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...
While the survival of extremely premature infants improved over the past decades, the rate of complications - especially for bronchopulmonary dysplasia (BPD) - remains unacceptably high. Over the past 50 years, no safe therapy has had a substantial impact on the incidence and severity of BPD. This may stem from the multifactorial disease pathogenesis and the increasing lung immaturity. Mesenchymal stromal cells (MSCs) display pleiotropic effects and showed promising results in neonatal rodents in preventing or rescuing lung injury without adverse effects. Early phase clinical trials are now underway to determine the safety and efficacy of this therapy in the extremely premature infants. This review summarizes our current knowledge about MSCs, their mechanism of action and the results of preclinical studies that provided the rationale for early phase clinical trials and discuss our remaining gaps in knowledge.
Primary Subject area Neonatal-Perinatal Medicine Background Hypoxic-ischemic encephalopathy (HIE) is a major contributor to morbidity and mortality. Therapeutic hypothermia (TH) is the standard of care for neonates with moderate to severe HIE. Brain magnetic resonance imaging (MRI) is the imaging modality of choice for confirmation of HIE, assessment of injury severity, and prognostication. Reliable, inexpensive and widely available laboratory measures for early identification of risk for neurological injury can play a critical role in the optimal management of neonatal HIE, especially in the resource-limited setting. Our study examined whether derangements in early routine laboratory measures (acid-base, haematological, metabolic) were worse in neonates with MRI findings of neurological injury. Objectives Primary objective: To evaluate the role of early laboratory measures in predicting neurological injury as detected by MRI at 72 hours. Secondary objective: To evaluate the role of early laboratory measures in predicting survival to NICU discharge in patients with HIE. Design/Methods This single-centre, retrospective cohort study included neonates ≥ 35 weeks gestation with moderate to severe HIE, who had undergone therapeutic hypothermia. Based on findings of brain MRI completed within 72 hours of life, our cohort was divided into 2 groups: neonates with, and without, evidence of neurological injury consistent with HIE. Baseline characteristics, as well as laboratory measures, were compared between groups, and a receiver operating characteristic (ROC) curve analysis was conducted to determine the cut-off for prediction of neurological injury based on the highest sensitivity and specificity values. Results 104 neonates were analyzed. Baseline characteristics (Table 1) were similar between both groups, except for cord venous pH and base excess (BE), which were significantly lower in the abnormal MRI group (p = 0.02). In bivariate analysis, pH (at 1 h of age, p = 0.027), BE (at 1 h, p = 0.001, and 6 h of age, p = 0.004), ionized calcium (at 6 h of age, p = 0.02), and platelets (at 1 h of age, p = 0.004) were significantly different in neonates with abnormal MRI. In ROC curve analysis, BE at 1 h of life was the best predictor of abnormal MRI (AUC = 0.71, p = 0.002), with a cut-off value of ≤ -14.95, sensitivity of 67% and specificity of 66% (Figure 1). Conclusion Among neonates with HIE undergoing TH, early laboratory measures such as acid-base status, ionized calcium, and platelet count were worse in neonates with abnormal MRI, in comparison to neonates with normal MRI. Base excess at 1 h of life is a good predictor of abnormal MRI. Future prospective studies to validate these findings are needed
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.