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Increased nitric oxide production in lymphatic endothelial cells causes impairment of lymphatic drainage in cirrhotic rats
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. (Rudbecklaboratoriet)
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2013 (English)In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 62, no 1, 138-145 p.Article in journal (Refereed) Published
Abstract [en]

Background and aim: The lymphatic network plays a major role in maintaining tissue fluid homoeostasis. Therefore several pathological conditions associated with oedema formation result in deficient lymphatic function. However, the role of the lymphatic system in the pathogenesis of ascites and oedema formation in cirrhosis has not been fully clarified. The aim of this study was to investigate whether the inability of the lymphatic system to drain tissue exudate contributes to the oedema observed in cirrhosis. Methods: Cirrhosis was induced in rats by CCl4 inhalation. Lymphatic drainage was evaluated using fluorescent lymphangiography. Expression of endothelial nitric oxide synthase (eNOS) was measured in primary lymphatic endothelial cells (LyECs). Inhibition of eNOS activity in cirrhotic rats with ascites (CH) was carried out by L-N G-methyl-L-arginine (L-NMMA) treatment (0.5 mg/kg/day). Results: The (CH) rats had impaired lymphatic drainage in the splanchnic and peripheral regions compared with the control (CT) rats. LyECs isolated from the CH rats showed a significant increase in eNOS and nitric oxide (NO) production. In addition, the lymphatic vessels of the CH rats showed a significant reduction in smooth muscle cell (SMC) coverage compared with the CT rats. CH rats treated with L-NMMA for 7 days showed a significant improvement in lymphatic drainage and a significant reduction in ascites volume, which were associated with increased plasma volume. This beneficial effect of L-NMMA inhibition was also associated with a significant increase in lymphatic SMC coverage. Conclusions: The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.

Place, publisher, year, edition, pages
2013. Vol. 62, no 1, 138-145 p.
National Category
Medical and Health Sciences Natural Sciences
URN: urn:nbn:se:uu:diva-192009DOI: 10.1136/gutjnl-2011-300703OAI: oai:DiVA.org:uu-192009DiVA: diva2:600451
Available from: 2013-01-24 Created: 2013-01-15 Last updated: 2013-01-24Bibliographically approved

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