Community-acquired pneumonia (CAP) is a significant global health concern, responsible for high mortality and morbidity. Recent research has revealed a potential link between disordered microbiome and metabolism in pneumonia, although the precise relationship between these factors and severe CAP remains unclear. To address this knowledge gap, we conducted a comprehensive analysis utilizing 16S sequencing and LC-MS/MS metabolomics data to characterize the microbial profile in sputum and metabolic profile in serum in patients with severe community-acquired pneumonia (sCAP). Our analysis identified 13 genera through LEfSe analysis and 15 metabolites meeting specific criteria (P < 0.05, VIP ≥ 2, and |Log2(FC)| ≥ 2). The findings of this study demonstrate the presence of altered coordination between the microbiome of the lower respiratory tract and host metabolism in patients with sCAP. The observed concentration trends of specific metabolites across different disease stages further support the potential involvement of the serum metabolism in the development of sCAP. These correlations between the airway microbiome and host metabolism in sCAP patients have important implications for optimizing early diagnosis and developing individualized therapeutic strategies.
{"title":"Integrative Analyses Reveal the Correlation Between the Airway Microbiome and Host Metabolism in Severe Community-acquired Pneumonia.","authors":"Siqin Chen, Ping Chen, Minhong Su, Jia Jiang, Xiang Liu, Panxiao Shen, Xi Li, Fu Rong, Shaofeng Zhang, Jiayi Liu, Yaling Zeng, Wei Lei, Junhang Li, Kongqiu Wang, Gongqi Chen, Xiaobin Zheng, Xin Chen, Qiang Xiao","doi":"10.1165/rcmb.2024-0030OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0030OC","url":null,"abstract":"<p><p>Community-acquired pneumonia (CAP) is a significant global health concern, responsible for high mortality and morbidity. Recent research has revealed a potential link between disordered microbiome and metabolism in pneumonia, although the precise relationship between these factors and severe CAP remains unclear. To address this knowledge gap, we conducted a comprehensive analysis utilizing 16S sequencing and LC-MS/MS metabolomics data to characterize the microbial profile in sputum and metabolic profile in serum in patients with severe community-acquired pneumonia (sCAP). Our analysis identified 13 genera through LEfSe analysis and 15 metabolites meeting specific criteria (P < 0.05, VIP ≥ 2, and |Log2(FC)| ≥ 2). The findings of this study demonstrate the presence of altered coordination between the microbiome of the lower respiratory tract and host metabolism in patients with sCAP. The observed concentration trends of specific metabolites across different disease stages further support the potential involvement of the serum metabolism in the development of sCAP. These correlations between the airway microbiome and host metabolism in sCAP patients have important implications for optimizing early diagnosis and developing individualized therapeutic strategies.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-05DOI: 10.1165/rcmb.2024-0226OC
Camila M Lopes-Ramos, Katherine H Shutta, Min Hyung Ryu, Yichen Huang, Enakshi Saha, John Ziniti, Robert Chase, Brian D Hobbs, Jeong H Yun, Peter Castaldi, Craig P Hersh, Kimberly Glass, Edwin K Silverman, John Quackenbush, Dawn L DeMeo
Compared to men, women often develop COPD at an earlier age with worse respiratory symptoms despite lower smoking exposure. However, most preventive, and therapeutic strategies ignore biological sex differences in COPD. Our goal was to better understand sex-specific gene regulatory processes in lung tissue and the molecular basis for sex differences in COPD onset and severity. We analyzed lung tissue gene expression and DNA methylation data from 747 individuals in the Lung Tissue Research Consortium (LTRC), and 85 individuals in an independent dataset. We identified sex differences in COPD-associated gene regulation using gene regulatory networks. We used linear regression to test for sex-biased associations of methylation with lung function, emphysema, smoking, and age. Analyzing gene regulatory networks in the control group, we identified that genes involved in the extracellular matrix (ECM) have higher transcriptional factor targeting in females than in males. However, this pattern is reversed in COPD, with males showing stronger regulatory targeting of ECM-related genes than females. Smoking exposure, age, lung function, and emphysema were all associated with sex-specific differential methylation of ECM-related genes. We identified sex-based gene regulatory patterns of ECM-related genes associated with lung function and emphysema. Multiple factors including epigenetics, smoking, aging, and cell heterogeneity influence sex-specific gene regulation in COPD. Our findings underscore the importance of considering sex as a key factor in disease susceptibility and severity.
与男性相比,女性患慢性阻塞性肺病的年龄往往较早,尽管吸烟量较少,但呼吸道症状却更严重。然而,大多数预防和治疗策略都忽视了慢性阻塞性肺病的生物学性别差异。我们的目标是更好地了解肺组织中的性别特异性基因调控过程,以及慢性阻塞性肺病发病和严重程度的性别差异的分子基础。我们分析了肺组织研究联合会(LTRC)中 747 人的肺组织基因表达和 DNA 甲基化数据,以及独立数据集中 85 人的肺组织基因表达和 DNA 甲基化数据。我们利用基因调控网络确定了 COPD 相关基因调控的性别差异。我们使用线性回归来检验甲基化与肺功能、肺气肿、吸烟和年龄之间是否存在性别差异。通过分析对照组的基因调控网络,我们发现涉及细胞外基质(ECM)的基因在女性中的转录因子靶向率高于男性。然而,这种模式在慢性阻塞性肺病中却相反,男性比女性对 ECM 相关基因的调控靶向性更强。吸烟暴露、年龄、肺功能和肺气肿都与 ECM 相关基因的性别特异性甲基化差异有关。我们确定了与肺功能和肺气肿相关的 ECM 相关基因的性别基因调控模式。包括表观遗传学、吸烟、衰老和细胞异质性在内的多种因素会影响慢性阻塞性肺病的性别特异性基因调控。我们的研究结果强调了将性别视为疾病易感性和严重程度的关键因素的重要性。
{"title":"Sex-biased Regulation of Extracellular Matrix Genes in COPD.","authors":"Camila M Lopes-Ramos, Katherine H Shutta, Min Hyung Ryu, Yichen Huang, Enakshi Saha, John Ziniti, Robert Chase, Brian D Hobbs, Jeong H Yun, Peter Castaldi, Craig P Hersh, Kimberly Glass, Edwin K Silverman, John Quackenbush, Dawn L DeMeo","doi":"10.1165/rcmb.2024-0226OC","DOIUrl":"10.1165/rcmb.2024-0226OC","url":null,"abstract":"<p><p>Compared to men, women often develop COPD at an earlier age with worse respiratory symptoms despite lower smoking exposure. However, most preventive, and therapeutic strategies ignore biological sex differences in COPD. Our goal was to better understand sex-specific gene regulatory processes in lung tissue and the molecular basis for sex differences in COPD onset and severity. We analyzed lung tissue gene expression and DNA methylation data from 747 individuals in the Lung Tissue Research Consortium (LTRC), and 85 individuals in an independent dataset. We identified sex differences in COPD-associated gene regulation using gene regulatory networks. We used linear regression to test for sex-biased associations of methylation with lung function, emphysema, smoking, and age. Analyzing gene regulatory networks in the control group, we identified that genes involved in the extracellular matrix (ECM) have higher transcriptional factor targeting in females than in males. However, this pattern is reversed in COPD, with males showing stronger regulatory targeting of ECM-related genes than females. Smoking exposure, age, lung function, and emphysema were all associated with sex-specific differential methylation of ECM-related genes. We identified sex-based gene regulatory patterns of ECM-related genes associated with lung function and emphysema. Multiple factors including epigenetics, smoking, aging, and cell heterogeneity influence sex-specific gene regulation in COPD. Our findings underscore the importance of considering sex as a key factor in disease susceptibility and severity.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141892700","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1165/rcmb.2024-0081OC
Rui Sun, Xingning Pan, Erin Ward, Rafael Intrevado, Arina Morozan, Anne-Marie Lauzon, James G Martin
The transcription factors (TFs) MyoCD (myocardin) and Elk-1 (ETS Like-1 protein) competitively bind to SRF (serum response factor) and control myogenic- and mitogenic-related gene expression in smooth muscle, respectively. Their functions are therefore mutually inhibitory, which results in a contractile-versus-proliferative phenotype dichotomy. Airway smooth muscle cell (ASMC) phenotype alterations occur in various inflammatory airway diseases, promoting pathological remodeling and contributing to airflow obstruction. We characterized MyoCD and Elk-1 interactions and their roles in phenotype determination in human ASMCs. MyoCD overexpression in ASMCs increased smooth muscle gene expression, force generation, and partially restored the loss of smooth muscle protein associated with prolonged culturing while inhibiting Elk-1 transcriptional activities and proliferation induced by EGF (epidermal growth factor). However, MyoCD overexpression failed to suppress these responses induced by FBS, as FBS also upregulated SRF expression to a degree that allowed unopposed function of both TFs. Inhibition of the RhoA pathway reversed said SRF changes, allowing inhibition of Elk-1 by MyoCD overexpression and suppressing FBS-mediated contractile protein gene upregulation. Our study confirmed that MyoCD in increased abundance can competitively inhibit Elk-1 function. However, SRF upregulation permits a dual contractile-proliferative ASMC phenotype that is anticipated to exacerbate pathological alterations, whereas therapies targeting SRF may inhibit pathological ASMC proliferation and contractile protein gene expression.
{"title":"Serum Response Factor Expression in Excess Permits a Dual Contractile-Proliferative Phenotype of Airway Smooth Muscle.","authors":"Rui Sun, Xingning Pan, Erin Ward, Rafael Intrevado, Arina Morozan, Anne-Marie Lauzon, James G Martin","doi":"10.1165/rcmb.2024-0081OC","DOIUrl":"10.1165/rcmb.2024-0081OC","url":null,"abstract":"<p><p>The transcription factors (TFs) MyoCD (myocardin) and Elk-1 (ETS Like-1 protein) competitively bind to SRF (serum response factor) and control myogenic- and mitogenic-related gene expression in smooth muscle, respectively. Their functions are therefore mutually inhibitory, which results in a contractile-versus-proliferative phenotype dichotomy. Airway smooth muscle cell (ASMC) phenotype alterations occur in various inflammatory airway diseases, promoting pathological remodeling and contributing to airflow obstruction. We characterized MyoCD and Elk-1 interactions and their roles in phenotype determination in human ASMCs. MyoCD overexpression in ASMCs increased smooth muscle gene expression, force generation, and partially restored the loss of smooth muscle protein associated with prolonged culturing while inhibiting Elk-1 transcriptional activities and proliferation induced by EGF (epidermal growth factor). However, MyoCD overexpression failed to suppress these responses induced by FBS, as FBS also upregulated SRF expression to a degree that allowed unopposed function of both TFs. Inhibition of the RhoA pathway reversed said SRF changes, allowing inhibition of Elk-1 by MyoCD overexpression and suppressing FBS-mediated contractile protein gene upregulation. Our study confirmed that MyoCD in increased abundance can competitively inhibit Elk-1 function. However, SRF upregulation permits a dual contractile-proliferative ASMC phenotype that is anticipated to exacerbate pathological alterations, whereas therapies targeting SRF may inhibit pathological ASMC proliferation and contractile protein gene expression.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Cytolytic ETosis is a type of programmed cell death distinct from apoptosis and necrosis and plays a major role in the innate immune system and disease progression. Through the process of ETosis, cells release their chromatin with diverse antimicrobial proteins into the extracellular milieu, forming extracellular traps (ETs). Although ETosis has been reported in several leukocyte types, few studies have compared ETosis and the component proteins of ETs in leukocytes. The aim of this study was to better understand the characteristics of eosinophil ETosis (EETosis) compared with other leukocytes. We isolated human blood eosinophils, neutrophils, basophils, monocytes, and lymphocytes and stimulated them with known ETosis inducers, a protein kinase C activator PMA, or a calcium ionophore A23187. Both stimuli induced eosinophil cell death and ET release after 180 minutes of stimulation in a NADPH-oxidase-dependent manner. PMA also induced NADPH-oxidase-dependent ETosis in neutrophils, whereas little or no significant ETosis was observed in basophils, monocytes, or lymphocytes at 180 minutes. Mass spectrometry-based proteomic analysis of eosinophil- and neutrophil-derived ETs identified 997 and 1415 proteins, respectively. Among the physiological stimuli tested, immobilized IgA and IgG induced EETosis. C-C motif chemokine ligand 11 (CCL11) and interleukin 5 (IL-5) were weak inducers of EETosis, but co-stimulation significantly induced rapid EETosis. Under high serum or albumin conditions, co-stimulation with CCL11 and IL-5 paradoxically prolonged cell survival by preventing spontaneous apoptosis. This study provides an in-depth characterization of EETosis and highlights the precise regulation of eosinophil survival and cell death pathways.
{"title":"Characteristics and Regulation of Human Eosinophil ETosis In Vitro.","authors":"Hiroki Tomizawa, Misaki Arima, Yui Miyabe, Chikako Furutani, Sahoko Kodama, Keisuke Ito, Ken Watanabe, Ryo Hasegawa, Shohei Nishiyama, Keinosuke Hizuka, Takechiyo Yamada, Shigeharu Ueki","doi":"10.1165/rcmb.2023-0438OC","DOIUrl":"https://doi.org/10.1165/rcmb.2023-0438OC","url":null,"abstract":"<p><p>Cytolytic ETosis is a type of programmed cell death distinct from apoptosis and necrosis and plays a major role in the innate immune system and disease progression. Through the process of ETosis, cells release their chromatin with diverse antimicrobial proteins into the extracellular milieu, forming extracellular traps (ETs). Although ETosis has been reported in several leukocyte types, few studies have compared ETosis and the component proteins of ETs in leukocytes. The aim of this study was to better understand the characteristics of eosinophil ETosis (EETosis) compared with other leukocytes. We isolated human blood eosinophils, neutrophils, basophils, monocytes, and lymphocytes and stimulated them with known ETosis inducers, a protein kinase C activator PMA, or a calcium ionophore A23187. Both stimuli induced eosinophil cell death and ET release after 180 minutes of stimulation in a NADPH-oxidase-dependent manner. PMA also induced NADPH-oxidase-dependent ETosis in neutrophils, whereas little or no significant ETosis was observed in basophils, monocytes, or lymphocytes at 180 minutes. Mass spectrometry-based proteomic analysis of eosinophil- and neutrophil-derived ETs identified 997 and 1415 proteins, respectively. Among the physiological stimuli tested, immobilized IgA and IgG induced EETosis. C-C motif chemokine ligand 11 (CCL11) and interleukin 5 (IL-5) were weak inducers of EETosis, but co-stimulation significantly induced rapid EETosis. Under high serum or albumin conditions, co-stimulation with CCL11 and IL-5 paradoxically prolonged cell survival by preventing spontaneous apoptosis. This study provides an in-depth characterization of EETosis and highlights the precise regulation of eosinophil survival and cell death pathways.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873877","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1165/rcmb.2024-0182ED
Benjamin W Ackermann, Andreas Merkenschlager
{"title":"The Role of TRPV1 in Febrile Seizure Susceptibility: Inflammation, Respiratory Alkalosis, and Seizure Threshold.","authors":"Benjamin W Ackermann, Andreas Merkenschlager","doi":"10.1165/rcmb.2024-0182ED","DOIUrl":"10.1165/rcmb.2024-0182ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299084/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140853515","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 : 2024-08-01DOI: 10.1165/rcmb.71i2RedAlert
{"title":"August Highlights/Papers by Junior Investigators/NIH News.","authors":"","doi":"10.1165/rcmb.71i2RedAlert","DOIUrl":"https://doi.org/10.1165/rcmb.71i2RedAlert","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1165/rcmb.2024-0310ED
Jin-Ah Park
{"title":"E-cad! That's a Big Switch from Epithelial Membrane Protein to Asthma Mediator.","authors":"Jin-Ah Park","doi":"10.1165/rcmb.2024-0310ED","DOIUrl":"10.1165/rcmb.2024-0310ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873879","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1165/rcmb.2024-0187ED
Manas Ranjan Gartia, Victor J Thannickal
{"title":"Lipids to the Rescue in Pulmonary Fibrosis: Biosynthesis, Bioenergetics, or Epigenetics?","authors":"Manas Ranjan Gartia, Victor J Thannickal","doi":"10.1165/rcmb.2024-0187ED","DOIUrl":"10.1165/rcmb.2024-0187ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140848466","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 : 2024-08-01DOI: 10.1165/rcmb.2024-0054OC
Merle S Hirsch, Christina B Hildebrand, Florian Geltinger, Andreas Pich, Christian Mühlfeld, Dirk Wedekind, Christina Brandenberger
Mortality of acute lung injury (ALI) increases with age. Alveolar epithelial type 2 cells (AEII) are the progenitor cells of the alveolar epithelium and crucial for repair after injury. We hypothesize that telomere dysfunction-mediated AEII senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII senescence in ALI, young (3 months) and old (18 months) Sftpc-Ai9 mice and young Sftpc-Ai9-Trf1 mice with inducible Trf1 knockout-mediated senescence in AEII were treated with 1 µg lipopolysaccharide (LPS)/g BW (n=9-11). Control mice received saline (n=7). Mice were sacrificed 4 or 7 days later. Lung mechanics, pulmonary inflammation and proteomes were analyzed and parenchymal injury, AEII proliferation and AEI differentiation rate were quantified using stereology. Old mice showed 55% mortality by day 4, whereas all young mice survived. Pulmonary inflammation was most severe in old mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by day 7, while Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII was only measured in young Sftpc-Ai9 mice at day 7. Aging and telomere dysfunction-mediated senescence had no impact on AEI differentiation rate in controls, but the reduced number of AEII in Sftpc-Ai9-Trf1 mice also affected de-novo differentiation after injury. In conclusion, telomere dysfunction-mediated AEII senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. While Differentiation rate remained functional with old age and AEII senescence, AEII proliferative capacity was impaired in ALI, affecting the regenerative ability.
{"title":"Senescence in Alveolar Epithelial Type II Cells Promotes Acute Lung Injury and Impairs Regeneration.","authors":"Merle S Hirsch, Christina B Hildebrand, Florian Geltinger, Andreas Pich, Christian Mühlfeld, Dirk Wedekind, Christina Brandenberger","doi":"10.1165/rcmb.2024-0054OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0054OC","url":null,"abstract":"<p><p>Mortality of acute lung injury (ALI) increases with age. Alveolar epithelial type 2 cells (AEII) are the progenitor cells of the alveolar epithelium and crucial for repair after injury. We hypothesize that telomere dysfunction-mediated AEII senescence impairs regeneration and promotes the development of ALI. To discriminate between the impact of old age and AEII senescence in ALI, young (3 months) and old (18 months) Sftpc-Ai9 mice and young Sftpc-Ai9-Trf1 mice with inducible Trf1 knockout-mediated senescence in AEII were treated with 1 µg lipopolysaccharide (LPS)/g BW (n=9-11). Control mice received saline (n=7). Mice were sacrificed 4 or 7 days later. Lung mechanics, pulmonary inflammation and proteomes were analyzed and parenchymal injury, AEII proliferation and AEI differentiation rate were quantified using stereology. Old mice showed 55% mortality by day 4, whereas all young mice survived. Pulmonary inflammation was most severe in old mice, followed by Sftpc-Ai9-Trf1 mice. Young Sftpc-Ai9 mice recovered almost completely by day 7, while Sftpc-Ai9-Trf1 mice still showed mild signs of injury. An expansion of AEII was only measured in young Sftpc-Ai9 mice at day 7. Aging and telomere dysfunction-mediated senescence had no impact on AEI differentiation rate in controls, but the reduced number of AEII in Sftpc-Ai9-Trf1 mice also affected de-novo differentiation after injury. In conclusion, telomere dysfunction-mediated AEII senescence promoted parenchymal inflammation in ALI, but did not enhance mortality like old age. While Differentiation rate remained functional with old age and AEII senescence, AEII proliferative capacity was impaired in ALI, affecting the regenerative ability.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-01DOI: 10.1165/rcmb.2024-0005MA
Katrin Wirz, Claudia Schulz, Franz Söbbeler, Federico Armando, Georg Beythien, Ingo Gerhauser, Nicole de Buhr, Veronika Pilchová, Christian Meyer Zu Natrup, Wolfgang Baumgärtner, Sabine Kästner, Maren von Köckritz-Blickwede
Oxygen as a key element has a high impact on cellular processes. Infection with a pathogen such as SARS-CoV-2 and after inflammation may lead to hypoxic conditions in tissue that impact cellular responses. To develop optimized translational in vitro models for a better understanding of physiologic and pathophysiologic oxygen conditions, it is a prerequisite to determine oxygen concentrations generated in vivo. Our study objective was the establishment of an invasive method for oxygen measurements using a luminescence-based microsensor to determine the dissolved oxygen in the lung tissue of ferrets as animal models for SARS-CoV-2 research. By way of analogy to humans, aged ferrets are more likely to show clinical signs after SARS-CoV-2 infection than are young animals. To investigate oxygen concentrations during a respiratory viral infection, we intratracheally infected nine aged (3-yr-old) ferrets with SARS-CoV-2. The aged SARS-CoV-2-infected ferrets showed mild to moderate clinical signs associated with prolonged viral RNA shedding until 14 days postinfection. SARS-CoV-2-infected ferrets showed histopathologic lung lesion scores that significantly negatively correlated with oxygen concentrations in lung tissue. At 4 days postinfection, oxygen concentrations in lung tissue were significantly lower (mean percentage O2, 3.89 ≙ ≈ 27.78 mm Hg) than in the negative control group (mean percentage O2, 8.65 ≙ ≈ 61.4 mm Hg). In summary, we succeeded in determining the pathophysiologic oxygen conditions in the lung tissue of aged SARS-CoV-2-infected ferrets.
{"title":"A New Methodology for the Oxygen Measurement in Lung Tissue of an Aged Ferret Model Proves Hypoxia during COVID-19.","authors":"Katrin Wirz, Claudia Schulz, Franz Söbbeler, Federico Armando, Georg Beythien, Ingo Gerhauser, Nicole de Buhr, Veronika Pilchová, Christian Meyer Zu Natrup, Wolfgang Baumgärtner, Sabine Kästner, Maren von Köckritz-Blickwede","doi":"10.1165/rcmb.2024-0005MA","DOIUrl":"10.1165/rcmb.2024-0005MA","url":null,"abstract":"<p><p>Oxygen as a key element has a high impact on cellular processes. Infection with a pathogen such as SARS-CoV-2 and after inflammation may lead to hypoxic conditions in tissue that impact cellular responses. To develop optimized translational <i>in vitro</i> models for a better understanding of physiologic and pathophysiologic oxygen conditions, it is a prerequisite to determine oxygen concentrations generated <i>in vivo</i>. Our study objective was the establishment of an invasive method for oxygen measurements using a luminescence-based microsensor to determine the dissolved oxygen in the lung tissue of ferrets as animal models for SARS-CoV-2 research. By way of analogy to humans, aged ferrets are more likely to show clinical signs after SARS-CoV-2 infection than are young animals. To investigate oxygen concentrations during a respiratory viral infection, we intratracheally infected nine aged (3-yr-old) ferrets with SARS-CoV-2. The aged SARS-CoV-2-infected ferrets showed mild to moderate clinical signs associated with prolonged viral RNA shedding until 14 days postinfection. SARS-CoV-2-infected ferrets showed histopathologic lung lesion scores that significantly negatively correlated with oxygen concentrations in lung tissue. At 4 days postinfection, oxygen concentrations in lung tissue were significantly lower (mean percentage O<sub>2</sub>, 3.89 ≙ ≈ 27.78 mm Hg) than in the negative control group (mean percentage O<sub>2</sub>, 8.65 ≙ ≈ 61.4 mm Hg). In summary, we succeeded in determining the pathophysiologic oxygen conditions in the lung tissue of aged SARS-CoV-2-infected ferrets.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":null,"pages":null},"PeriodicalIF":5.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11299086/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141858804","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}