N-methyl-D-aspartate receptor activation mediates lung fibroblast proliferation and differentiation in hyperoxia-induced chronic lung disease in newborn rats.

Yanrui Wang,Chuanding Cao,Mingjie Wang,Ziqiang Luo,Shaojie Yue,Xiaohe Yu,Zhengchang Liao

doi:10.1186/s12931-016-0453-1

Abstract

BackgroundPrevious studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions.MethodsIn order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4 days after cessation of hyperoxia exposure (on postnatal day 8). The role of NMDAR activation in hyperoxia-induced lung fibroblast proliferation and differentiation was examined in vitro using primary cells derived from the lungs of 8-day-old Sprague-Dawley rats exposed to hyperoxic conditions.ResultsHyperoxia for 3 days induced acute lung injury in newborn rats. The acute injury almost completely disappeared 4 days after cessation of hyperoxia exposure. However, pulmonary fibrosis, impaired alveolarization, and decreased pulmonary compliance were observed on postnatal days 15 and 22. MK-801 treatment during the recovery period was found to alleviate the chronic damage induced by hyperoxia. Four NMDAR 2 s were found to be upregulated in the lung fibroblasts of newborn rats exposed to hyperoxia. In addition, the proliferation and upregulation of alpha-smooth muscle actin and (pro) collagen I in lung fibroblasts were detected in hyperoxia-exposed rats. MK-801 inhibited these changes.ConclusionsNMDAR activation mediated lung fibroblast proliferation and differentiation and played a role in the development of hyperoxia-induced chronic lung damage in newborn rats.

Highlights

Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats
We previously demonstrated that large amounts of endogenous glutamate were released into the lungs of newborn rats exposed to hyperoxic conditions for 1 to 3 days; this phenomenon was found to be unrelated to nonspecific acute lung injury and airway inflammation
Three-day exposure to hyperoxia induced chronic lung disease (CLD) in newborn rats Lung histology revealed that there few inflammatory cells in some of the alveolar spaces in the hyperoxia group at day 4

Summary

Introduction

Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We previously demonstrated that large amounts of endogenous glutamate were released into the lungs of newborn rats exposed to hyperoxic conditions for 1 to 3 days; this phenomenon was found to be unrelated to nonspecific acute lung injury and airway inflammation. Previous studies strongly suggest that endogenous glutamate and NMDARs play important roles during acute lung injury and airway inflammation [7,8,9,10]. Lung NMDARs are strongly expressed after a 3–7-day exposure to hyperoxia [3], and the NMDAR antagonist MK-801 was shown to decrease hyperoxia-induced acute lung damage [3, 11] These results indicated that glutamate and its NMDAR play important roles in hyperoxia-induced acute lung injury

Methods

Results

Conclusion