Sodium Tanshinone IIA Sulfonate Decreases Cigarette Smoke-Induced Inflammation and Oxidative Stress via Blocking the Activation of MAPK/HIF-1α Signaling Pathway.

Wenju Lu,Jian Wang,Li Zhao,Defu Li,Guihua Xu,Lian Dong,Ruijuan Guan,Chenting Zhang,Ziying Li,Zhou Cai,Yuqin Chen,Tao Wang,Dejun Sun,Mingjing Ding,Xue Liang,Zhen Long,Qian Yang,Haiyun Zhang

doi:10.3389/fphar.2018.00263

Abstract

Aberrant activation of hypoxia-inducible factor (HIF)-1α is frequently encountered and promotes oxidative stress and inflammation in chronic obstructive pulmonary disease (COPD). The present study investigated whether sodium tanshinone IIA sulfonate (STS), a water-soluble derivative of tanshinone IIA, can mediate its effect through inhibiting HIF-1α–induced oxidative stress and inflammation in cigarette smoke (CS)-induced COPD in mice. Here, we found that STS improved pulmonary function, ameliorated emphysema and decreased the infiltration of inflammatory cells in the lungs of CS-exposed mice. STS reduced CS- and cigarette smoke extract (CSE)-induced upregulation of tumor necrosis factor (TNF)-α and interleukin (IL)-1β in the lungs and macrophages. STS also inhibited CSE-induced reactive oxygen species (ROS) production, as well as the upregulation of heme oxygenase (HO)-1, NOX1 and matrix metalloproteinase (MMP)-9 in macrophages. In addition, STS suppressed HIF-1α expression in vivo and in vitro, and pretreatment with HIF-1α siRNA reduced CSE-induced elevation of TNF-α, IL-1β, and HO-1 content in the macrophages. Moreover, we found that STS inhibited CSE-induced the phosphorylation of ERK, p38 MAPK and JNK in macrophages, and inhibition of these signaling molecules significantly repressed CSE-induced HIF-1α expression. It indicated that STS inhibits CSE-induced HIF-1α expression likely by blocking MAPK signaling. Furthermore, STS also promoted HIF-1α protein degradation in CSE-stimulated macrophages. Taken together, these results suggest that STS prevents COPD development possibly through the inhibition of HIF-1α signaling, and may be a novel strategy for the treatment of COPD.

Highlights

Chronic obstructive pulmonary disease (COPD) is a progressive lung malady that affects most of the long-term smokers and is predicted to be the third leading cause of death globally by 2030 (Lundback et al, 2003; Nowrin et al, 2014)
RAW 264.7 cells were transfected with hypoxia-inducible factor (HIF)-1α siRNA by using GenMuteTM siRNA Transfection Reagent (SignaGen, United States) in accordance to the manufacturer’s instructions
We investigated the possible role of sodium tanshinone IIA sulfonate (STS) in the development of COPD and determined whether STS exerted its anti-oxidative and anti-inflammatory effects via the blockade of HIF-1α signaling pathway

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a progressive lung malady that affects most of the long-term smokers and is predicted to be the third leading cause of death globally by 2030 (Lundback et al, 2003; Nowrin et al, 2014). Inflammation, starting prior to the onset of clinical symptoms, is seen throughout the bronchial tree and parenchyma of lungs from animals and patients with COPD (Kang and Shadel, 2016; Zhou et al, 2016). It has been recognized as the primary determinant of multimorbidities in COPD patients (Niewoehner et al, 1974). These activated inflammatory cells including macrophages can release enormous amounts of reactive oxygen species (ROS) and induces oxidative stress, resulting in activation of metalloproteases and lung cell death (Han et al, 2011). Effective control of inflammation and oxidative stress in animals and patients with COPD is becoming very crucial

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Conclusion