title: HJP272, a novel endothelin receptor antagonist, attenuates lipopolysaccharide-induced acute lung injury in hamsters.
abstract: BACKGROUND
  Previous studies from this laboratory indicate that endothelin-1 (ET-1), a potent vasoconstrictor, may play an important role in lipopolysaccharide (LPS)-induced release of neutrophils from the pulmonary microvasculature. To further test this concept, Syrian hamsters were treated with a novel endothelin receptor A (ETA) antagonist (HJP272) prior to intratracheal instillation of LPS.
  
  
  METHODS
  The effect of HJP272 on the LPS-induced inflammatory reaction was determined by measuring: (1) lung histopathological changes, (2) total neutrophils in bronchoalveolar lavage fluid (BALF), (3) expression of tumor necrosis factor receptor 1 (TNFR1) by BALF macrophages, and (4) alveolar septal cell apoptosis.
  
  
  RESULTS
  Treatment with HJP272 significantly reduced each of these parameters during a 24-hr period following LPS instillation, supporting the concept that limiting the activity of ET-1 may reduce the extent of lung injury. This hypothesis was further tested by giving ET-1 prior to LPS instillation, which resulted in a marked enhancement of LPS-induced lung inflammation, as measured by BALF neutrophils and TNFR1-positive macrophages. Furthermore, the increase in neutrophils resulting from treatment with ET-1 was significantly reduced by HJP272, again demonstrating the ability of ETA receptor antagonists to limit the influx of these cells into the lung.
  
  
  CONCLUSIONS
  These findings suggest a potential therapeutic role for these agents in diseases where neutrophils are a significant cause of lung injury, such as bronchopneumonia, respiratory distress syndrome, and chronic obstructive pulmonary disease.
authors.affiliation: College of Pharmacy and Health Sciences, St John's University, Queens, NY, USA.
authors.forename: Shikha
authors.initials: S
authors.lastname: Patel
authors.forename: Xingjian
authors.initials: X
authors.lastname: Liu
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
authors.forename: Ralph
authors.initials: R
authors.lastname: Stephani
authors.forename: Hardik
authors.initials: H
authors.lastname: Patel
authors.forename: Jerome
authors.initials: J
authors.lastname: Cantor
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D019610:Cytoprotection; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism*; D005260:Female; D006912:Hydroxyquinolines / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008647:Mesocricetus; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000187:drug effects* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: C532839:3-(3-carboxybenzyl)-1-((6-ethylbenzo(d)(1,3)dioxol-5-yl)methyl)-6-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylic acid; D065130:Endothelin A Receptor Antagonists; D019332:Endothelin-1; D006912:Hydroxyquinolines; D008070:Lipopolysaccharides; D044022:Receptor, Endothelin A; D047888:Receptors, Tumor Necrosis Factor, Type I
references.citation: J Clin Invest. 2006 Mar;116(3):695-702
references.pmid: 16485040
references.citation: Am J Respir Cell Mol Biol. 2000 Sep;23(3):404-10
references.pmid: 10970833
references.citation: Respir Res. 2006 Oct 11;7:125
references.pmid: 17034639
references.citation: Cytokine. 2008 May;42(2):145-151
references.pmid: 18304834
references.citation: Exp Lung Res. 2008 Dec;34(10):707-16
references.pmid: 19085567
references.citation: Chest. 2003 Jul;124(1):247-54
references.pmid: 12853530
references.citation: Am J Respir Cell Mol Biol. 1995 Feb;12(2):232-7
references.pmid: 7865221
references.citation: Cell Signal. 2010 Nov;22(11):1615-25
references.pmid: 20466059
references.citation: Ind Health. 1997 Jul;35(3):353-8
references.pmid: 9248218
references.citation: J Immunol. 2001 Oct 1;167(7):4017-25
references.pmid: 11564821
references.citation: FASEB J. 1995 Sep;9(12):1196-204
references.pmid: 7672512
references.citation: J Pathol. 1992 Jul;167(3):349-56
references.pmid: 1517904
references.citation: J Immunol Methods. 1997 Mar 10;202(1):49-57
references.pmid: 9075771
references.citation: FASEB J. 2001 Oct;15(12):2230-40
references.pmid: 11641250
references.citation: Expert Rev Respir Med. 2010 Dec;4(6):773-83
references.pmid: 21128752
references.citation: Nat Rev Cancer. 2013 Sep;13(9):637-51
references.pmid: 23884378
references.citation: J Surg Res. 2001 Dec;101(2):232-7
references.pmid: 11735280
references.citation: J Leukoc Biol. 1995 Oct;58(4):468-76
references.pmid: 7561524
references.citation: Respir Res. 2001;2(2):90-101
references.pmid: 11686871
references.citation: Expert Opin Drug Saf. 2012 Nov;11(6):1003-11
references.pmid: 22861496
references.citation: Nat Med. 1997 Aug;3(8):904-7
references.pmid: 9256283
references.citation: Can J Physiol Pharmacol. 2012 Feb;90(2):187-99
references.pmid: 22320712
references.citation: J Clin Invest. 2000 Dec;106(11):1311-9
references.pmid: 11104784
references.citation: Am J Respir Crit Care Med. 2004 Sep 1;170(5):492-8
references.pmid: 15184206
references.citation: Nat Rev Drug Discov. 2013 Jul;12(7):543-59
references.pmid: 23977698
references.citation: Front Immunol. 2013 Nov 18;4:387
references.pmid: 24302927
references.citation: J Surg Res. 2005 Sep;128(1):21-7
references.pmid: 15993898
references.citation: Immunol Cell Biol. 2001 Apr;79(2):132-40
references.pmid: 11264706
references.citation: Int J Chron Obstruct Pulmon Dis. 2008;3(3):477-81
references.pmid: 18990977
references.citation: Acta Biochim Biophys Sin (Shanghai). 2006 Feb;38(2):119-28
references.pmid: 16474903
references.citation: Exp Lung Res. 2008 Mar;34(3):141-54
references.pmid: 18307123