Caffeic acid phenethyl ester alleviates asthma by regulating the airway microenvironment via the ROS-responsive MAPK/Akt pathway

Free Radic Biol Med. 2016 Dec;101:163-175. doi: 10.1016/j.freeradbiomed.2016.09.012. Epub 2016 Oct 13.


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.

Keywords: Airway microenvironment; CAPE; ROS; TGF-β1; TNF-α.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Airway Remodeling / drug effects
  • Airway Remodeling / immunology
  • Animals
  • Anti-Asthmatic Agents / pharmacology*
  • Asthma / chemically induced
  • Asthma / drug therapy*
  • Asthma / immunology
  • Asthma / pathology
  • Caffeic Acids / pharmacology*
  • Chemokine CCL11 / genetics
  • Chemokine CCL11 / immunology
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Female
  • Gene Expression Regulation
  • Humans
  • Immunoglobulin E / genetics
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / immunology
  • Interleukin-13 / genetics
  • Interleukin-13 / immunology
  • Interleukin-4 / genetics
  • Interleukin-4 / immunology
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / immunology*
  • Ovalbumin
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / pharmacology
  • Proto-Oncogene Proteins c-akt / genetics
  • Proto-Oncogene Proteins c-akt / immunology*
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / immunology*
  • Reactive Oxygen Species / metabolism
  • Transforming Growth Factor beta1 / genetics
  • Transforming Growth Factor beta1 / immunology
  • Tumor Necrosis Factor-alpha / genetics
  • Tumor Necrosis Factor-alpha / immunology


  • Anti-Asthmatic Agents
  • Caffeic Acids
  • Ccl11 protein, mouse
  • Ccl2 protein, mouse
  • Chemokine CCL11
  • Chemokine CCL2
  • Interleukin-13
  • Reactive Oxygen Species
  • Transforming Growth Factor beta1
  • Tumor Necrosis Factor-alpha
  • Intercellular Adhesion Molecule-1
  • Interleukin-4
  • Immunoglobulin E
  • Ovalbumin
  • Proto-Oncogene Proteins c-akt
  • Mitogen-Activated Protein Kinases
  • caffeic acid phenethyl ester
  • Phenylethyl Alcohol