title: Blocking macrophage leukotriene b4 prevents endothelial injury and reverses pulmonary hypertension.
abstract: 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.
authors.affiliation: Veterans Affairs Palo Alto Health Care System/Stanford University, Palo Alto, CA 94304, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Tian
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.forename: Rasa
authors.initials: R
authors.lastname: Tamosiuniene
authors.forename: Yon K
authors.initials: YK
authors.lastname: Sung
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.forename: Gundeep
authors.initials: G
authors.lastname: Dhillon
authors.forename: Lajos
authors.initials: L
authors.lastname: Gera
authors.forename: Laszlo
authors.initials: L
authors.lastname: Farkas
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.forename: Roham T
authors.initials: RT
authors.lastname: Zamanian
authors.forename: Mohammed
authors.initials: M
authors.lastname: Inayathullah
authors.forename: Marina
authors.initials: M
authors.lastname: Fridlib
authors.forename: Jayakumar
authors.initials: J
authors.lastname: Rajadas
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015777:Eicosanoids / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary / Q000473:pathology* / Q000517:prevention & control*; D006984:Hypertrophy; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism; D011651:Pulmonary Artery / Q000473:pathology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D000099157:Sphingosine Kinase
chemical_list: D015777:Eicosanoids; D007975:Leukotriene B4; D052250:Nitric Oxide Synthase Type III; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase