Effect of the oestrogen receptor antagonist fulvestrant on the cirrhotic rat lung.
It has been postulated that cirrhosis-related lung vasodilatation and the subsequent hepatopulmonary syndrome are partly explained by an increased estradiol level through an enhanced endothelial formation of nitric oxide (NO). In this study, we assessed whether the oestrogen receptor antagonist fulvestrant (F) improves cirrhosis-related lung abnormalities. Cirrhosis was induced in rats by chronic bile duct ligation (CBDL). Four groups were studied: CBDL, CBDL+F, sham, and sham+F. Histological, immunohistochemical, and Western blot analyses were performed on lung samples. In the lung, the endothelial NO synthase and the nitrotyrosine protein expressions were increased in CBDL as compared to sham rats. Both parameters were significantly reduced by fulvestrant in the CBDL rats. Surprisingly, the level of pVASP (an indirect marker of NO formation and action) was decreased in CBDL rats, and fulvestrant had no effect on this parameter. The level of the vascular endothelial growth factor, the diameter of small lung vessels, and the number of macrophages were increased in CBDL lungs in comparison with sham lungs, and these parameters were unaffected by fulvestrant treatment. In conclusion, fulvestrant may not be relevant to improve lung abnormalities in cirrhosis because NO may not be biologically active and because key events contributing to the lung abnormalities are not affected by fulvestrant.
Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg et EA 3072, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Monique
M
Oswald-Mammosser
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
Sherzad
S
Rashid
Institut d'Histologie et INSERM U1119, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Nelly
N
Boehm
Laboratoire d'Hormonologie et Icube, Faculté de Médecine, CNRS, FMTS, Université de Strasbourg, Strasbourg, France.
Arnaud
A
Agin
Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg et EA 3072, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Bernard
B
Geny
UMR CNRS 7213, Laboratoire de Biophotonique et de Pharmacologie, Faculté de Pharmacie, Université de Strasbourg, Illkirch, France.
Valérie
V
Schini-Kerth
Service de Physiologie et d'Explorations Fonctionnelles, Pôle de Pathologie Thoracique, Hôpitaux Universitaires de Strasbourg et EA 3072, Faculté de Médecine, Université de Strasbourg, Strasbourg, France.
Anne
A
Charloux
D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism; D004195:Disease Models, Animal; D004958:Estradiol / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D065171:Estrogen Receptor Antagonists / Q000494:pharmacology*; D000077267:Fulvestrant; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism; D020065:Hepatopulmonary Syndrome / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D017208:Rats, Wistar; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
D015815:Cell Adhesion Molecules; D065171:Estrogen Receptor Antagonists; D008840:Microfilament Proteins; D010750:Phosphoproteins; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D000098662:Vasodilator-Stimulated Phosphoprotein; D000077267:Fulvestrant; C002744:3-nitrotyrosine; D014443:Tyrosine; D004958:Estradiol; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat
angiogenesis; cirrhosis; fulvestrant; hepatopulmonary syndrome; nitric oxide