{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T15:54:47Z","timestamp":1782489287415,"version":"3.54.5"},"reference-count":55,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T00:00:00Z","timestamp":1712707200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Using a lipopolysaccharide model of acute lung injury, we previously showed that endothelin-1 (ET-1), a potent mediator of vasoconstriction, may act as a \u201cgatekeeper\u201d for the influx of inflammatory cells into the lung. These studies provided a rationale for testing the effect of HJP272, an endothelin receptor antagonist (ERA), in hamster models of pulmonary fibrosis induced by intratracheal instillation of either bleomycin (BLM) or amiodarone (AM). To determine the temporal effects of blocking ET-1 activity, animals were given HJP272 either 1 h before initiation of lung injury or 24 h afterward. The results indicated that pretreatment with this agent caused significant reductions in various inflammatory parameters, whereas post-treatment was ineffective. This finding suggests that ERAs are only effective at a very early stage of pulmonary fibrosis and explains their lack of success in clinical trials involving patients with this disease. Nevertheless, ERAs could serve as prophylactic agents when combined with drugs that may induce pulmonary fibrosis. Furthermore, developing a biomarker for the initial changes in the lung extracellular matrix could increase the efficacy of ERAs and other therapeutic agents in preventing the progression of the disease. While no such biomarker currently exists, we propose the ratio of free to peptide-bound desmosine, a unique crosslink of elastin, as a potential candidate for detecting the earliest modifications in lung microarchitecture associated with pulmonary fibrosis.<\/jats:p>","DOI":"10.3390\/ijms25084184","type":"journal-article","created":{"date-parts":[[2024,4,10]],"date-time":"2024-04-10T06:07:46Z","timestamp":1712729266000},"page":"4184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Maximizing the Therapeutic Effect of Endothelin Receptor Antagonists in Pulmonary Fibrosis: A Paradigm for Treating the Disease"],"prefix":"10.3390","volume":"25","author":[{"given":"Jerome","family":"Cantor","sequence":"first","affiliation":[{"name":"School of Pharmacy and Health Sciences, Queens, NY 11439, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.2353\/ajpath.2009.081170","article-title":"Emerging concepts in the pathogenesis of lung fibrosis","volume":"175","author":"Hardie","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2434","DOI":"10.1161\/01.CIR.102.19.2434","article-title":"Endothelins and endothelin receptor antagonists: Therapeutic considerations for a novel class of cardiovascular drugs","volume":"102","author":"Barton","year":"2000","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2863","DOI":"10.1073\/pnas.86.8.2863","article-title":"The human endothelin family: Three structurally and pharmacologically distinct isopeptides predicted by three separate genes","volume":"86","author":"Inoue","year":"1989","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/332411a0","article-title":"A novel potent vasoconstrictor peptide produced by vascular endothelial cells","volume":"332","author":"Yanagisawa","year":"1988","journal-title":"Nature"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1139\/Y08-057","article-title":"Effect of the putative novel selective ETA-receptor antagonist HJP272, a 1,3,6-trisubstituted-2-carboxy-quinol-4-one, on infection-mediated premature delivery","volume":"86","author":"Olgun","year":"2008","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1007\/s00408-014-9628-z","article-title":"HJP272, a novel endothelin receptor antagonist, attenuates lipopolysaccharide-induced acute lung injury in hamsters","volume":"192","author":"Patel","year":"2014","journal-title":"Lung"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"477","DOI":"10.2147\/COPD.S2837","article-title":"Preferential recruitment of neutrophils by endothelin-1 in acute lung inflammation induced by lipopolysaccharide or cigarette smoke","volume":"3","author":"Bhavsar","year":"2008","journal-title":"Int. J. Chron. Obstruct. Pulmon. Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4017","DOI":"10.4049\/jimmunol.167.7.4017","article-title":"Immobilized IL-8 triggers progressive activation of neutrophils rolling in vitro on P-selectin and intercellular adhesion molecule-1","volume":"167","author":"DiVietro","year":"2001","journal-title":"J. Immunol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1172\/JCI27009","article-title":"Critical role of endothelial CXCR2 in LPS-induced neutrophil migration into the lung","volume":"116","author":"Reutershan","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1165\/ajrcmb.23.3.4057","article-title":"Endothelin-1 changes polymorphonuclear leukocytes\u2019 deformability and CD11b expression and promotes their retention in the lun","volume":"23","author":"Sato","year":"2000","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1186\/1465-9921-7-125","article-title":"Role of TNFalpha in pulmonary pathophysiology","volume":"7","author":"Mukhopadhyay","year":"2006","journal-title":"Respir. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1006\/jsre.2001.6274","article-title":"TNF receptor I mediates chemokine production and neutrophil accumulation in the lung following systemic lipopolysaccharide","volume":"101","author":"Calkins","year":"2001","journal-title":"J. Surg. Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1159\/000481201","article-title":"Highly Selective Endothelin-1 Receptor A Inhibition Prevents Bleomycin-Induced Pulmonary Inflammation and Fibrosis in Mice","volume":"95","author":"Manitsopoulos","year":"2017","journal-title":"Respiration"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1164\/ajrccm.156.2.9607123","article-title":"Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist","volume":"156","author":"Park","year":"1997","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11636","DOI":"10.1016\/S0021-9258(19)68452-8","article-title":"Activated bleomycin. A transient complex of drug, iron, and oxygen that degrades DNA","volume":"256","author":"Burger","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"353","DOI":"10.2486\/indhealth.35.353","article-title":"Quantitative time-course profiles of bronchoalveolar lavage cells following intratracheal instillation of lipopolysaccharide in mice","volume":"35","author":"Hirano","year":"1997","journal-title":"Ind. Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1046\/j.1365-2613.2002.00220.x","article-title":"Time course of bleomycin-induced lung fibrosis","volume":"83","author":"Izbicki","year":"2002","journal-title":"Int. J. Exp. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1165\/rcmb.2007-0448OC","article-title":"Chronic LPS inhalation causes emphysema-like changes in mouse lung that are associated with apoptosis","volume":"39","author":"Brass","year":"2008","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.pupt.2017.06.003","article-title":"Time-dependent effects of HJP272, an endothelin receptor antagonist, in bleomycin-induced pulmonary fibrosis","volume":"45","author":"Liu","year":"2017","journal-title":"Pulm. Pharmacol. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1136\/jcp.41.4.467","article-title":"Simple method of estimating severity of pulmonary fibrosis on a numerical scale","volume":"41","author":"Ashcroft","year":"1988","journal-title":"J. Clin. Pathol."},{"key":"ref_21","first-page":"391","article-title":"The induction of pulmonary phospholipidosis and the inhibition of lysosomal phospholipases by amiodarone","volume":"66","author":"Heath","year":"1985","journal-title":"Br. J. Exp. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1006\/taap.1995.1075","article-title":"Pulmonary responses to amiodarone in hamsters: Comparison of intratracheal and oral administrations","volume":"131","author":"Blake","year":"1995","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1111\/j.1540-8167.1993.tb01220.x","article-title":"The role of free radicals in the pathogenesis of amiodarone toxicity","volume":"4","author":"Vereckei","year":"1993","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1097\/00005344-198807000-00004","article-title":"Amiodarone causes acute oxidant lung injury in ventilated and perfused rabbit lungs","volume":"12","author":"Kennedy","year":"1988","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1097\/PAS.0b013e318243fd9a","article-title":"Lymphoid hyperplasia and eosinophilic pneumonia as histologic manifestations of amiodarone-induced lung toxicity","volume":"36","author":"Larsen","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1007\/s00408-018-0103-0","article-title":"Transient Blockade of Endothelin-1 Mitigates Amiodarone-Induced Pulmonary Fibrosis","volume":"196","author":"Liu","year":"2018","journal-title":"Lung"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1007\/s10753-007-9032-4","article-title":"Eosinophil cationic protein stimulates TGF-beta1 release by human lung fibroblasts in vitro","volume":"30","author":"Zagai","year":"2007","journal-title":"Inflammation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1016\/j.cell.2009.11.007","article-title":"Epithelial-mesenchymal transitions in development and disease","volume":"139","author":"Thiery","year":"2009","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1776","DOI":"10.1172\/JCI200320530","article-title":"Epithelial-mesenchymal transition and its implications for fibrosis","volume":"112","author":"Kalluri","year":"2003","journal-title":"J. Clin. Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1016\/j.humpath.2009.02.020","article-title":"Direct contribution of epithelium to organ fibrosis: Epithelial-mesenchymal transition","volume":"40","author":"Guarino","year":"2009","journal-title":"Hum. Pathol."},{"key":"ref_31","first-page":"751","article-title":"Interstitial fibrosis and growth factors","volume":"108","author":"Lasky","year":"2000","journal-title":"Environ. Health Perspect."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2129","DOI":"10.1016\/j.biocel.2008.02.012","article-title":"Fibrocytes are a potential source of lung fibroblasts in idiopathic pulmonary fibrosis","volume":"40","author":"Nihlberg","year":"2008","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1172\/JCI200420997","article-title":"Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis","volume":"114","author":"Phillips","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.bcp.2014.01.030","article-title":"Endothelin-1 induces connective tissue growth factor expression in human lung fibroblasts by ETAR-dependent JNK\/AP-1 pathway","volume":"88","author":"Weng","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e29981","DOI":"10.1097\/MD.0000000000029981","article-title":"The potential benefit of endothelin receptor antagonists\u2019 therapy in idiopathic pulmonary fibrosis: A meta-analysis of results from randomized controlled trials","volume":"101","author":"Li","year":"2022","journal-title":"Medicine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"641","DOI":"10.7326\/0003-4819-158-9-201305070-00003","article-title":"Treatment of idiopathic pulmonary fibrosis with ambrisentan: A parallel, randomized trial","volume":"158","author":"Raghu","year":"2013","journal-title":"Ann. Intern. Med."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2186","DOI":"10.3899\/jrheum.110499","article-title":"Effect of Bosentan on systemic sclerosis-associated interstitial lung disease ineligible for cyclophosphamide therapy: A prospective open-label study","volume":"38","author":"Furuya","year":"2011","journal-title":"J. Rheumatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1164\/rccm.201011-1874OC","article-title":"BUILD-3: A randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis","volume":"184","author":"King","year":"2011","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.plrev.2016.08.002","article-title":"Pattern transitions in spatial epidemics: Mechanisms and emergent properties","volume":"19","author":"Sun","year":"2016","journal-title":"Phys. Life Rev."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Heitjans, P., and Karger, J. (2005). Diffusion in Condensed Matter, Springer.","DOI":"10.1007\/3-540-30970-5"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1152\/japplphysiol.01244.2010","article-title":"Lung tissue mechanics as an emergent phenomenon","volume":"110","author":"Suki","year":"2011","journal-title":"J. Appl. Physiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1164\/rccm.200611-1739OC","article-title":"Linking parenchymal disease progression to changes in lung mechanical function by percolation","volume":"176","author":"Bates","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Stainer, A., Faverio, P., Busnelli, S., Catalano, M., Della Zoppa, M., Marruchella, A., Pesci, A., and Luppi, F. (2021). Molecular Biomarkers in Idiopathic Pulmonary Fibrosis: State of the Art and Future Directions. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22126255"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s12931-018-0747-6","article-title":"Increased circulating desmosine and age-dependent elastinolysis in idiopathic pulmonary fibrosis","volume":"19","author":"Drent","year":"2018","journal-title":"Respir. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1007\/s00408-016-9956-2","article-title":"The Pattern of Elastic Fiber Breakdown in Bleomycin-Induced Pulmonary Fibrosis May Reflect Microarchitectural Changes","volume":"195","author":"Liu","year":"2017","journal-title":"Lung"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1007\/s00408-015-9712-z","article-title":"The Ratio of Free to Bound Desmosine and Isodesmosine May Reflect Emphysematous Changes in COPD","volume":"193","author":"Liu","year":"2015","journal-title":"Lung"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"106402","DOI":"10.1016\/j.rmed.2021.106402","article-title":"A 28-day clinical trial of aerosolized hyaluronan in alpha-1 antiprotease deficiency COPD using desmosine as a surrogate marker for drug efficacy","volume":"182","author":"Cantor","year":"2021","journal-title":"Respir. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.mehy.2013.05.024","article-title":"What percolation theory can tell us about COPD","volume":"81","author":"Cantor","year":"2013","journal-title":"Med. Hypotheses"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3325","DOI":"10.1080\/14786430500197934","article-title":"Evidence of emergent scaling in mechanical systems","volume":"86","author":"Murphy","year":"2006","journal-title":"Philos. Mag."},{"key":"ref_50","first-page":"675","article-title":"Collagen lysyl oxidase activity in the lung increases during bleomycin-induced lung fibrosis","volume":"219","author":"Counts","year":"1981","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_51","first-page":"169","article-title":"Stimulation of lung lysyl oxidase activity in hamsters with elastase-induced emphysema","volume":"131","author":"Osman","year":"1985","journal-title":"Am. Rev. Respir. Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1126\/science.7089570","article-title":"Lung fibrosis and emphysema: Divergent responses to a common injury?","volume":"217","author":"Niewoehner","year":"1982","journal-title":"Science"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1183\/13993003.01824-2015","article-title":"Circulating desmosine levels do not predict emphysema progression but are associated with cardiovascular risk and mortality in COPD","volume":"47","author":"Rabinovich","year":"2016","journal-title":"Eur. Respir. J."},{"key":"ref_54","first-page":"560","article-title":"Free Urinary Desmosine and Isodesmosine as COPD Biomarkers: The Relevance of Confounding Factors","volume":"3","author":"Ongay","year":"2016","journal-title":"Chronic Obstr. Pulm. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1183\/09031936.00172911","article-title":"Desmosine, a biomarker for COPD: Old and in the way","volume":"39","author":"Luisetti","year":"2012","journal-title":"Eur. Respir. J."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/8\/4184\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:25:37Z","timestamp":1760106337000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/8\/4184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,10]]},"references-count":55,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["ijms25084184"],"URL":"https:\/\/doi.org\/10.3390\/ijms25084184","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,10]]}}}