Pulmonary Toxicity After Treatment with Bleomycin Alone or in Combination with Hyperoxia Studies in the Rat

Blom-Muilwijk, M. C.; Vriesendorf, R.; Veninga, T.S.; Hofstra, W.; Sleyfer, D. T.; Wieringa, Roeland; Konings, Awt

doi:10.1097/00132586-198810000-00005

Cited by 8 publications

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“…LTs are produced by, recruit, and activate immune cells, thus initiating, augmenting, and sustaining tissue inflammation. The concerted action of 5-lipoxygenase (5-LPO) and 5-LPO-activating protein (FLAP) on arachidonic acid produces LTA 4 , which is converted either by LTA 4 hydrolase (LTA4H) to LTB 4 or is conjugated with reduced glutathione by LTC 4 synthase to produce cysteinyl (cys) LTs (LTC 4 , LTD 4 , and LTE 4 ) (32) (illustrated in Fig. 1).…”

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confidence: 99%

“…5-LPO activity requires perinuclear translocation from the cytosol (9) and association with FLAP homodimer (7,27,39) and is increased by phosphorylation at serine 271 (55). LTB 4 and cysLTs exert their actions by binding to distinct G proteincoupled receptors: BLT1 and BLT2 for LTB 4 , and cysLT 1 and 2 receptors (cysLT 1 R and cysLT 2 R) for cysLTs ( Fig. 1).…”

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confidence: 99%

“…1). LTB 4 is a particularly potent chemoattractant for multiple inflammatory cell types, especially neutrophils and macrophages. Due to the wide-ranging pathological effects of LTs, including increased production of matrix proteins, increased smooth muscle contractility and proliferation, and enhanced cell survival, critical roles have been proposed for a number of lung disorders, including asthma, pulmonary fibrosis, and chronic PHT (36,50).…”

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confidence: 99%

“…In neonatal animals, LTB 4 receptor blockade prevented acute hyperoxic lung injury in preterm guinea pigs (37), and a 5-LPO inhibitor decreased lung inflammation and edema induced by saline lavage in newborn piglets (1). Inhibitors of 5-LPO or FLAP prevented inhibited alveolar development secondary to severe hyperoxia (6), whereas montelukast (a cysLT 1 R antagonist) had no effect on chronic neonatal lung injury secondary to moderate hyperoxia (21) in neonatal rats.…”

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Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Kantores

Ivanovska

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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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...

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Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Kantores

Ivanovska

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The chemotherapeutic agent bleomycin sulfate causes a pulmonary inflammatory and fibrotic response in rodents when instilled as a single intratracheal dose (27) or by repeated intraperitoneal injection (3). Bleomycin-induced lung injury is characterized by induction of proinflammatory cytokines (18), influx of macrophages and other inflammatory cells (23), "emphysematous" lung morphology, and severe PHT (49,60).…”

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Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Grasemann

Dhaliwal

Ivanovska

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycininduced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. nitric oxide; oxidative stress; chronic lung disease ARGINASES METABOLIZE L-ARGININE to form L-ornithine and urea. L-Ornithine is the precursor for the production of polyamines and collagen, which have been implicated in tissue repair and remodeling, respectively. Arginases also regulate nitric oxide (NO) production by controlling substrate L-arginine availability for NO synthases (NOSs) (46). There is accumulating evidence that arginase activity contributes to the development of pulmonary fibrosis and pulmonary hypertension (PHT) (9,14,25,29,32,63).PHT is a common complication of moderate-severe bronchopulmonary dysplasia (BPD), a chronic lung disease affecting extremely premature infants (6). The underlying pathogenesis of BPD is complex and multifactorial (39). Previous studies from our group have established a model of repeated systemic bleomycin injection in neonatal rats that results in lung injury mimicking characteristics typical of BPD. This model is a useful tool to help understand mechanisms contributing to lung development and remodeling (31) but also to study the effects of therapeutic interventions aimed at preventing lung parenchymal and vascular injury (31,50,56).The chemotherapeutic agent bleomycin sulfate causes a pulmonary inflammatory and fibrotic response in rodents when instilled as a single intratracheal dose (27) or by repeated intraperitoneal injection (3). Bleomycin-induced lung injury is characterized by induction of proinflammatory cytokines (18), influx of macrophages and other inflammatory cells (23), "emphysematous" lung morphology, and severe PHT (49, 60). Herein, we report that arginase expression is greatly increased in the lungs of bleomycin-exposed neonatal rats and that concomitant treatment with an arginase inhibitor, ami...

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Thymoquinone-induced relaxation of isolated rat pulmonary artery

Suddеk

2010

Journal of Ethnopharmacology

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Pulmonary Toxicity After Treatment with Bleomycin Alone or in Combination with Hyperoxia Studies in the Rat

Cited by 8 publications

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Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Thymoquinone-induced relaxation of isolated rat pulmonary artery

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Pulmonary Toxicity After Treatment with Bleomycin Alone or in Combination with Hyperoxia Studies in the Rat

Cited by 8 publications

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Leukotriene B4mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Leukotriene B4mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Thymoquinone-induced relaxation of isolated rat pulmonary artery

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Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury

Leukotriene B₄mediates macrophage influx and pulmonary hypertension in bleomycin-induced chronic neonatal lung injury