Cigarette Smoke-Induced Pulmonary Inflammation and Autophagy Are Attenuated in Ephx2-Deficient Mice
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ORIGINAL ARTICLE
Cigarette Smoke-Induced Pulmonary Inflammation and Autophagy Are Attenuated in Ephx2-Deficient Mice Yunxiao Li,1 Ganggang Yu,1 Shaopeng Yuan,2 Chunting Tan,1 Puqiao Lian,2 Lixia Fu,2 Qi Hou,2 Bo Xu,1 and Haoyan Wang1,3
Abstract—Cigarette smoke (CS) increases the risk of chronic obstructive pulmonary disease (COPD) by causing inflammation, emphysema, and reduced lung function. Additionally, CS can induce autophagy which contributes to COPD. Arachidonic acid-derived epoxyeicosatrienoic acids (EETs) have promising anti-inflammatory properties that may protect the heart and liver by regulating autophagy. For this reason, the effect of decreased soluble epoxide hydrolase (sEH, Ephx2)-mediated EET hydrolysis on inflammation, emphysema, lung function, and autophagy was here studied in CS-induced COPD in vivo. Adult male wild-type (WT) C57BL/6J and Ephx2−/− mice were exposed to air or CS for 12 weeks, and lung inflammatory responses, air space enlargement (emphysema), lung function, and autophagy were assessed. Lungs of Ephx2−/− mice had a less pronounced inflammatory response and less autophagy with mild distal airspace enlargement accompanied by restored lung function and steady weight gain. These findings support the idea that Ephx2 may hold promise as a therapeutic target for COPD induced by CS, and it may be protective property by inhibiting autophagy. KEY WORDS: Ephx2; epoxyeicosatrienoic acids; inflammation; autophagy; cigarette smoke.
INTRODUCTION Chronic obstructive pulmonary disease (COPD) is an inflammatory disease characterized by emphysema, persistent airflow limitations, and reduced lung function [31]. It is the third leading cause of death worldwide and it represents an important public health challenge [44]. Cigarette smoking (CS) is the main risk factor for developing COPD Qi Hou and Bo Xu contributed equally to this work. 1
The Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xichen District, Beijing, 100050, China 2 Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China 3 To whom correspondence should be addressed at The Department of Respiratory Medicine, Beijing Friendship Hospital, Capital Medical University, No. 95 Yong An Road, Xichen District, Beijing, 100050, China. E-mail: [email protected]
and airway inflammation, which contributes to airway remodeling and pulmonary emphysema [42]. Chronic exposure to CS leads to lung inflammation and increased levels of macrophages [37], neutrophils [8, 16], and dendritic cells (DCs) [40]. An uncontrolled and prolonged inflammatory response may destroy lung tissue and promote remodeling [5, 36]. Elimination of inflammation is a key treatment target for COPD. Epoxyeicosatrienoic acids (EETs), arachidonic acidderived epoxides, are important regulators of inflammation and vascular homeostasis [6]. Manipulating them may be a suit
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