Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats

Abstract

Inhibition of tumour necrosis factor-alpha (TNF-alpha), levels of which are increased in the blood of cirrhotic rats, prevents hyperdynamic circulatory state, mainly by decreasing the vascular overproduction of nitric oxide. Hepatopulmonary syndrome, which is characterised by intrapulmonary vascular dilatation and increased alveolar to arterial oxygen tension difference (PA-a,O2), is mainly related to pulmonary over-production of NO by macrophages accumulated in lung vessels. Since TNF-alpha is a potent activator of macrophagic inducible nitric oxide synthase (NOS), the aim of this study was to investigate whether TNF-alpha inhibition prevented hepatopulmonary syndrome and hyperdynamic circulatory state in rats with cirrhosis. TNF-alpha was inhibited by 5 weeks of pentoxifylline (10 mg x kg body weigh(-1) x day(-1)) in rats with cirrhosis induced by common bile duct ligation. Cardiac output, pulmonary and systemic vascular resistance, PA-a,O2 and cerebral uptake of intravenous technetium-99m-labelled albumin macroaggregates (which reflects intrapulmonary vascular dilatation) were similar in sham- and pentoxifylline-treated cirrhotic rats. Blood TNF-alpha concentrations and pulmonary intravascular macrophage sequestration, as assessed by morphometric analysis and radioactive colloid uptake, were decreased with pentoxifylline. Pentoxifylline also prevented increases in aorta and lung NOS activities and inducible NOS expression. Thus pentoxifylline prevents development of hyperdynamic circulatory state and hepatopulmonary syndrome, probably by inhibiting the effects of tumour necrosis factor-alpha on vascular nitric oxide synthase and intravascular macrophages. These results support an important role for tumour necrosis factor-alpha in the genesis of hepatopulmonary syndrome.

Intrapulmonary vascular dilatations are common in portopulmonary hypertension and may be associated with decreased survival

“…35,38,39 Inhibition of nitric oxide synthase, the endothelin-B receptor, and vascular endothelial growth factor has mitigated HPS in animal models. [40][41][42] Notably, these same mediators have also been implicated in POPH and endothelin receptor antagonists (dual and selective), and phosphodiesterase-5 inhibitors are mainstays of therapy for PAH and POPH. 14 Additionally, a substantial degree of overlap has been described in the histologic findings of each condition.…”

Pulmonary–Hepatic vascular Disorders (PHD)

“…Furthermore, treatment of CBDL with norfloxacin decreased macrophage accumulation and normalised iNOS but not eNOS levels [68], hence, supporting a role for bacterial translocation in pulmonary macrophage accumulation and its contribution to IPVD. Pentoxifylline, an inhibitor of tumour necrosis factor (TNF)-a production in macrophages [70], also prevented HPS in the rat model [71], thereby supporting its pathogenic role. Recent work suggests that ET-1 and TNF-a can both interact in the development of experimental HPS [72].…”

Study of Risk Factors of Hepatopulmonary Syndrome and Role of Propranolol in Its Occurrence

“…Pentoxifyllin. 5 and methylene blue. 6 till date are found effective up to a certain extent in HPS reversal.…”