Medical Hypotheses 83 (2014) 302–305

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Roles of cyclooxygenase 2 and hepatic venous flow in patients with HHT or hepatopulmonary syndrome Alexis Lacout ⇑, Pierre Yves Marcy, Juliette Thariat, Jacques Sellier, Mostafa El Hajjam, Pascal Lacombe Pluridisciplinary HHT team, Ambroise Paré Hospital, Groupement des Hôpitaux Ile-de-France Ouest, Assistance Publique Hôpitaux de Paris, Université de Versailles Saint Quentin en Yvelines, 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France

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Article history: Received 13 January 2014 Accepted 1 June 2014

a b s t r a c t Background: Hereditary hemorrhagic telangiectasia (HHT) and hepatopulmonary syndrome are disorders characterized by the development of multiple pulmonary arteriovenous malformations (PAVM). Presentation of the hypothesis: COX2 may be at the origin of a cascade of pro inflammatory events to favour angiogenesis and PAVM development. Testing the hypothesis: HHT and hepatopulmonary syndrome mouse models may be used to show its effects on PAVM formation. Anti COX-2 therapy could also be tested in human individuals, particularly in patients presenting a hepatopulmonary syndrome or HHT with small PAVM. Implication of the hypothesis: PAVMs are one of the main causes of morbidity in patients presenting with HHT disease, owing to the risks of rupture as well as paradoxical embolism exposing to stroke and/or cerebral abscess. Percutaneous embolization has become the treatment of choice of PAVM. Anti COX2 may prevent from PAVM development and subsequent related complications and avoid either surgery and/or percutaneous embolization and thus subsequent related complication. Ó 2014 Elsevier Ltd. All rights reserved.

Background Hereditary hemorrhagic telangiectasia (HHT) disease is an autosomic dominant disorder characterized by the development of multiple arteriovenous malformations in either the skin, mucous membranes, and/or visceral organs. Pulmonary arteriovenous malformations (PAVMs) are critical as they may either rupture or be responsible for a right-to-left shunting and subsequent paradoxical embolism causing stroke or cerebral abscess [1,2]. Two main types of HHT disease represent 80% of the cases and are due to the mutations in the ENG gene (encoding for endoglin) or activin type-II-like receptor kinase 1 (ACVRL1) gene (encoding for the activin receptor like kinase (ALK1)), causing respectively HHT type 1 and HHT type 2 diseases. The ENG and ACVRL1 genes code for proteins of the TGF beta receptor, which is involved in angiogenesis (the negative feed-

Abbreviations: ACVRL1, activin type-II-like receptor kinase 1; ALK1, activin receptor like kinase; ANG, angiopoietin; HHT, hereditary hemorrhagic telangiectasia; MIP, maximum intensity projection; NSAID, non steroidal anti inflammatory drugs; PAVMs, pulmonary arteriovenous malformations; SMAD, small mothers against decapentaplegic. ⇑ Corresponding author. Address: Service de Radiologie, Hôpital Ambroise PARE (APHP), 9, Avenue Charles de GAULLE, 92100 Boulogne Billancourt, France. Tel.: +33 4 71 48 00 50; fax: +33 4 71 48 53 48. E-mail address: [email protected] (A. Lacout). http://dx.doi.org/10.1016/j.mehy.2014.06.001 0306-9877/Ó 2014 Elsevier Ltd. All rights reserved.

back acts upon vessel proliferation, favouring maturation and stability of the new vessels) [3]. The mutation of the small mothers against decapentaplegic (SMAD) 4 gene, which is involved in TGF beta signal transduction, may also cause HHT disease, in association with juvenile polyposis [4] (Fig. 1). Hepatopulmonary syndrome is a disorder in which altered gas exchange is involved. As a matter of fact, the cornerstone is abnormal capillary dilatation and/or PAVM that will cause severe hypoxemia. Increased nitric oxide production with subsequent vasodilation has been suggested as a factor to explain the pathogenesis. However, angiogenesis process could also represent a second important factor [5]. The first step of PAVM development corresponds to the dilatation of post capillary veinules, surrounded by a mononuclear inflammatory cell infiltrate mostly composed of lymphocytes. Histopathologically, a lack of maturation of the vascular system is observed, characterized by inappropriate endothelial cell proliferation which leads to fragilized immature vessel [6,7].

Relationship between PAVM, inflammation and angiogenesis Apart from the well-known TGF beta pathway as being the primary cause of HHT disease, COX2 may be at the centre of a cascade of pro inflammatory events to favour angiogenesis and the

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Fig. 1. COX2 pathway involvement hypothesis in the PAVM development.

expression of the HHT related mutated gene (ENG and ACVRL1) products (Fig. 1). As previously hypothetized, inflammatory and angiogenesis process may play a key role in the initiation step of PAVM development, before the malformation evolves to its own account [8–10]. Roles of COX2 and hepatic venous blood flow in PAVM development (Fig. 1) As a matter of fact, we hypothetize that COX2-dependent proinflammatory molecular mechanisms may favour the PAVM angiogenesis by the various following mechanisms. Firstly, COX2 pathway may directly inhibit SMAD 2/3 action [11]. Interestingly, SMAD 2/3–SMAD 4 are molecules that are implicated in the TGF beta negative angiogenesis regulation pathway, ensuring the signal transduction of the TGF beta receptor ALK1 (encoded by ACVRL1 gene). In this setting, COX2 pathway may favour the angiogenesis process, thus subsequently promote the HHT phenotype expression. Secondly, angiopoietin (Ang) 2, whose serum level is increased during the inflammatory process is a cytokine that favours the development of new vessels probably in order to repair tissue damages [12]. COX2 may favour the Ang 2 expression as recently reported by Wang et al. [13]. Furthermore, Ang 2 counteracts Ang 1, a cytokin implicated in the blood vessel maturation and stability [12]. In HHT patients in whom the negative feedback of TGF beta pathway on angiogenesis is deficient, we guess that the inflammation process may thus both promote the angiogenesis process and inhibit the vessel maturation–stabilization. Last but not least, anti-VEGF action may also favour anarchic vasculature changes towards a more ‘‘mature’’ or ‘‘normal’’ phenotype [14]. Interestingly, on the one hand, VEGF tissue expression is significantly higher in HHT patients compared to healthy controls [15]. On the other hand, a close relationship between hepatic disorders, venous hepatic blood flow and PAVM development does exist. Indeed, patients who underwent Glenn’s surgical procedure, which consists of superior vena cava anastomosis with pulmonary artery and subsequent decrease or absence of inferior vena caval return to lungs may further develop PAVM [16]. These arteriove-

nous fistulas usually disappear when the hepatic blood flow is re-routed to the lungs. Similarly, we observed a case of Williams–Beuren syndrome in whom PAVM developed downstream pulmonary artery occlusions (Fig. 2). The absence of hepatic venous flow passing through the pulmonary artery obstruction may also explain the development of these PAVM. These findings suggests a deficiency of an anti-angiogenic factor or an excess of an angiogenic factor in the hepatic blood venous flow. Interestingly, recent studies have reported increased levels of VEGF-A in alveolar macrophages and endothelial cells of hepatopulmonary syndrome experimental rat models [5]. As VEGF expression may be induced by COX2 [17], we hypothetize that anti-COX2 may avoid the angiogenesis process thus preventing PAVM formation.

Fig. 2. 39 year-old patient presenting with Williams–Beuren syndrome. MIP CT scan frontal oblique reformation of the lower lungs. Two pulmonary arteries are displayed in the right lower lobe. One shows a long and tight stenosis (arrow) and further enlarges progressively. On the second pulmonary artery, the proximal segment is totally occluded and enlarges (large arrow). Both vessels are feeding the same pulmonary arteriovenous malformation located downstream (arrowhead).

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Vicious circles promoting COX2 expression in PAVM patients Vicious circles, may also worsen the COX2 role in the angiogenesis process. Indeed, patients may suffer from chronic hypoxia owing to the PAVM related right-to-left shunt, which may favour COX2 expression [18]. By promoting both inflammatory and angiogenesis processes, PAVM may initiate via the different mechanisms described above. Interestingly, Wang et al. found that COX-2 inhibition may reverse the hypoxia induced pro angiogenetic cytokine Ang 2 [13]. VEGF (whose expression is induced by COX2 as stated above) may also harbour a positive feed back by stimulating the COX2 pathway expression [19]. Furthermore, as endoglin inhibits the COX2 expression [20], HHT1 patients presenting with endoglin deficiency may show an increase of the COX2 inflammation – angiogenesis pathway. Hypothesis We hypothetize that the hepatic venous blood flow returning through the lungs is involved in the PAVM development in which the angiogenic factor VEGF plays a key role. Anti COX2 may diminish inflammatory processes, decrease the serum Ang 2/VEGF levels (diminishing the neovasculature formation), favour SMAD 2-3–4/ Ang 1 expression (and subsequent maturation and stabilization of new vasculature) thus avoiding the genesis of PAVM.

bronchial artery supply, post embolization systemic supply may be responsible for delayed hemoptysis. Conclusion PAVMs are one of the main causes of morbidity in patients presenting with HHT disease, owing to the risks of rupture as well as of paradoxical embolism exposing to stroke and/or cerebral abscess. Percutaneous embolization has become the treatment of choice of PAVM, due to its safety and efficiency in experienced hands. Both angiogenesis (mainly VEGF related angiogenesis) and modification of the hepatic venous flow may play an important role in PAVM development. Anti COX2 therapy may be tested as a prophylaxis or a curative therapy in PAVM patients, either presenting with HHT or hepatopulmonary syndrome. In treated patients, anti COX2 therapy may either avoid surgery and percutaneous embolization and thus subsequent related life theatening complications. Conflict of interest The authors declare no conflict of interest Authors’ contributions

Evaluation of the hypothesis Anti-COX2 therapy effects on PAVM formation may be tested on a HHT or hepatopulmonary syndrome mouse model. Anti COX2 therapy could also be tested in human individuals, particularly in patients presenting HHT with tiny PAVMS. Consequences of the hypothesis and discussion PAVMs should be treated before the complication may appear, owing to the high complication rate reaching almost 50% in the literature [21]. In patients presenting with diffuse clinical forms, the neurological morbidity (stroke and brain abscess) rate of untreated PAVMs reaches up to 70% [22]. It is recommended that patients presenting with PAVMs should undergo antibiotic prophylaxis prior to dental and surgical interventions to reduce paradoxical embolic abscess risks [23]. The risk of cerebral complications is usually considered significant when the feeding artery of the PAVM exceeds 3 mm in diameter, and may also increase in patients with multiple PAVMs. The 3 mm cut-off size is solely based on empirical datas regarding patients who never experienced such cerebral ischemic events below that size [24]. Surgery has long been the treatment of reference until the seventies, including pneumonectomy, lobectomy, segmentectomy, wedge resection or vascular ligation [25]. Pulmonary transplantation has been performed in diffuse forms associated with respiratory insufficiency [26] Percutaneous image-guided embolotherapy is nowadays preferable in most disease cases. The aim of transcatheter embolization is to occlude all the PAVM feeding arteries by a selective catheterization of pulmonary arteries by using a coaxial system. Complications include device migration, gazeous embolism, stroke, pulmonary infarctions and hemoptysis. Regarding mid- to long-term complications, reperfusion of the embolized PAVM may be due to the following mechanisms including: reperfusion through or around the anchored coils; development of pulmonary to PAVM neovasculature anastomoses, reperfusion by systemic bronchial and/or non bronchial arteries [27]. In case of systemic

Alexis Lacout: participated in the design of the article; important intellectual content. Pierre Yves Marcy: participated in the design of the article; important intellectual content; writing assistance. Juliette Thariat: participated in the design of the article; important intellectual content; writing assistance. Mostafa El Hajjam: participated in the design of the article; litterature research; important intellectual content. Jacques Sellier: participated in the design of the article; litterature research; important intellectual content. Pascal Lacombe: has given final approval of the version to be published; important intellectual content. All authors read and approved the final manuscript. References [1] Guttmacher AE, Marchuk DA, White RI. Hereditary hemorrhagic telangiectasia. N Engl J Med 1995;333:918–24. [2] Fuchizaki U, Miyamori H, Kitagawa S, Kaneko S, Kobayashi K. Hereditary haemorrhagic telangiectasia (Rendu–Osler–Weber disease). Lancet 2003;362:1490–4. [3] Bayrak-Toydemir P, Mao R, Lewin S, McDonald J. Hereditary hemorrhagic telangiectasia: an overview of diagnosis and management in the molecular era for clinicians. Genet Med 2004;6:175–91. [4] Iyer NK, Burke CA, Leach BH, Parambil JG. SMAD 4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia. Thorax 2010;65:745–6. [5] Fallon MB, Abrams GA, McGrath JW, Hou Z, Luo B. Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome. Am J Physiol 1997;272:G779–84. [6] Robinson Jr JR, Awad IA, Zhou P, Barna BP, Estes ML. Expression of basement membrane and endothelial cell adhesion molecules in vascular malformations of the brain: preliminary observations and working hypothesis. Neurol Res 1995;17:49–58. [7] Mahmoud M, Allinson KR, Zhai Z, Oakenfull R, Ghandi P, Adams RH, et al. Pathogenesis of arteriovenous malformations in the absence of endoglin. Circ Res 2010;106:1425–33. [8] Lacout A, Marcy PY, Hajjam ME, Lacombe P. Pulmonary arteriovenous malformations etiologies in HHT patients and potential utility of thalidomide. Med Hypotheses 2013;80:587–8. [9] Gately S, Li WW. Multiple roles of COX-2 in tumor angiogenesis: a target for antiangiogenic therapy. Semin Oncol 2004;31:2–11. [10] Jackson JR, Seed MP, Kircher CH, Willoughby DA, Winkler JD. The codependence of angiogenesis and chronic inflammation. FASEB J 1997;11:457–65.

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