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It is due to vasodilation and angiogenesis in the pulmonary vascular bed, which leads to ventilation\u2010perfusion mismatching, diffusion limitation to oxygen exchange, and arteriovenous shunting. There is evidence, primarily from animal studies, that vasodilation is mediated by a number of endogenous vasoactive molecules, including endothelin\u20101 and nitric oxide (<jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>). In experimental <jats:styled-content style=\"fixed-case\">HPS<\/jats:styled-content>, liver injury stimulates release of endothelin\u20101 and results in increased expression of <jats:styled-content style=\"fixed-case\">ET<jats:sub>B<\/jats:sub><\/jats:styled-content> receptors on pulmonary endothelial cells, leading to upregulation of endothelial <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> synthase (e<jats:styled-content style=\"fixed-case\">NOS<\/jats:styled-content>) and subsequent increased production of <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content>, which causes vasodilation. In addition, increased phagocytosis of bacterial endotoxin in the lung not only promotes stimulation of inducible NO synthase, which increases <jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> production, but also contributes to intrapulmonary accumulation of monocytes, which may stimulate angiogenesis via vascular endothelial growth factor pathway. Despite these insights into the pathogenesis of experimental <jats:styled-content style=\"fixed-case\">HPS<\/jats:styled-content>, there is no established medical therapy, and liver transplantation remains the main treatment for symptomatic <jats:styled-content style=\"fixed-case\">HPS<\/jats:styled-content>, although selected patients may benefit from other surgical or radiological interventions. In this review, we focus on recent advances in our understanding of the pathophysiology of <jats:styled-content style=\"fixed-case\">HPS<\/jats:styled-content>, and discuss current approaches to the investigation and treatment of this condition.<\/jats:p>","DOI":"10.1111\/jgh.12061","type":"journal-article","created":{"date-parts":[[2012,11,29]],"date-time":"2012-11-29T01:04:55Z","timestamp":1354151095000},"page":"213-219","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":87,"title":["Hepatopulmonary syndrome: Update on recent advances in pathophysiology, investigation, and treatment"],"prefix":"10.1111","volume":"28","author":[{"given":"Josephine A","family":"Grace","sequence":"first","affiliation":[{"name":"Department of Medicine Austin Health The University of Melbourne  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter W","family":"Angus","sequence":"additional","affiliation":[{"name":"Victorian Liver Transplant Unit Austin Health Austin Hospital  Melbourne Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2013,1,22]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"crossref","first-page":"e136","DOI":"10.1097\/MCG.0b013e3181da76fc","article-title":"Coexisting hepatopulmonary syndrome and portopulmonary hypertension: implications for liver transplantation","volume":"44","author":"Pham DM","year":"2010","journal-title":"J. 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