American Journal of Respiratory Cell and Molecular Biology最新文献

{"title":"Nasal Epithelium Transcriptomics Predict Clinical Response to Elexacaftor/Tezacaftor/Ivacaftor.","authors":"Molin Yue, Daniel J Weiner, Kristina M Gaietto, Franziska J Rosser, Christopher M Qoyawayma, Michelle L Manni, Michael M Myerburg, Joseph M Pilewski, Juan C Celedón, Wei Chen, Erick Forno","doi":"10.1165/rcmb.2024-0103OC","DOIUrl":"10.1165/rcmb.2024-0103OC","url":null,"abstract":"<p><p>Elexacaftor/tezacaftor/ivacaftor (ETI) has had a substantial positive impact for people living with cystic fibrosis (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF before ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in forced expiratory volume in 1 second (ΔFEV₁), year's best FEV₁ (ΔybFEV₁), and body mass index (ΔBMI). Using the top differentially expressed genes, we generated transcriptomic risk scores (TRSs) and evaluated their predictive performance. The study included 40 pwCF ≥6 years of age (mean, 27.7 [SD, 15.1] years; 40% female). After ETI initiation, FEV₁ improved by ≥5% in 22 (61.1%) participants, and ybFEV₁ improved by ≥5% in 19 (50%). TRSs were constructed using top overexpressed and underexpressed genes for each outcome. Adding the ΔFEV₁ TRS to a model with age, sex, and baseline FEV₁ increased the area under the receiver operating characteristic curve (AUC) from 0.41 to 0.88, the ΔybFEV₁ TRS increased the AUC from 0.51 to 0.88, and the ΔBMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ∼85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV₁ and BMI with ETI treatment. These novel TRSs could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"730-739"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622631/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141726750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Redox-Shifted Fibroblast Subpopulation Emerges in the Fibrotic Lung.","authors":"Patrick A Link, Jeffrey A Meridew, Nunzia Caporarello, Ashley Y Gao, Victor Peters, Mauricio Rojas, Daniel J Tschumperlin","doi":"10.1165/rcmb.2023-0346OC","DOIUrl":"10.1165/rcmb.2023-0346OC","url":null,"abstract":"<p><p>Idiopathic pulmonary fibrosis (IPF) is an aggressive and, thus far, incurable disease characterized by aberrant fibroblast-mediated extracellular matrix deposition. Our understanding of the disease etiology is incomplete; however, there is consensus that a reduction-oxidation (redox) imbalance plays a role. In this study, we use the autofluorescent properties of two redox molecules, NAD(P)H and FAD, to quantify changes in their relative abundance in living lung tissue of mice with experimental lung fibrosis and in freshly isolated cells from mouse lungs and humans with IPF. Our results identify cell population-specific intracellular redox changes in the lungs in experimental and human fibrosis. We focus particularly on redox changes within collagen-producing cells, where we identified a bimodal distribution of NAD(P)H concentrations, establishing NAD(P)H^high and NAD(P)H^low subpopulations. NAD(P)H^high fibroblasts exhibited elevated profibrotic gene expression and decreased collagenolytic protease activity relative to NAD(P)H^low fibroblasts. The NAD(P)H^high population was present in healthy lungs but expanded with time after bleomycin injury, suggesting a potential role in fibrosis progression. We identified a similar increased abundance of NAD(P)H^high cells in freshly dissociated lungs of subjects with IPF relative to control subjects, as well as similar reductions in collagenolytic activity in this cell population. These data highlight the complexity of redox state changes in experimental and human pulmonary fibrosis and the need for selective approaches to restore redox imbalances in the fibrotic lung.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"718-729"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141496882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Hidden Link between Chronic Kidney Disease and Lung Injury.","authors":"Elizabeth F Redente","doi":"10.1165/rcmb.2024-0326ED","DOIUrl":"10.1165/rcmb.2024-0326ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"628-629"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622630/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141974863","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Yield and Diversity of Human Distal Lung Epithelial Cells Isolated by Different Sorting Strategies.","authors":"A Scott McCall, Ujjal K Singha, Timothy S Blackwell, Jason J Gokey, Jonathan A Kropski","doi":"10.1165/rcmb.2024-0206LE","DOIUrl":"10.1165/rcmb.2024-0206LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"71 6","pages":"743-745"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regenerative Signatures in BAL of Acute Respiratory Distress Syndrome.","authors":"Runzhen Zhao, Marco Hadisurya, Harrison Ndetan, Nan Miles Xi, Sitaramaraju Adduri, Nagarjun Venkata Konduru, Buka Samten, Jiwang Zhang, W Andy Tao, Karan P Singh, Hong-Long Ji","doi":"10.1165/rcmb.2024-0193LE","DOIUrl":"10.1165/rcmb.2024-0193LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":"71 6","pages":"740-742"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622636/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724834","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Respiratory Epithelial Cell Surface Decoration Provides Defense against Bacterial Damage during Infection.","authors":"Harriet R Ellis, Luke P Allsopp","doi":"10.1165/rcmb.2024-0306ED","DOIUrl":"10.1165/rcmb.2024-0306ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"625-627"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622635/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141756658","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Chronic Kidney Disease-associated Lung Injury Is Mediated by Phosphate-induced MAPK/AKT Signaling.","authors":"Seth Bollenbecker, Meghan June Hirsch, Emma Lea Matthews, Molly Easter, Shia Vang, Patrick Henry Howze, Angela N Morales, Elex Harris, Jarrod W Barnes, Christian Faul, Stefanie Krick","doi":"10.1165/rcmb.2024-0008OC","DOIUrl":"10.1165/rcmb.2024-0008OC","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is associated with systemic phosphate elevations, called hyperphosphatemia. Translational studies have shown that hyperphosphatemia contributes to CKD-associated inflammation and injury in various tissues, including the kidney, heart, liver, and parathyroid gland. Mechanisms underlying pathologic actions of elevated phosphate on cells are not well understood but seem to involve uptake of phosphate through sodium phosphate cotransporters and phosphate-induced signaling via FGFR1 (fibroblast growth factor receptor 1). Clinical studies indicate patients with CKD are more likely to develop inflammatory and restrictive lung diseases, such as fibrotic interstitial lung diseases, and here we aimed to determine whether hyperphosphatemia can cause lung injury. We found that a mouse model of CKD and hyperphosphatemia, induced by an adenine-rich diet, develops lung fibrosis and inflammation. Elevation of systemic phosphate concentration by administration of a high-phosphate diet in a mouse model of primary lung inflammation and fibrosis, induced by bleomycin, exacerbated lung injury in the absence of kidney damage. Our <i>in vitro</i> studies identified increases of proinflammatory cytokines in human lung fibroblasts exposed to phosphate elevations. Phosphate activated ERK 1/2 (extracellular signal-related kinase 1/2) and PKB/AKT (protein kinase B) signaling, and pharmacological inhibition of ERK, AKT, FGFR1, or sodium phosphate cotransporters prevented phosphate-induced proinflammatory cytokine upregulation. In addition, inhibition of FGFR1 or sodium phosphate cotransporters decreased the phosphate-induced activation of ERK and AKT. Our study suggests that phosphate can directly target lung fibroblasts and induce an inflammatory response and that hyperphosphatemia in CKD and non-CKD models contributes to lung injury. Phosphate-lowering strategies might protect from CKD-associated lung injury.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":"659-676"},"PeriodicalIF":5.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11622639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141873878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Homeobox Transcription Factor Cux1 Coordinates Postnatal Epithelial Developmental Timing but Is Dispensable for Lung Organogenesis and Regeneration.","authors":"Barbara Zhao, Jacob Socha, Andrea Toth, Sharlene Fernandes, Helen Warheit-Niemi, Brandy Ruff, Gurjit K Khurana Hershey, Kelli L VanDussen, Daniel Swarr, William J Zacharias","doi":"10.1165/rcmb.2024-0147OC","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0147OC","url":null,"abstract":"<p><p>Lung epithelial progenitors use a complex network of known and predicted transcriptional regulators to influence early lung development. Here, we evaluate the function of one predicted regulator, Cux1, that we identified from transcriptional regulatory analysis of the SOX9+ distal lung progenitor network. We generated a new Cux1-floxed mouse model and created an epithelial-specific knockout of Cux1 using Shh-Cre (Cux1^ShhCre-LOF). Postnatal Cux1^ShhCre-LOF animals recapitulated key skin phenotypic features found in prior constitutive Cux1 knockout animals, confirming functionality of our new floxed model. Postnatal Cux1^ShhCre-LOF mice displayed subtle alveolar simplification and a transient delay in alveologenesis and alveolar type 1 cell development without persistent lung phenotypes. Cux1^ShhCre-LOF mice developed failure to thrive in their second and third weeks of life due to delayed ileal maturation, which similarly resolves by postnatal day 35. Finally, we challenged Cux1^ShhCre-LOF with influenza-mediated lung injury to demonstrate that Cux1^ShhCre-LOF mice undergo productive alveolar regeneration that is indistinguishable from WT animals. Together, these findings indicate that epithelial-specific loss of Cux1 leads to transient developmental delays in the skin, lung, and intestine without defects in definitive organogenesis. We conclude that Cux1 function is required for temporal optimization of developmental maturation in multiple organs with implications for susceptibility windows in developmental disease pathogenesis.</p>","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Channeling Relaxation through Multiple Means: TMEM16A Antagonism for Asthma.","authors":"Arun K Jannu, Raymond B Penn","doi":"10.1165/rcmb.2024-0521ED","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0521ED","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Murine Model of <i>Mycobacterium abscessus</i> Infection Mimics Pathology of Chronic Human Lung Disease.","authors":"Kenneth C Malcolm, Alma E Ochoa, Jack H Congel, Patrick S Hume, Jodi M Corley, Emily A Wheeler, Xiyuan Bai, Jerry A Nick, William J Janssen, Edward D Chan, Carlyne D Cool, Katherine B Hisert","doi":"10.1165/rcmb.2024-0376LE","DOIUrl":"https://doi.org/10.1165/rcmb.2024-0376LE","url":null,"abstract":"","PeriodicalId":7655,"journal":{"name":"American Journal of Respiratory Cell and Molecular Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142715025","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}