Hepatopulmonary syndrome (HPS) following rat common bile duct ligation (CBDL) results from pulmonary molecular changes that may be influenced by circulating tumor necrosis factor alpha (TNF-) and increased vascular shear stress, through activation of nuclear factor B (NF-B) or Akt. Increased pulmonary microvascular endothelin B (ET_B) receptor and endothelial nitric oxide synthase (eNOS) levels contribute to nitric oxide production and the development of experimental HPS. Pentoxifylline (PTX), a phosphodiesterase and nonspecific TNF- inhibitor, ameliorates experimental HPS when begun prior to hepatic injury. However, how PTX influences the molecular events associated with initiation of experimental HPS after liver injury is established is unknown. We assessed the effects of PTX on the molecular and physiologic features of HPS in vivo and on shear stress or TNF- mediated events in rat pulmonary microvascular endothelial cells (RPMVECs) in vitro. PTX significantly improved HPS without altering portal or systemic hemodynamics and down-regulated pulmonary ET_B receptor levels and eNOS expression and activation. These changes were associated with a reduction in circulating TNF- levels and NF-B activation and complete inhibition of Akt activation. In RPMVECs, PTX inhibited shear stress induced ET_B receptor and eNOS expression and eNOS activation. These effects were also associated with inhibition of Akt activation and were reproduced by wortmanin. In contrast, TNF- had no effects on endothelial ET_B and eNOS alterations in vitro. PTX has direct effects in the pulmonary microvasculature, likely mediated through Akt inhibition, that ameliorate experimental HPS.