Ee MT, Kantores C, Ivanovska J, Wong MJ, Jain A, Jankov RP. Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury. Am J Physiol Lung Cell Mol Physiol 311: L292-L302, 2016. First published June 17, 2016 doi:10.1152/ajplung.00120.2016.-Systemically-administered bleomycin causes inflammation, arrested lung growth, and pulmonary hypertension (PHT) in the neonatal rat, similar to human infants with severe bronchopulmonary dysplasia (BPD). Leukotrienes (LTs) are inflammatory lipid mediators produced by multiple cell types in the lung. The major LTs, LTB4 and cysteinyl LTs, are suggested to contribute to BPD, but their specific roles remain largely unexplored in experimental models. We hypothesized that LTs are increased in bleomycin-induced BPD-like injury, and that inhibition of LT production would prevent inflammatory cell influx and thereby ameliorate lung injury. Rat pups were exposed to bleomycin (1 mg·kg Ϫ1 ·day Ϫ1 ip) or vehicle (control) from postnatal days 1-14 and were treated with either zileuton (5-lipoxygenase inhibitor), montelukast (cysteinyl LT1 receptor antagonist), or SC57461A (LTA4 hydrolase inhibitor) 10 mg·kg Ϫ1 ·day Ϫ1 ip. Bleomycin led to increased lung content of LTB4, but not cysteinyl LTs. Bleomycininduced increases in tissue neutrophils and macrophages and lung contents of LTB4 and tumor necrosis factor-␣ were all prevented by treatment with zileuton. Treatment with zileuton or SC57461A also prevented the hemodynamic and structural markers of chronic PHT, including raised pulmonary vascular resistance, increased Fulton index, and arterial wall remodeling. However, neither treatment prevented impaired alveolarization or vascular hypoplasia secondary to bleomycin. Treatment with montelukast had no effect on macrophage influx, PHT, or on abnormal lung structure. We conclude that LTB4 plays a crucial role in lung inflammation and PHT in experimental BPD. Agents targeting LTB4 or LTB4-mediated signaling may have utility in infants at risk of developing BPD-associated PHT. rat; newborn; inflammation; lung injury THE SURVIVAL OF EXTREMELY low-birth-weight infants has improved over recent decades, but at the cost of a high risk of developing chronic lung injury, known as bronchopulmonary dysplasia (BPD) (3). Chronic pulmonary hypertension (PHT) is common in infants with severe BPD, heralding a greatly increased morbidity and mortality (11,31,34,47). The pathogenesis of BPD is multifactorial, with upregulation of inflammatory mediators leading to, or caused by, infiltration of inflammatory cells playing a major role (38,43,46). However, the specific mediators contributing to inflammatory neonatal lung injury remain unclear, and there are presently no effective treatments.Leukotrienes (LTs) are potent lipid mediators, first described in 1979 by Borgeat and Samuelsson (5) as a new lineage of arachidonic acid-derived metabolites. LTs are produced by, recruit, and activate immune cells, thus initiating, augmenting, and sustaining tissue in...