Pulmonary hypertension (PH) is a serious condition that affects mainly young and middle-aged women, and its etiology is poorly understood. A prominent pathological feature of PH is accumulation of macrophages near the arterioles of the lung. In both clinical tissue and the
SU5416 (SU)/athymic rat model of severe PH, we found that the accumulated macrophages expressed high levels of
leukotriene A4 hydrolase (LTA4H), the biosynthetic
enzyme for
leukotriene B4 (
LTB4). Moreover, macrophage-derived
LTB4 directly induced apoptosis in pulmonary artery endothelial cells (PAECs). Further,
LTB4 induced proliferation and
hypertrophy of human pulmonary artery smooth muscle cells. We found that
LTB4 acted through its receptor, BLT1, to induce PAEC apoptosis by inhibiting the protective endothelial
sphingosine kinase 1 (Sphk1)-endothelial
nitric oxide synthase (eNOS) pathway. Blocking LTA4H decreased in vivo
LTB4 levels, prevented PAEC apoptosis, restored Sphk1-eNOS signaling, and reversed fulminant PH in the SU/athymic rat model of PH. Antagonizing BLT1 similarly reversed established PH. Inhibition of
LTB4 biosynthesis or signal transduction in SU-treated athymic rats with established disease also improved cardiac function and reopened obstructed arterioles; this approach was also effective in the
monocrotaline model of severe PH. Human plexiform lesions, one hallmark of PH, showed increased numbers of macrophages, which expressed LTA4H, and patients with
connective tissue disease-associated
pulmonary arterial hypertension exhibited significantly higher
LTB4 concentrations in the systemic circulation than did healthy subjects. These results uncover a possible role for macrophage-derived
LTB4 in PH pathogenesis and identify a pathway that may be amenable to therapeutic targeting.