The Hepatopulmonary syndrome: NO way out?
By Ðinh-Xuân Anh-Tuấn, M.D., Ph.D. and R. Naeije
(Tồn Trữ Tài Liệu Khảo Cứu Y Dược Khoa Của Người Việt)
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Eur Respir J 2004; 23:661-662
Copyright ©ERS Journals Ltd 2004

The hepatopulmonary syndrome: NO way out?
A.T. Dinh-Xuan1 and R. Naeije2
1 Service de Physiologie-Explorations Fonctionnelles, Centre Hospitalier Universitaire Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris V, Paris, France. 2 Dept of Physiology, Faculty of Medicine, Free University of Brussels, Brussels, Belgium

CORRESPONDENCE: A.T. Dinh-Xuan, Service de Physiologie-Explorations Fonctionnelles, Hôpital Cochin, 27, rue du faubourg Saint-Jacques, 75679 Paris cedex 14, France. Fax: 33 158412345. E-mail: anh-tuan.dinh-xuan@cch.ap-hop-paris.fr

"How diseases of the liver affect lung function?" is one of those puzzling questions that can turn obsessive for those who want to understand how two seemingly distinctive organs can interact and eventually lead to severe disorders 1, 2. The most common respiratory consequence of liver disease is hypoxaemia, which is often mild to moderate 3. Seldom severe hypoxaemia occurs when the arterial pressure of oxygen (Pa,O2) falls below 8 kPa (60 mmHg), heralding the occurrence of a condition known as the "hepatopulmonary syndrome" (HPS). HPS is characterised by a triad of conditions, namely: 1) advanced liver disease (with or without liver cirrhosis); 2) widespread intrapulmonary vasodilatation; and 3) alveolar-arterial oxygen gradient (PA-a,O2) >2.6 kPa (20 mmHg) whilst breathing room air 2, 3. Clinical symptoms typically include shortness of breath, which may either worsen on standing (platypnoea) and/or be accompanied by a 10% fall in Pa,O2 (orthodeoxia). As with other lung disorders, hypoxaemia results from impaired gas exchange, which, in HPS, is particularly perturbed by excessive and widespread dilatation of intrapulmonary vessels. After decades of careful investigations, the underlying mechanisms linking altered gas exchange and pulmonary vasodilatation are now well delineated 2–4. Reduced tone causing vascular relaxation occurs at both ends of the capillary bed, i.e. affecting pre-capillary and post-capillary vessels. This allows mixed venous blood to speed through, or even bypass, gas exchange units. It is believed that hypoxaemia occurs as a result of one (or the combination of several) of these following mechanisms: 1) ventilation-perfusion mismatching (reflecting excess perfusion for a given ventilation); 2) true intrapulmonary anatomical shunts; and 3) diffusion-perfusion impairment (due to increased oxygen diffusion distance from alveoli to haemoglobin across the dilated vessels) 5–9. Vascular dilatation can be observed using contrast-enhanced echocardiography or fractional brain uptake after lung perfusion of technetium-99m macroaggregated albumin lung scanning 10.
As pulmonary vasodilatation is the main culprit, hunting endogenous vasodilators that reduce pulmonary vascular tone logically became a sound strategy for those whose quest was to unravel the missing "molecular" link between the diseased liver and the affected lung. Nitric oxide (NO), one of the most potent and prominent endogenous pulmonary vasodilators 11, soon appeared as a very likely candidate, not only for the hyperdynamic circulatory syndrome in cirrhosis 12, but also for HPS 13. This hypothesis has been further consolidated in the light of clinical and experimental results from several recent studies 2. First, pulmonary endogenous production of NO, which can be assessed by measuring exhaled NO 14, is increased in patients with HPS 15–18 and returns to normal values 3–12 months after orthotopic liver transplantation 17, 18. Interestingly, normalisation of exhaled NO concentrations was observed either whilst the patient achieved normoxaemia again 17 or correlated with reduced PA-a,O2 18 after liver transplantation. This is consistent with the hypothesis of a major contributory role of endogenous NO in causing inadequate pulmonary vasodilatation, hence ventilation-perfusion mismatching and hypoxaemia, in HPS. The second question that naturally arises from these observations is "what is (are) the origin(s) of the increased NO production in HPS?". Early studies from our group have provided evidence of vascular hyporeactivity, which resulted from increased NO production in both systemic and pulmonary vascular beds of animals with experimental cirrhosis 19, 20. Applying the technique of multiple flow analysis, which allows to differentiate alveolar from bronchial origins of exhaled NO, Delclaux et al. 21 have elegantly zoomed in on the alveoli as the major source of increased NO production in cirrhotic patients. "What are the cellular types, and the NO synthases (NOS) subtypes, which are involved in this overproduction of NO?" came naturally as the question to ask at this stage. In experimental cirrhosis, overexpression of both inducible (NOS-2) and constitutive (NOS-3) isoforms are seen in alveolar macrophages and pulmonary endothelial cells, respectively 22, 23. Although the same pattern of lung NOS overexpression has not yet been documented in patients with HPS, this probably occurs in most cases, at least in patients who have been successfully treated with synthesis inhibitors of either NO or its target, namely the second messenger cyclic guanosine monophosphate (cGMP). Two reports recently described successful use of this therapeutic strategy in HPS patients, who were improved by either nebulisation of the NOS inhibitor, NG-nitro-l-arginine methyl ester 24, or intravenous administration of methylene blue, an inhibitor of the main molecular target of NO, the cGMP-synthesising enzyme soluble guanylyl cyclase 25 (fig. 1).
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Fig. 1.— Possible interactions between nitric oxide (NO), endothelin (ET)-1 and tumour necrosis factor (TNF)- in the pathogenesis of hepatopulmonary syndrome. cGMP: cyclic guanosine monophosphate; ET-A and ET-B: endothelin receptors A and B; GTP: guanosine triphosphate; l-NAME: NG-nitro-l-arginine methyl ester; NF-B: nuclear factor-B; NOS: nitric oxide synthase; sGC: soluble guanylyl; TNF-R: TNF- receptors.
In the current issue of the European Respiratory Journal, Sztrymf et al. 26 have taken us a step further down the path exploring intracellular signalisation of NO with their study on the effect of pentoxifylline, a nonspecific inhibitor of synthesis of the pro-inflammatory cytokine tumour necrosis factor (TNF)- 26. It is known that synthesis of NO by the inducible enzyme NOS-2 is regulated at a transcriptional level, mainly through activation of transcription factors, e.g. nuclear factor-B or activator protein-1, both of which are stimulated by TNF- 27 (fig. 1). Thus, targeting TNF- would be a logical approach, especially after the recent finding of increased production of this cytokine in experimental HPS 28. The paper by Sztrymf et al. 26, demonstrating that pretreatment with pentoxyfilline prevented HPS and the hyperdynamic circulatory syndrome, presumably through inhibition of TNF- synthesis and NOS-2 induction, elegantly adds a new piece of information to our knowledge on the pathophysiology of HPS. This further supports the central role of excess NO synthesis as a major molecular mechanism. The recent suggestion of a possible implication of endothelin (ET)-1 in HPS may further complicate an already complex scheme 28. However, as overexpression of pulmonary ET-B receptors, which provides another mechanism for the stimulation of NO release (fig. 1), is seen in experimental HPS 29, 30, NO is likely to keep on focussing our interest for a while yet.
Therefore, the spotlight is pinpointing down on nitric oxide. But we all know the interest and pitfall of this approach. Too much focus certainly allows greater scrutiny for a given factor, but also favours the risk of overlooking the others. Let's keep both nitric oxide in mind and our mind open for other forthcoming players in hepatopulmonary syndrome pathogenesis.

References
Rodriguez-Roisin R, Agustí AGN, Roca J. The hepatopulmonary syndrome: new name, old complexities. Thorax 1992;47:897–902.[Abstract]
Hervé P, Lebrec D, Brenot F, et al. Pulmonary vascular disorders in portal hypertension. Eur Respir J 1998;11:1153–1166.[Abstract/Free Full Text]
Naeije R. Hepatopulmonary syndrome and portopulmonary hypertension. Swiss Med Wkly 2003;133:163–169.[ISI][Medline] [Order article via Infotrieve]
Wagner PD. Impairment of gas exchange in liver cirrhosis. Eur Respir J 1995;8:1993–1995.[Free Full Text]
Rodriguez-Roisin R, Roca J, Agustí AGN, Mastai R, Wagner PD, Bosch J. Gas exchange and pulmonary vascular reactivity in patients with liver cirrhosis. Am Rev Respir Dis 1987;135:1085–1092.[ISI][Medline] [Order article via Infotrieve]
Mélot C, Naeije R, Dechamps P, Hallemans R, Lejeune P. Pulmonary and extrapulmonary contributors to hypoxemia in liver cirrhosis. Am Rev Respir Dis 1989;139:632–640.[ISI][Medline] [Order article via Infotrieve]
Hedenstierna G, Söderman C, Eriksson LS, Wahren J. Ventilation-perfusion inequality in patients with non-alcoholic liver cirrhosis. Eur Respir J 1991;4:711–717.[Abstract]
Thorens JB, Junod AF. Hypoxaemia and liver cirrhosis: a new argument in favour of a "diffusion-perfusion defect". Eur Respir J 1992;5:754–756.[Abstract]
Crawford ABH, Regnis J, Laks L, Donnelly P, Engel LA, Young IH. Pulmonary vascular dilatation and diffusion-dependent impairment of gas exchange in liver cirrhosis. Eur Respir J 1995;8:2015–2021.[Abstract/Free Full Text]
Krowka MJ, Wiseman GA, Burnett OL, et al. Hepatopulmonary syndrome: a prospective study of relationships between severity of liver disease, PaO2 response to 100% oxygen, and brain uptake after 99mTc MAA lung scanning. Chest 2000;118:615–624.[Abstract/Free Full Text]
Dinh-Xuan AT. Endothelial modulation of pulmonary vascular tone. Eur Respir J 1992;5:757–762.[Abstract]
Vallance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide?. Lancet 1991;337:776–778.[ISI][Medline] [Order article via Infotrieve]
Rolla G. Is nitric oxide the ultimate mediator in hepatopulmonary syndrome?. J Hepatol 2003;38:668–670.[CrossRef][ISI][Medline] [Order article via Infotrieve]
Dinh-Xuan AT, Texereau J. Measuring exhaled nitric oxide: not only a matter of how–but also why–should we do it? Eur Respir J 1998;12:1005–1007[Free Full Text]
Matsumoto A, Ogura K, Hirata Y, et al. Increased nitric oxide in the exhaled air of patients with decompensated liver cirrhosis. Ann Intern Med 1995;123:110–113. [Abstract/Free Full Text]
Sogni P, Garnier P, Gadano A, et al. Endogenous pulmonary nitric oxide production measured from exhaled air is increased in patients with severe cirrhosis. J Hepatol 1995;23:471–473.[CrossRef][ISI][Medline] [Order article via Infotrieve]
Cremona G, Higenbottam TW, Mayoral V, et al. Elevated exhaled nitric oxide in patients with hepatopulmonary syndrome. Eur Respir J 1995;8:1883–1885. [Abstract/Free Full Text]
Rolla G, Brussino L, Colagrande P, et al. Exhaled nitric oxide and impaired oxygenation in cirrhotic patients before and after liver transplantation. Ann Intern Med 1998;129:375–378. [Abstract/Free Full Text]
Sogni P, Sabry S, Moreau R, Gadano A, Lebrec D, Dinh-Xuan AT. Hyporeactivity of mesenteric resistance arteries in portal hypertensive rats. J Hepatol 1996;24:487–490. [CrossRef][ISI][Medline] [Order article via Infotrieve]
Chabot F, Mestiri H, Sabry S, Dall'Ava-Santucci J, Lockhart A, Dinh-Xuan AT. Role of NO in the pulmonary artery hyporeactivity to phenylephrine in experimental biliary cirrhosis. Eur Respir J 1996;9:560–564.[Abstract/Free Full Text]
Delclaux C, Mahut B, Zerah-Lancner F, et al. Increased nitric oxide output from alveolar origin during liver cirrhosis versus bronchial source during asthma. Am J Respir Crit Care Med 2002;165:332–337.[Abstract/Free Full Text]
Nunes H, Lebrec D, Mazmanian M, et al. Role of nitric oxide in hepatopulmonary syndrome in cirrhotic rats. Am J Respir Crit Care Med 2001;164:879–885. [Abstract/Free Full Text]
Zhang J, Ling Y, Luo B, et al. Analysis of pulmonary heme oxygenase-1 and nitric oxide synthase alterations in experimental hepatopulmonary syndrome. Gastroenterology 2003;125:1441–1451.[CrossRef][ISI][Medline] [Order article via Infotrieve]
Brussino L, Bucca C, Morello M, Scappaticci E, Mauro M, Rolla G. Effect on dyspnoea and hypoxaemia of inhaled NG-nitro-L-arginine methyl ester in hepatopulmonary syndrome. Lancet 2003;362:43–44.[CrossRef][ISI][Medline] [Order article via Infotrieve]
Schenk P, Madl C, Rezaie-Majd S, Lehr S, Muller C. Methylene blue improves the hepatopulmonary syndrome. Ann Intern Med 2000;133:701–706. [Abstract/Free Full Text]
Sztrymf B, Rabiller A, Nunes H, et al. Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. Eur Respir J 2004;23:752–758. [Abstract/Free Full Text]
Barnes PJ, Adcock IM. Transcription factors and asthma. Eur Respir J1998;12:221- 234 [Abstract/Free Full Text]
Luo B, Liu L, Tang L, Zhang J, Ling Y, Fallon MB. ET-1 and TNF- in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats. Am J Physiol Gastrointest Liver Physiol 2004;286:G294–G303.[Abstract/Free Full Text]
Zhang M, Luo B, Chen SJ, Abrams GA, Fallon MB. Endothelin-1 stimulation of endothelial nitric oxide synthase in the pathogenesis of hepatopulmonary syndrome. Am J Physiol Gastrointest Liver Physiol 1999;277: G944–G952. [Abstract/Free Full Text]
Luo B, Liu L, Tang L, et al. Increased pulmonary vascular endothelin B receptor expression and responsiveness to endothelin-1 in cirrhotic and portal hypertensive rats: a potential mechanism in experimental hepatopulmonary syndrome. J Hepatol 2003;38:556–563.[CrossRef][ISI][Medline] [Order article via Infotrieve]