{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T11:09:43Z","timestamp":1781089783542,"version":"3.54.1"},"reference-count":107,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      <jats:italic>Pseudomonas aeruginosa (PA)<\/jats:italic>\n                      causes severe respiratory infections utilizing multiple virulence functions. Previous findings on the PA secreted quorum sensing (QS)-regulated small molecule, 2\u2019-aminoacetophenone (2-AA), revealed its impact on immune and metabolic functions, favouring a long-term presence of PA in the host. However, the 2-AA\u2019s specific effects on bronchial-airway epithelium and pulmonary endothelium remain elusive. To evaluate the spatiotemporal changes in 2AA within the human airway, considering endothelial cells as the primary point of contact when the route of lung infection is hematogenic, we utilized the airway-on-achip platform. This dynamic culture system recapitulates critical elements of the human airway microphysiological environment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We utilized the microfluidic airway-on-chip platform, lined by polarized primary human pulmonary microvascular endothelial cells (HPMEC) and adjacent primary normal human bronchial epithelial cells (NHBE) obtained from healthy female donors. Cells exposed to 2-AA (20 \u03bcm) through continuous flow for 12 hours were used for whole-genome RNA sequencing and analyzed for their responses and potential cross-talk. Transcriptome findings were validated through\n                      <jats:italic>in vivo<\/jats:italic>\n                      studies in mice and additional cell culture experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Analyses revealed that 2-AA differentially regulates specific signaling and biosynthesis pathways in epithelial cells, including HIF-1 and pyrimidine signaling, glycosaminoglycan and glycosphingolipid biosynthesis. In endothelial cells, fatty acid metabolism, phosphatidylinositol, and estrogen receptor signaling, as well as proinflammatory signaling pathways, were identified. Significant overlap was found in both cell types in response to 2-AA in genes implicated in immune response and cellular functions. In contrast, we found that genes related to barrier permeability, cholesterol metabolism, and oxidative phosphorylation were differentially regulated in response to 2-AA exposure in the studied cell types. Murine\n                      <jats:italic>in vivo<\/jats:italic>\n                      and additional\n                      <jats:italic>in vitro<\/jats:italic>\n                      cell culture studies confirmed the accumulation of cholesterol in epithelial cells. Results also revealed that specific biomarkers associated with cystic fibrosis and idiopathic pulmonary fibrosis were modulated by 2-AA in both cell types, with the expression of cystic fibrosis transmembrane regulator being affected only in endothelial cells.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1592597","type":"journal-article","created":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:54:41Z","timestamp":1752573281000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["Revealing the impact of Pseudomonas aeruginosa quorum sensing molecule 2\u2019-aminoacetophenone on the human bronchial-airway epithelium and pulmonary endothelium using a human airway-on-a-chip"],"prefix":"10.3389","volume":"16","author":[{"given":"Shifu","family":"Aggarwal","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arijit","family":"Chakraborty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay K.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Lory","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Karalis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence G.","family":"Rahme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,15]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.01292-24","article-title":"Skeletal muscle mitochondrial dysfunction mediated by Pseudomonas aeruginosa quorum-sensing transcription factor MvfR: reversing effects with anti-MvfR and mitochondrial-targeted compounds","volume":"15","author":"Aggarwal","year":"2024","journal-title":"Mbio"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.97568.3","article-title":"The bacterial quorum sensing signal 2\u2019-aminoacetophenone rewires immune cell bioenergetics through the Ppargc1a\/Esrra axis to mediate tolerance to infection","volume":"13","author":"Arijit","year":"2024","journal-title":"eLife"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.00159-23","article-title":"Quorum-sensing signaling molecule 2-aminoacetophenone mediates the persistence of pseudomonas aeruginosa in macrophages by interference with autophagy through epigenetic regulation of lipid biosynthesis","volume":"14","author":"Chakraborty","year":"2023","journal-title":"MBio"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.4103\/0974-2727.78553","article-title":"Quorum sensing and bacterial pathogenicity: from molecules to disease","volume":"3","author":"Deep","year":"2011","journal-title":"J Lab Physicians"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2006.00734.x","article-title":"Pseudomonas aeruginosa autoinducer modulates host cell responses through calcium signalling","volume":"8","author":"Shiner","year":"2006","journal-title":"Cell Microbiol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"5103","DOI":"10.1038\/s41467-022-32833-9","article-title":"Tackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy","volume":"13","author":"Singh","year":"2022","journal-title":"Nat Commun"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2024.1374466","article-title":"Antimicrobial resistance of Pseudomonas aeruginosa: navigating clinical impacts, current resistance trends, and innovations in breaking therapies","volume":"15","author":"Elfadadny","year":"2024","journal-title":"Front Microbiol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1038\/s41392-022-01056-1","article-title":"Pseudomonas aeruginosa: pathogenesis, virulence factors, antibiotic resistance, interaction with host, technology advances and emerging therapeutics","volume":"7","author":"Qin","year":"2022","journal-title":"Signal Transduct Target Ther"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2023.1159798","article-title":"Revisiting ESKAPE Pathogens: Virulence, resistance, and combating strategies focusing on quorum sensing","volume":"13","author":"Venkateswaran","year":"2023","journal-title":"Front Cell Infect Microbiol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1128\/cmr.00181-19","article-title":"Antimicrobial resistance in ESKAPE pathogens","volume":"33","author":"De Oliveira","year":"2020","journal-title":"Clin Microbiol Rev"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201705-1043SO","article-title":"Mechanisms and targeted therapies for Pseudomonas aeruginosa lung infection","volume":"197","author":"Curran","year":"2018","journal-title":"Am J Respir Crit Care Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1405376","article-title":"Pseudomonas aeruginosa in chronic lung disease: untangling the dysregulated host immune response","volume":"15","author":"Nickerson","year":"2024","journal-title":"Front Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00185.2019","article-title":"cAMP signaling primes lung endothelial cells to activate caspase-1 during Pseudomonas aeruginosa infection","volume":"318","author":"Renema","year":"2020","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.96.09081601","article-title":"Lung function in bronchiectasis: the influence of Pseudomonas aeruginosa","volume":"9","author":"Evans","year":"1996","journal-title":"Eur Respir J"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.10135","article-title":"Early infection and progression of cystic fibrosis lung disease","volume":"34","author":"Koch","year":"2002","journal-title":"Pediatr Pulmonol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1017\/S0950268803008872","article-title":"Bacterial infection in exacerbated COPD with changes in sputum characteristics","volume":"131","author":"Monso","year":"2003","journal-title":"Epidemiol Infect"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.57.9.759","article-title":"Relationship between bacterial colonisation and the frequency, character, and severity of COPD exacerbations","volume":"57","author":"Patel","year":"2002","journal-title":"Thorax"},{"key":"B18","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1128\/MMBR.05007-11","article-title":"The multiple signaling systems regulating virulence in Pseudomonas aeruginosa","volume":"76","author":"Nadal Jimenez","year":"2012","journal-title":"Microbiol Mol Biol Rev"},{"key":"B19","doi-asserted-by":"publisher","first-page":"e1003024","DOI":"10.1371\/journal.ppat.1003024","article-title":"The quorum sensing volatile molecule 2-amino acetophenon modulates host immune responses in a manner that promotes life with unwanted guests","volume":"8","author":"Bandyopadhaya","year":"2012","journal-title":"PloS Pathogens"},{"key":"B20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/nmicrobiol.2016.174","article-title":"A quorum-sensing signal promotes host tolerance training through HDAC1-mediated epigenetic reprogramming","volume":"1","author":"Bandyopadhaya","year":"2016","journal-title":"Nat Microbiol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2017.01211","article-title":"NF-\u03baBp50 and HDAC1 interaction is implicated in the host tolerance to infection mediated by the bacterial quorum sensing signal 2-aminoacetophenone","volume":"8","author":"Bandyopadhaya","year":"2017","journal-title":"Front Microbiol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.251465298","article-title":"A quorum sensing-associated virulence gene of Pseudomonas aeruginosa encodes a LysR-like transcription regulator with a unique self-regulatory mechanism","volume":"98","author":"Cao","year":"2001","journal-title":"Proc Natl Acad Sci"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0307694100","article-title":"Analysis of Pseudomonas aeruginosa 4-hydroxy-2-alkylquinolines (HAQs) reveals a role for 4-hydroxy-2-heptylquinoline in cell-to-cell communication","volume":"101","author":"D\u00e9ziel","year":"2004","journal-title":"Proc Natl Acad Sci"},{"key":"B24","doi-asserted-by":"publisher","first-page":"e1002192","DOI":"10.1371\/journal.ppat.1002192","article-title":"A quorum sensing regulated small volatile molecule reduces acute virulence and promotes chronic infection phenotypes","volume":"7","author":"Kesarwani","year":"2011","journal-title":"PloS Pathogens"},{"key":"B25","doi-asserted-by":"publisher","first-page":"e80140","DOI":"10.1371\/journal.pone.0080140","article-title":"A quorum sensing small volatile molecule promotes antibiotic tolerance in bacteria","volume":"8","author":"Que","year":"2013","journal-title":"PloS One"},{"key":"B26","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.cub.2015.11.056","article-title":"Auto poisoning of the respiratory chain by a quorum-sensing-regulated molecule favors biofilm formation and antibiotic tolerance","volume":"26","author":"Hazan","year":"2016","journal-title":"Curr Biol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1471-2466-10-56","article-title":"2-Aminoacetophenone as a potential breath biomarker for Pseudomonas aeruginosa in the cystic fibrosis lung","volume":"10","author":"Scott-Thomas","year":"2010","journal-title":"BMC Pulmon Med"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2100528","article-title":"Small molecule metabolites at the host\u2013microbiota interface","volume":"207","author":"Bishai","year":"2021","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"1254766","DOI":"10.1126\/science.1254766","article-title":"Small molecules from the human microbiota","volume":"349","author":"Donia","year":"2015","journal-title":"Science"},{"key":"B30","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1161\/CIRCRESAHA.116.306534","article-title":"Protein interactions at endothelial junctions and signaling mechanisms regulating endothelial permeability","volume":"120","author":"Komarova","year":"2017","journal-title":"Circ Res"},{"key":"B31","doi-asserted-by":"publisher","first-page":"33","DOI":"10.3390\/cells11010033","article-title":"Bacterial lymphatic metastasis in infection and immunity","volume":"11","author":"Siggins","year":"2022","journal-title":"Cells"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3892\/ijmm.2016.2487","article-title":"Bacterial-excreted small volatile molecule 2-aminoacetophenone induces oxidative stress and apoptosis in murine skeletal muscle","volume":"37","author":"Bandyopadhaya","year":"2016","journal-title":"Int J Mol Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1128\/mbio.02211-19","article-title":"Pseudomonas aeruginosa quorum sensing molecule alters skeletal muscle protein homeostasis by perturbing the antioxidant defense system","volume":"10","author":"Bandyopadhaya","year":"2019","journal-title":"MBio"},{"key":"B34","doi-asserted-by":"publisher","first-page":"e74528","DOI":"10.1371\/journal.pone.0074528","article-title":"A small volatile bacterial molecule triggers mitochondrial dysfunction in murine skeletal muscle","volume":"8","author":"Tzika","year":"2013","journal-title":"PloS One"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2022.1043117","article-title":"3D organ-on-a-chip: The convergence of microphysiological systems and organoids","volume":"10","author":"Baptista","year":"2022","journal-title":"Front Cell Dev Biol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.3390\/mi13081200","article-title":"Engineering organ-on-a-chip to accelerate translational research","volume":"13","author":"Ko","year":"2022","journal-title":"Micromachines"},{"key":"B37","doi-asserted-by":"publisher","first-page":"2278236","DOI":"10.1080\/15476278.2023.2278236","article-title":"Organ-on-a-chip: an emerging research platform","volume":"19","author":"Nithin","year":"2023","journal-title":"Organogenesis"},{"key":"B38","doi-asserted-by":"publisher","first-page":"394","DOI":"10.1038\/s41551-019-0495-z","article-title":"On-chip recapitulation of clinical bone marrow toxicities and patient-specific pathophysiology","volume":"4","author":"Chou","year":"2020","journal-title":"Nat Biomed Eng"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41551-019-0498-9","article-title":"Quantitative prediction of human pharmacokinetic responses to drugs via fluidically coupled vascularized organ chips","volume":"4","author":"Herland","year":"2020","journal-title":"Nat Biomed Eng"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3004249","article-title":"A human disease model of drug toxicity\u2013induced pulmonary edema in a lung-on-a-chip microdevice","volume":"4","author":"Huh","year":"2012","journal-title":"Sci Trans Med"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1126\/science.1188302","article-title":"Reconstituting organ-level lung functions on a chip","volume":"328","author":"Huh","year":"2010","journal-title":"Science"},{"key":"B42","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1146\/annurev-pharmtox-010716-104748","article-title":"Physiologically based pharmacokinetic and pharmacodynamic analysis enabled by microfluidically linked organs-on-chips","volume":"58","author":"Prantil-Baun","year":"2018","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B43","doi-asserted-by":"publisher","first-page":"108472","DOI":"10.1016\/j.isci.2023.108472","article-title":"Integrating mechanical cues with engineered platforms to explore cardiopulmonary development and disease","volume":"26","author":"Ahmed","year":"2023","journal-title":"IScience"},{"key":"B44","doi-asserted-by":"publisher","first-page":"1602","DOI":"10.3390\/cells10071602","article-title":"Airway-on-a-chip: designs and applications for lung repair and disease","volume":"10","author":"Bennet","year":"2021","journal-title":"Cells"},{"key":"B45","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/s43586-022-00118-6","article-title":"A guide to the organ-on-a-chip","volume":"2","author":"Leung","year":"2022","journal-title":"Nat Rev Methods Primers"},{"key":"B46","doi-asserted-by":"publisher","first-page":"e1000420","DOI":"10.1371\/journal.ppat.1000420","article-title":"A complex extracellular sphingomyelinase of Pseudomonas aeruginosa inhibits angiogenesis by selective cytotoxicity to endothelial cells","volume":"5","author":"Vasil","year":"2009","journal-title":"PloS Pathogens"},{"key":"B47","doi-asserted-by":"publisher","first-page":"W3","DOI":"10.1093\/nar\/gkw343","article-title":"The Galaxy platform for accessible, reproducible and collaborative biomedical analyses: 2016 update","volume":"44","author":"Afgan","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.160.7.3513","article-title":"IL-17 stimulates the production and expression of proinflammatory cytokines, IL-\u03b2 and TNF-\u03b1, by human macrophages","volume":"160","author":"Jovanovic","year":"1998","journal-title":"J Immunol"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1710-1492-2-3-98","article-title":"Mechanisms of degranulation in neutrophils","volume":"2","author":"Lacy","year":"2006","journal-title":"Allergy Asthma Clin Immunol"},{"key":"B50","doi-asserted-by":"publisher","first-page":"a005058","DOI":"10.1101\/cshperspect.a005058","article-title":"Extracellular matrix degradation and remodeling in development and disease","volume":"3","author":"Lu","year":"2011","journal-title":"Cold Spring Harbor Perspect Biol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.90578.2008","article-title":"MMP9 modulates tight junction integrity and cell viability in human airway epithelia","volume":"296","author":"Vermeer","year":"2009","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B52","doi-asserted-by":"publisher","first-page":"e0171427","DOI":"10.1371\/journal.pone.0171427","article-title":"Metalloproteinase-9 contributes to endothelial dysfunction in atherosclerosis via protease activated receptor-1","volume":"12","author":"Florence","year":"2017","journal-title":"PloS One"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvad130","article-title":"Targeting endothelial vascular cell adhesion molecule-1 in atherosclerosis: drug discovery and development of vascular cell adhesion molecule-1\u2013directed novel therapeutics","volume":"119","author":"Pickett","year":"2023","journal-title":"Cardiovasc Res"},{"key":"B54","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.mce.2018.08.004","article-title":"Role of hydroxysteroid (17beta) dehydrogenase type 1 in reproductive tissues and hormone-dependent diseases","volume":"489","author":"Heinosalo","year":"2019","journal-title":"Mol Cell Endocrinol"},{"key":"B55","doi-asserted-by":"publisher","first-page":"108850","DOI":"10.1016\/j.abb.2021.108850","article-title":"Structural hallmarks of lung surfactant: Lipid-protein interactions, membrane structure and future challenges","volume":"703","author":"Castillo-S\u00e1nchez","year":"2021","journal-title":"Arch Biochem Biophys"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M404648200","article-title":"Cholesterol rules: direct observation of the coexistence of two fluid phases in native pulmonary surfactant membranes at physiological temperatures","volume":"279","author":"de la Serna","year":"2004","journal-title":"J Biol Chem"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1099\/mic.0.2008\/022772-0","article-title":"Structure and function of the LysR-type transcriptional regulator (LTTR) family proteins","volume":"154","author":"Maddocks","year":"2008","journal-title":"Microbiology"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00004.2016","article-title":"Idiopathic pulmonary fibrosis: a genetic disease that involves mucociliary dysfunction of the peripheral airways","volume":"96","author":"Evans","year":"2016","journal-title":"Physiol Rev"},{"key":"B59","doi-asserted-by":"publisher","first-page":"17421","DOI":"10.1038\/s41598-020-74502-1","article-title":"Lung function over the life course of paediatric and adult patients with cystic fibrosis from a large multi-centre registry","volume":"10","author":"Earnest","year":"2020","journal-title":"Sci Rep"},{"key":"B60","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.3390\/cells9071607","article-title":"KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway","volume":"9","author":"Sousa","year":"2020","journal-title":"Cells"},{"key":"B61","doi-asserted-by":"publisher","first-page":"e1501228","DOI":"10.1126\/sciadv.1501228","article-title":"Structural basis for KCNE3 modulation of potassium recycling in epithelia","volume":"2","author":"Kroncke","year":"2016","journal-title":"Sci Adv"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1152\/ajprenal.00605.2013","article-title":"HK-ATPase type 2: relevance for renal physiology and beyond","volume":"306","author":"Crambert","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.688485","article-title":"Lactate is a metabolic mediator that shapes immune cell fate and function","volume":"12","author":"Caslin","year":"2021","journal-title":"Front Physiol"},{"key":"B64","first-page":"346","article-title":"The NF\u03baB signaling in cystic fibrosis lung disease: pathophysiology and therapeutic potential","volume":"9","author":"Bodas","year":"2010","journal-title":"Discov Med"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.152.6.8520783","article-title":"Inflammatory cytokines in cystic fibrosis lungs","volume":"152","author":"Bonfield","year":"1995","journal-title":"Am J Respir Crit Care Med"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2004.06.006","article-title":"Cytokines and inflammatory mediators in cystic fibrosis","volume":"3","author":"Courtney","year":"2004","journal-title":"J Cystic Fibrosis"},{"key":"B67","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1465-9921-6-63","article-title":"CD14 C-159T and early infection with Pseudomonas aeruginosa in children with cystic fibrosis","volume":"6","author":"Martin","year":"2005","journal-title":"Respir Res"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.07.021","article-title":"Differential toll like receptor expression in cystic fibrosis patients\u2019 airways during rhinovirus infection","volume":"81","author":"Scagnolari","year":"2020","journal-title":"J Infect"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.58.7.613","article-title":"Expression of S100A12 (EN-RAGE) in cystic fibrosis","volume":"58","author":"Foell","year":"2003","journal-title":"Thorax"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2015.12.011","article-title":"Advanced glycation end products are elevated in cystic fibrosis-related diabetes and correlate with worse lung function","volume":"15","author":"Hunt","year":"2016","journal-title":"J Cystic Fibrosis"},{"key":"B71","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1186\/1465-9921-7-51","article-title":"Expression of S100A8 correlates with inflammatory lung disease in congenic mice deficient of the cystic fibrosis transmembrane conductance regulator","volume":"7","author":"Tirkos","year":"2006","journal-title":"Respir Res"},{"key":"B72","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1165\/rcmb.2023-0408OC","article-title":"Akt-driven TGF-\u03b2 and DKK1 secretion impairs F508del cystic fibrosis airway epithelium polarity","volume":"71","author":"Idris","year":"2024","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1080\/14728222.2018.1406922","article-title":"TGF\u03b2 as a therapeutic target in cystic fibrosis","volume":"22","author":"Kramer","year":"2018","journal-title":"Expert Opin Ther Targets"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/nature07811","article-title":"Identification of IFRD1 as a modifier gene for cystic fibrosis lung disease","volume":"458","author":"Gu","year":"2009","journal-title":"Nature"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1183\/09031936.00173210","article-title":"The role of matrix metalloproteases in cystic fibrosis lung disease","volume":"38","author":"Gaggar","year":"2011","journal-title":"Eur Respir J"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.31.21491","article-title":"Matrix metalloproteinases *","volume":"274","author":"Nagase","year":"1999","journal-title":"J Biol Chem"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.722170","article-title":"Periostin in allergy and inflammation","volume":"12","author":"Sonnenberg-Riethmacher","year":"2021","journal-title":"Front Immunol"},{"key":"B78","doi-asserted-by":"crossref","first-page":"49","DOI":"10.2147\/MNM.S96916","article-title":"Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives","volume":"3","author":"Rojas-Quintero","year":"2016","journal-title":"Metalloproteinases In Med"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.202004-0991OC","article-title":"Single-cell transcriptional archetypes of airway inflammation in cystic fibrosis","volume":"202","author":"Schupp","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"B80","doi-asserted-by":"publisher","first-page":"e0183526","DOI":"10.1371\/journal.pone.0183526","article-title":"Transcriptomic profile of cystic fibrosis patients identifies type I interferon response and ribosomal stalk proteins as potential modifiers of disease severity","volume":"12","author":"Kormann","year":"2017","journal-title":"PloS One"},{"key":"B81","doi-asserted-by":"publisher","first-page":"e122490","DOI":"10.1172\/jci.insight.122490","article-title":"MEG3 is increased in idiopathic pulmonary fibrosis and regulates epithelial cell differentiation","volume":"3","author":"Gokey","year":"2018","journal-title":"JCI Insight"},{"key":"B82","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1038\/s42003-023-05739-5","article-title":"Proinflammatory chemokine CXCL14 activates MAS-related G protein-coupled receptor MRGPRX2 and its putative mouse ortholog MRGPRB2","volume":"7","author":"Al Hamwi","year":"2024","journal-title":"Commun Biol"},{"key":"B83","doi-asserted-by":"publisher","first-page":"6255","DOI":"10.3390\/ijms22126255","article-title":"Molecular biomarkers in idiopathic pulmonary fibrosis: state of the art and future directions","volume":"22","author":"Stainer","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00383","article-title":"Prominence of IL6, IGF, TLR, and bioenergetics pathway perturbation in lung tissues of scleroderma patients with pulmonary fibrosis","volume":"11","author":"Renaud","year":"2020","journal-title":"Front Immunol"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201909-1726LE","article-title":"Ineffectual type 2\u2013to\u2013type 1 alveolar epithelial cell differentiation in idiopathic pulmonary fibrosis: persistence of the KRT8hi transitional state","volume":"201","author":"Jiang","year":"2020","journal-title":"Am J Respir Crit Care Med"},{"key":"B86","doi-asserted-by":"publisher","first-page":"6502","DOI":"10.3390\/ijms22126502","article-title":"MUC16 is overexpressed in idiopathic pulmonary fibrosis and induces fibrotic responses mediated by transforming growth factor-\u03b21 canonical pathway","volume":"22","author":"Ballester","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B87","doi-asserted-by":"publisher","first-page":"100524","DOI":"10.1016\/j.mcpro.2023.100524","article-title":"Serum proteomics identifies biomarkers associated with the pathogenesis of idiopathic pulmonary fibrosis","volume":"22","author":"Wang","year":"2023","journal-title":"Mol Cell Proteomics"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03376-x","article-title":"An organotypic atlas of human vascular cells","volume":"30","author":"Barnett","year":"2024","journal-title":"Nat Med"},{"key":"B89","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1165\/rcmb.2023-0426TR","article-title":"Cell cross-talk in alveolar microenvironment: from lung injury to fibrosis","volume":"71","author":"Song","year":"2024","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B90","doi-asserted-by":"publisher","first-page":"4411","DOI":"10.3390\/ijms20184411","article-title":"Vascular endothelial cell biology: an update","volume":"20","author":"Kr\u00fcger-Genge","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B91","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00323.2020","article-title":"Overlapping and distinct biological effects of IL-6 classic and trans-signaling in vascular endothelial cells","volume":"320","author":"Montgomery","year":"2021","journal-title":"Am J Physiol Cell Physiol"},{"key":"B92","doi-asserted-by":"publisher","DOI":"10.1016\/j.jss.2013.04.079","article-title":"Regulation of tumor necrosis factor-\u03b1\u2013induced microvascular endothelial cell hyperpermeability by recombinant B-cell lymphoma-extra large","volume":"184","author":"Sawant","year":"2013","journal-title":"J Surg Res"},{"key":"B93","doi-asserted-by":"publisher","first-page":"a016295","DOI":"10.1101\/cshperspect.a016295","article-title":"IL-6 in inflammation, immunity, and disease","volume":"6","author":"Tanaka","year":"2014","journal-title":"Cold Spring Harbor Perspect Biol"},{"key":"B94","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-024-03376-x","article-title":"Endothelial overexpression of TGF-\u03b2-induced protein impairs venous thrombus resolution: possible role in CTEPH","volume":"9","author":"Bochenek","year":"2024","journal-title":"Basic to Trans Sci"},{"key":"B95","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(17)44129-9","article-title":"Biosynthetic and structural properties of endothelial cell type VIII collagen","volume":"258","author":"Sage","year":"1983","journal-title":"J Biol Chem"},{"key":"B96","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00368.2010","article-title":"Collagen IV contributes to nitric oxide-induced angiogenesis of lung endothelial cells","volume":"300","author":"Wang","year":"2011","journal-title":"Am J Physiol Cell Physiol"},{"key":"B97","doi-asserted-by":"publisher","first-page":"119876","DOI":"10.1016\/j.lfs.2021.119876","article-title":"Mitochondrial dynamics and mitophagy in lung disorders","volume":"284","author":"Sharma","year":"2021","journal-title":"Life Sci"},{"key":"B98","doi-asserted-by":"publisher","DOI":"10.1128\/iai.00248-23","article-title":"Aerobic glycolysis of bronchial epithelial cells rewires Mycoplasma pneumoniae pneumonia and promotes bacterial elimination","volume":"92","author":"He","year":"2024","journal-title":"Infect Immun"},{"key":"B99","doi-asserted-by":"publisher","DOI":"10.1529\/biophysj.106.099762","article-title":"Effect of cholesterol on the biophysical and physiological properties of a clinical pulmonary surfactant","volume":"93","author":"Keating","year":"2007","journal-title":"Biophys J"},{"key":"B100","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2016-0011PS","article-title":"Surfactant lipids at the host\u2013environment interface. Metabolic sensors, suppressors, and effectors of inflammatory lung disease","volume":"54","author":"Fessler","year":"2016","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B101","doi-asserted-by":"publisher","first-page":"e59961","DOI":"10.7554\/eLife.59961","article-title":"A lung-on-chip model of early Mycobacterium tuberculosis infection reveals an essential role for alveolar epithelial cells in controlling bacterial growth","volume":"9","author":"Thacker","year":"2020","journal-title":"Elife"},{"key":"B102","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201702-136AW","article-title":"A new frontier in immunometabolism. Cholesterol in lung health and disease","volume":"14","author":"Fessler","year":"2017","journal-title":"Ann Am Thorac Soc"},{"key":"B103","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcf.2019.07.005","article-title":"The role of endothelial cells in cystic fibrosis","volume":"18","author":"Declercq","year":"2019","journal-title":"J Cystic Fibrosis"},{"key":"B104","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)81724-9","article-title":"Evidence for periciliary liquid layer depletion, not abnormal ion composition, in the pathogenesis of cystic fibrosis airways disease","volume":"95","author":"Matsui","year":"1998","journal-title":"Cell"},{"key":"B105","doi-asserted-by":"publisher","DOI":"10.1038\/labinvest.2017.74","article-title":"Establishment and long-term culture of human cystic fibrosis endothelial cells","volume":"97","author":"Plebani","year":"2017","journal-title":"Lab Invest"},{"key":"B106","doi-asserted-by":"publisher","first-page":"2000261","DOI":"10.1183\/13993003.00261-2020","article-title":"Transcriptomic analysis of CFTR-impaired endothelial cells reveals a pro-inflammatory phenotype","volume":"57","author":"Declercq","year":"2021","journal-title":"Eur Respir J"},{"key":"B107","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbadis.2017.08.011","article-title":"Mechanisms of endothelial cell dysfunction in cystic fibrosis","volume":"1863","author":"Totani","year":"2017","journal-title":"Biochim Biophys Acta (BBA) Mol Basis Dis"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1592597\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T09:54:42Z","timestamp":1752573282000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1592597\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,15]]},"references-count":107,"alternative-id":["10.3389\/fimmu.2025.1592597"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1592597","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2025.03.21.644589","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,15]]},"article-number":"1592597"}}