that glycocalyx degradation and NETs are induced by VILI and suppressed by recombinant thrombomodulin, recombinant antithrombin, or their combination.</p><p><strong>Methods: </strong>VILI was induced in male C57BL/6J mice by intraperitoneal lipopolysaccharide injection (20 mg/kg) and high tidal volume ventilation (20 mL/kg). In the intervention groups, recombinant thrombomodulin, recombinant antithrombin, or their combination was administered at the start of mechanical ventilation. Glycocalyx degradation was quantified by measuring serum syndecan-1, fluorescence-labeled lectin intensity, and glycocalyx-occupied area in the pulmonary vascular lumen. Double-stranded DNA in the bronchoalveolar fluid and fluorescent areas of citrullinated histone H3 and myeloperoxidase were quantified as NET formation.</p><p><strong>Results: </strong>Serum syndecan-1 increased, and lectin fluorescence intensity decreased in VILI. Electron microscopy revealed decreases in glycocalyx-occupied areas within pulmonary microvessels in VILI. Double-stranded DNA levels in the bronchoalveolar lavage fluid and the fluorescent area of citrullinated histone H3 and myeloperoxidase in lung tissues increased in VILI. Recombinant thrombomodulin, recombinant antithrombin, and their combination reduced glycocalyx injury and NET marker levels. There was little difference in glycocalyx injury and NET makers between the intervention groups.</p><p><strong>Conclusion: </strong>VILI induced glycocalyx degradation and NET formation. Recombinant thrombomodulin and recombinant antithrombin attenuated glycocalyx degradation and NETs in our VILI model. The effect of their combination did not differ from that of either drug alone. Recombinant thrombomodulin and antithrombin have the potential to be therapeutic agents for biotrauma in VILI.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373098/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127123","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 : 2024-09-03DOI: 10.1186/s12931-024-02964-2
TaoHu Zhou, Yu Guan, XiaoQing Lin, XiuXiu Zhou, Liang Mao, YanQing Ma, Bing Fan, Jie Li, ShiYuan Liu, Li Fan
Background: Preserved Ratio Impaired Spirometry (PRISm) is considered to be a precursor of chronic obstructive pulmonary disease. Radiomics nomogram can effectively identify the PRISm subjects from non-COPD subjects, especially when during large-scale CT lung cancer screening.
Methods: Totally 1481 participants (864, 370 and 247 in training, internal validation, and external validation cohorts, respectively) were included. Whole lung on thin-section computed tomography (CT) was segmented with a fully automated segmentation algorithm. PyRadiomics was adopted for extracting radiomics features. Clinical features were also obtained. Moreover, Spearman correlation analysis, minimum redundancy maximum relevance (mRMR) feature ranking and least absolute shrinkage and selection operator (LASSO) classifier were adopted to analyze whether radiomics features could be used to build radiomics signatures. A nomogram that incorporated clinical features and radiomics signature was constructed through multivariable logistic regression. Last, calibration, discrimination and clinical usefulness were analyzed using validation cohorts.
Results: The radiomics signature, which included 14 stable features, was related to PRISm of training and validation cohorts (p < 0.001). The radiomics nomogram incorporating independent predicting factors (radiomics signature, age, BMI, and gender) well discriminated PRISm from non-COPD subjects compared with clinical model or radiomics signature alone for training cohort (AUC 0.787 vs. 0.675 vs. 0.778), internal (AUC 0.773 vs. 0.682 vs. 0.767) and external validation cohorts (AUC 0.702 vs. 0.610 vs. 0.699). Decision curve analysis suggested that our constructed radiomics nomogram outperformed clinical model.
Conclusions: The CT-based whole lung radiomics nomogram could identify PRISm to help decision-making in clinic.
{"title":"CT-based whole lung radiomics nomogram for identification of PRISm from non-COPD subjects.","authors":"TaoHu Zhou, Yu Guan, XiaoQing Lin, XiuXiu Zhou, Liang Mao, YanQing Ma, Bing Fan, Jie Li, ShiYuan Liu, Li Fan","doi":"10.1186/s12931-024-02964-2","DOIUrl":"10.1186/s12931-024-02964-2","url":null,"abstract":"<p><strong>Background: </strong>Preserved Ratio Impaired Spirometry (PRISm) is considered to be a precursor of chronic obstructive pulmonary disease. Radiomics nomogram can effectively identify the PRISm subjects from non-COPD subjects, especially when during large-scale CT lung cancer screening.</p><p><strong>Methods: </strong>Totally 1481 participants (864, 370 and 247 in training, internal validation, and external validation cohorts, respectively) were included. Whole lung on thin-section computed tomography (CT) was segmented with a fully automated segmentation algorithm. PyRadiomics was adopted for extracting radiomics features. Clinical features were also obtained. Moreover, Spearman correlation analysis, minimum redundancy maximum relevance (mRMR) feature ranking and least absolute shrinkage and selection operator (LASSO) classifier were adopted to analyze whether radiomics features could be used to build radiomics signatures. A nomogram that incorporated clinical features and radiomics signature was constructed through multivariable logistic regression. Last, calibration, discrimination and clinical usefulness were analyzed using validation cohorts.</p><p><strong>Results: </strong>The radiomics signature, which included 14 stable features, was related to PRISm of training and validation cohorts (p < 0.001). The radiomics nomogram incorporating independent predicting factors (radiomics signature, age, BMI, and gender) well discriminated PRISm from non-COPD subjects compared with clinical model or radiomics signature alone for training cohort (AUC 0.787 vs. 0.675 vs. 0.778), internal (AUC 0.773 vs. 0.682 vs. 0.767) and external validation cohorts (AUC 0.702 vs. 0.610 vs. 0.699). Decision curve analysis suggested that our constructed radiomics nomogram outperformed clinical model.</p><p><strong>Conclusions: </strong>The CT-based whole lung radiomics nomogram could identify PRISm to help decision-making in clinic.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373438/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142127122","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: The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.
Methods and results: To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.
Conclusions: Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.
{"title":"Unraveling the Mfn2-Warburg effect nexus: a therapeutic strategy to combat pulmonary arterial hypertension arising from catch-up growth after IUGR.","authors":"Lingling Yan, Xiaofei Luo, Chengcheng Hang, YuWang, Ziming Zhang, Shanshan Xu, Lizhong Du","doi":"10.1186/s12931-024-02957-1","DOIUrl":"10.1186/s12931-024-02957-1","url":null,"abstract":"<p><strong>Background: </strong>The interplay between intrauterine and early postnatal environments has been associated with an increased risk of cardiovascular diseases in adulthood, including pulmonary arterial hypertension (PAH). While emerging evidence highlights the crucial role of mitochondrial pathology in PAH, the specific mechanisms driving fetal-originated PAH remain elusive.</p><p><strong>Methods and results: </strong>To elucidate the role of mitochondrial dynamics in the pathogenesis of fetal-originated PAH, we established a rat model of postnatal catch-up growth following intrauterine growth restriction (IUGR) to induce pulmonary arterial hypertension (PAH). RNA-seq analysis of pulmonary artery samples from the rats revealed dysregulated mitochondrial metabolic genes and pathways associated with increased pulmonary arterial pressure and pulmonary arterial remodeling in the RC group (postnatal catch-up growth following IUGR). In vitro experiments using pulmonary arterial smooth muscle cells (PASMCs) from the RC group demonstrated elevated proliferation, migration, and impaired mitochondrial functions. Notably, reduced expression of Mitofusion 2 (Mfn2), a mitochondrial outer membrane protein involved in mitochondrial fusion, was observed in the RC group. Reconstitution of Mfn2 resulted in enhanced mitochondrial fusion and improved mitochondrial functions in PASMCs of RC group, effectively reversing the Warburg effect. Importantly, Mfn2 reconstitution alleviated the PAH phenotype in the RC group rats.</p><p><strong>Conclusions: </strong>Imbalanced mitochondrial dynamics, characterized by reduced Mfn2 expression, plays a critical role in the development of fetal-originated PAH following postnatal catch-up growth after IUGR. Mfn2 emerges as a promising therapeutic strategy for managing IUGR-catch-up growth induced PAH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370119/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120938","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 : 2024-08-31DOI: 10.1186/s12931-024-02954-4
Dihui Zhang, Xiaowei Pu, Man Zheng, Guanghui Li, Jia Chen
Background: Asthma, a prevalent chronic inflammatory disorder, is shaped by a multifaceted interplay between genetic susceptibilities and environmental exposures. Despite strides in deciphering its pathophysiological landscape, the intricate molecular underpinnings of asthma remain elusive. The focus has increasingly shifted toward the metabolic aberrations accompanying asthma, particularly within the domain of pyrimidine metabolism (PyM)-a critical pathway in nucleotide synthesis and degradation. While the therapeutic relevance of PyM has been recognized across various diseases, its specific contributions to asthma pathology are yet underexplored. This study employs sophisticated bioinformatics approaches to delineate and confirm the involvement of PyM genes (PyMGs) in asthma, aiming to bridge this significant gap in knowledge.
Methods: Employing cutting-edge bioinformatics techniques, this research aimed to elucidate the role of PyMGs in asthma. We conducted a detailed examination of 31 PyMGs to assess their differential expression. Through Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), we explored the biological functions and pathways linked to these genes. We utilized Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) to pinpoint critical hub genes and to ascertain the diagnostic accuracy of eight PyMGs in distinguishing asthma, complemented by an extensive correlation study with the clinical features of the disease. Validation of the gene expressions was performed using datasets GSE76262 and GSE147878.
Results: Our analyses revealed that eleven PyMGs-DHODH, UMPS, NME7, NME1, POLR2B, POLR3B, POLR1C, POLE, ENPP3, RRM2B, TK2-are significantly associated with asthma. These genes play crucial roles in essential biological processes such as RNA splicing, anatomical structure maintenance, and metabolic processes involving purine compounds.
Conclusions: This investigation identifies eleven PyMGs at the core of asthma's pathogenesis, establishing them as potential biomarkers for this disease. Our findings enhance the understanding of asthma's molecular mechanisms and open new avenues for improving diagnostics, monitoring, and progression evaluation. By providing new insights into non-cancerous pathologies, our work introduces a novel perspective and sets the stage for further studies in this field.
{"title":"Employing a synergistic bioinformatics and machine learning framework to elucidate biomarkers associating asthma with pyrimidine metabolism genes.","authors":"Dihui Zhang, Xiaowei Pu, Man Zheng, Guanghui Li, Jia Chen","doi":"10.1186/s12931-024-02954-4","DOIUrl":"10.1186/s12931-024-02954-4","url":null,"abstract":"<p><strong>Background: </strong>Asthma, a prevalent chronic inflammatory disorder, is shaped by a multifaceted interplay between genetic susceptibilities and environmental exposures. Despite strides in deciphering its pathophysiological landscape, the intricate molecular underpinnings of asthma remain elusive. The focus has increasingly shifted toward the metabolic aberrations accompanying asthma, particularly within the domain of pyrimidine metabolism (PyM)-a critical pathway in nucleotide synthesis and degradation. While the therapeutic relevance of PyM has been recognized across various diseases, its specific contributions to asthma pathology are yet underexplored. This study employs sophisticated bioinformatics approaches to delineate and confirm the involvement of PyM genes (PyMGs) in asthma, aiming to bridge this significant gap in knowledge.</p><p><strong>Methods: </strong>Employing cutting-edge bioinformatics techniques, this research aimed to elucidate the role of PyMGs in asthma. We conducted a detailed examination of 31 PyMGs to assess their differential expression. Through Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA), we explored the biological functions and pathways linked to these genes. We utilized Lasso regression and Support Vector Machine-Recursive Feature Elimination (SVM-RFE) to pinpoint critical hub genes and to ascertain the diagnostic accuracy of eight PyMGs in distinguishing asthma, complemented by an extensive correlation study with the clinical features of the disease. Validation of the gene expressions was performed using datasets GSE76262 and GSE147878.</p><p><strong>Results: </strong>Our analyses revealed that eleven PyMGs-DHODH, UMPS, NME7, NME1, POLR2B, POLR3B, POLR1C, POLE, ENPP3, RRM2B, TK2-are significantly associated with asthma. These genes play crucial roles in essential biological processes such as RNA splicing, anatomical structure maintenance, and metabolic processes involving purine compounds.</p><p><strong>Conclusions: </strong>This investigation identifies eleven PyMGs at the core of asthma's pathogenesis, establishing them as potential biomarkers for this disease. Our findings enhance the understanding of asthma's molecular mechanisms and open new avenues for improving diagnostics, monitoring, and progression evaluation. By providing new insights into non-cancerous pathologies, our work introduces a novel perspective and sets the stage for further studies in this field.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11365277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113936","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}
Objectives: In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH).
Methods: Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH.
Results: The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression.
Conclusions: NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.
{"title":"Ubiquitination of angiotensin-converting enzyme 2 contributes to the development of pulmonary arterial hypertension mediated by neural precursor cell-expressed developmentally down-regulated gene 4-Like.","authors":"Rui Wang, Rui Wang, Siqi Zhou, Tianya Liu, Jingjing Dang, Qianmin Chen, Jingyu Chen, Zhiping Wang","doi":"10.1186/s12931-024-02953-5","DOIUrl":"10.1186/s12931-024-02953-5","url":null,"abstract":"<p><strong>Objectives: </strong>In this study, we investigated whether neural precursor cell-expressed developmentally down-regulated gene 4-like (NEDD4L) is the E3 enzyme of angiotensin-converting enzyme 2 (ACE2) and whether NEDD4L degrades ACE2 via ubiquitination, leading to the progression of pulmonary arterial hypertension (PAH).</p><p><strong>Methods: </strong>Bioinformatic analyses were used to explore the E3 ligase that ubiquitinates ACE2. Cultured pulmonary arterial smooth muscle cells (PASMCs) and specimens from patients with PAH were used to investigate the crosstalk between NEDD4L and ACE2 and its ubiquitination in the context of PAH.</p><p><strong>Results: </strong>The inhibition of ubiquitination attenuated hypoxia-induced proliferation of PASMCs. The levels of NEDD4L were increased, and those of ACE2 were decreased in lung tissues from patients with PAH and in PASMCs. NEDD4L, the E3 ligase of ACE2, inhibited the expression of ACE2 in PASMCs, possibly through ubiquitination-mediated degradation. PAH was associated with upregulation of NEDD4L expression and downregulation of ACE2 expression.</p><p><strong>Conclusions: </strong>NEDD4L, the E3 ubiquitination enzyme of ACE2, promotes the proliferation of PASMCs, ultimately leading to PAH.</p>","PeriodicalId":49131,"journal":{"name":"Respiratory Research","volume":null,"pages":null},"PeriodicalIF":5.8,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363581/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142113937","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}