Leukotriene B4 mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury.
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(-1)·day(-1) 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(-1)·day(-1) ip. Bleomycin led to increased lung content of LTB4, but not cysteinyl LTs. Bleomycin-induced increases in tissue neutrophils and macrophages and lung contents of LTB4 and tumor necrosis factor-α 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.
Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada;
Mong Tieng
MT
Ee
Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada;
Crystal
C
Kantores
Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada;
Julijana
J
Ivanovska
Department of Physiology, University of Toronto, Toronto, Ontario, Canada;
Mathew J
MJ
Wong
Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
Amish
A
Jain
Program in Physiology and Experimental Medicine, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neonatology, Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Heart and Stroke Richard Lewar Centre of Excellence in Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada; and robert.jankov@sickkids.ca.
Robert P
RP
Jankov
D000818:Animals; D000831:Animals, Newborn; D001761:Bleomycin; D001997:Bronchopulmonary Dysplasia / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D005260:Female; D015870:Gene Expression; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D007975:Leukotriene B4 / Q000502:physiology*; D008264:Macrophages / Q000276:immunology*; D017207:Rats, Sprague-Dawley
D001761:Bleomycin; D007975:Leukotriene B4
inflammation; lung injury; newborn; rat