title: Caffeic acid phenethyl ester alleviates asthma by regulating the airway microenvironment via the ROS-responsive MAPK/Akt pathway.
abstract: In the pathophysiology of asthma, structural cell dysfunction and concomitant microenvironment changes in airways are crucial to pathological progression, which involves oxidative stress. Caffeic acid phenethyl ester (CAPE) is an active anti-oxidative component obtained from propolis, and has been shown to have beneficial effects on several respiratory disorders, such as chronic obstructive pulmonary disease and lung cancer. However, the impact of CAPE on asthma is not well understood. Therefore, this study investigated the advantages of using CAPE to treat asthma and demonstrated the roles of CAPE in the regulation of airway microenvironments. In ovalbumin (OVA)-sensitized mice, CAPE treatments notably reduced airway hyperresponsiveness, attenuated extensive inflammatory cell infiltration and inhibited goblet cell hyperplasia and collagen deposition and fibrosis. In addition, CAPE improved the airway microenvironment in a dose-dependent manner by inhibiting OVA-induced increases in immunoglobulin E, tumor necrosis factor alpha (TNF-α), transforming growth factor-β1 (TGF-β1), interleukin (IL)-4 and IL-13 and suppressing matrix metalloproteinase-9 and alpha-smooth muscle actin expression as well as malondialdehyde production. To determine the underlying mechanisms responsible for these effects, we used TNF-α-stimulated BECs and TGF-β1-challenged human ASMCs to explore the impacts of CAPE on pro-inflammatory proteins and ASMC proliferation. The results indicated that CAPE significantly limited the secretion of eotaxin-1, monocyte chemoattractant protein-1, IL-8 and intercellular adhesion molecule-1 and dramatically inhibited the proliferation of ASMCs. These effects were shown to be associated with decreased reactive oxidant species (ROS) levels. The phosphorylation of Akt and Mitogen-Activated Protein Kinase (MAPK) caused by increased ROS was significantly decreased by CAPE, which implied a contribution of ROS-MAPK/Akt signaling to the attenuation of asthma. Our findings indicated for the first time that CAPE alleviates airway inflammation and remodeling in chronic asthma by balancing the airway microenvironment, which highlights a novel profile of CAPE as a potent agent for asthma management.
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
authors.forename: Jia-Xiang
authors.initials: JX
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China; Department of Respiratory Medicine, the Affiliated Hospital of Xuzhou Medical College, 99 Huaihai West Road, Xuzhou, Jiangsu 221000, China.
authors.forename: Ya-Nan
authors.initials: YN
authors.lastname: Liu
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
authors.forename: Ai
authors.initials: A
authors.lastname: Ge
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Gu
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China.
authors.forename: Wang-Jian
authors.initials: WJ
authors.lastname: Zha
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. Electronic address: zeng_xiao_ning@hotmail.com.
authors.forename: Xiao-Ning
authors.initials: XN
authors.lastname: Zeng
authors.affiliation: Department of Respiratory Medicine, the First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, China. Electronic address: huangmao6114@126.com.
authors.forename: Mao
authors.initials: M
authors.lastname: Huang
mesh_terms: D056151:Airway Remodeling / Q000187:drug effects / Q000276:immunology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D001249:Asthma / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002109:Caffeic Acids / Q000494:pharmacology*; D054413:Chemokine CCL11 / Q000235:genetics / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007073:Immunoglobulin E / Q000235:genetics; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000276:immunology; D018793:Interleukin-13 / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D010047:Ovalbumin; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000276:immunology* / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: D018927:Anti-Asthmatic Agents; D002109:Caffeic Acids; C515457:Ccl11 protein, mouse; C491768:Ccl2 protein, mouse; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D018793:Interleukin-13; D017382:Reactive Oxygen Species; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D007073:Immunoglobulin E; D010047:Ovalbumin; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; C055494:caffeic acid phenethyl ester; D010626:Phenylethyl Alcohol
keywords: Airway microenvironment; CAPE; ROS; TGF-β1; TNF-α