NOX4 expression and distal arteriolar remodeling correlate with pulmonary hypertension in COPD

Xiaotong Guo,Binwei Hao,Xiao Sun,Jieda Cui,Juan Chen,Xiaoming Liu,Jianda Dong,Yuchun Fan,Yanyang Wang,Li Zhu,Jiali Yang,Jinxi He

doi:10.1186/s12890-018-0680-y

Abstract

BackgroundPulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis however remain elusive. The dysregulated expression of nicotinamide adenine dinucleotide phosphate (NADPH)-oxidases and superoxide generation by pulmonary vasculatures have significant implications in the hypoxia-induced PH.MethodsIn this study, the involvement of NADPH oxidase subunit 4 (NOX4) in pulmonary arteriolar remodeling of PH in COPD was investigated by ascertaining the morphological alteration of pulmonary arteries and pulmonary blood flow using cardiac magnetic resonance imaging (cMRI), and the expression and correlation of NOX4 with pulmonary vascular remodeling and pulmonary functions in COPD lungs.ResultsResults demonstrated that an augmented expression of NOX4 was correlated with the increased volume of pulmonary vascular wall in COPD lung. While the volume of distal pulmonary arteries was inversely correlated with pulmonary functions, despite it was positively associated with the main pulmonary artery distensibility, right ventricular myocardial mass end-systolic and right ventricular myocardial mass end-diastolic in COPD. In addition, an increased malondialdehyde and a decreased superoxide dismutase were observed in sera of COPD patients. Mechanistically, the abundance of NOX4 and production of reactive oxygen species (ROS) in pulmonary artery smooth muscle cells could be dynamically induced by transforming growth factor-beta (TGF-β), which in turn led pulmonary arteriolar remodeling in COPD lungs.ConclusionThese results suggest that the NOX4-derived ROS production may play a key role in the development of PH in COPD by promoting distal pulmonary vascular remodeling.

Highlights

Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis remain elusive
Demographic data Fifteen patients with COPD were enrolled in this study, included 3 females and 12 males with a mean age of 54.40 ± 6.84 years
The results demonstrated an involvement of NADPH oxidase subunit 4 (NOX4), the imbalance of oxidant/antioxidants in pulmonary vascular remodeling and pulmonary functions in COPD patients

Summary

Introduction

Pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) is suggested as the consequence of emphysematous destruction of vascular bed and hypoxia of pulmonary microenvironment, mechanisms underpinning its pathogenesis remain elusive. Chronic obstructive pulmonary disease (COPD) is a complex disease characterized by airflow limitation, inflammation and airway remodeling It is one of the most important causes of death in aging population, and is associated with a significantly economic burden worldwide [1, 2]. Despite the pathogenesis of PH in COPD remains incompletely understood, the loss of pulmonary capillary bed in emphysema is suggested to contribute to the increased pressure in pulmonary circulation. In this regard, the pulmonary vascular remodeling is widely recognized as a key factor in development of hypoxic pulmonary hypertension (HPH), and a main cause of COPD. It is worthy to note that the process of pulmonary vascular remodeling includes the proliferation and hypertrophy of pulmonary smooth muscle cells and deposition of extracellular matrixes (ECM) [4]

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