The airway epithelium is thought to play an important role in the pathogenesis of asthma. Airway epithelial activation may contribute to inflammatory and airway-remodeling events characteristic of asthma. Kaempferol, a flavonoid with antioxidative and antitumor properties, has been studied as an antiinflammatory agent. However, little is known regarding its effects on allergic asthma. Human airway epithelial BEAS-2B cells and eosinophils were used to investigate the effects of kaempferol on endotoxin- or cytokine-associated airway inflammation. Kaempferol, nontoxic at 1-20 μmol/L, suppressed LPS-induced eotaxin-1 protein expression that may be mediated, likely via Janus kinase 2 (JAK2) JAK2 signaling. Additionally, 1-20 μmol/L kaempferol dose-dependently attenuated TNFα-induced expression of epithelial intracellular cell adhesion molecule-1 and eosinophil integrin β2, thus encumbering the eosinophil-airway epithelium interaction. Kaempferol blunted TNFα-induced airway inflammation by attenuating monocyte chemoattractant protein-1 transcription, possibly by disturbing NF-κB signaling. This study further investigated antiallergic activity of kaempferol in BALB/c mice sensitized with ovalbumin (OVA) and challenged with a single dose of OVA. Oral administration of kaempferol attenuated OVA challenge-elevated expression of eotaxin-1 and eosinophil major basic protein via the blockade of NF-κB transactivation, thereby blunting eosinophil accumulation in airway and lung tissue. Therefore, dietary kaempferol is effective in ameliorating allergic and inflammatory airway diseases through disturbing NF-κB signaling.

Chronic airway remodeling is characterized by structural changes within the airway wall, including smooth muscle hypertrophy, submucosal fibrosis and epithelial shedding. Epithelial-to-mesenchymal transition (EMT) is a fundamental mechanism of organ fibrosis, which can be induced by TGF-b. In the in vitro study, we investigated whether 1-20 mM kaempferol inhibited lipopolysaccharide (LPS)-induced bronchial EMT in BEAS-2B cells. The in vivo study explored demoting effects of 10-20 mg/kg kaempferol on airway fibrosis in BALB/c mice sensitized with ovalbumin (OVA). LPS induced airway epithelial TGF-b1 signaling that promoted EMT with concurrent loss of E-cadherin and induction of a-smooth muscle actin (a-SMA). Nontoxic kaempferol significantly inhibited TGF-b-induced EMT process through reversing E-cadherin expression and retarding the induction of N-cadherin and a-SMA. Consistently, OVA inhalation resulted in a striking loss of epithelial morphology by displaying myofibroblast appearance, which led to bronchial fibrosis with submucosal accumulation of collagen fibers. Oral administration of kaempferol suppressed collagen deposition, epithelial excrescency and goblet hyperplasia observed in the lung of OVA-challenged mice. The specific inhibition of TGF-b entailed epithelial protease-activated receptor-1 (PAR-1) as with 20 mM kaempferol. The epithelial PAR-1 inhibition by SCH-79797 restored E-cadherin induction and deterred a-SMA induction, indicating that epithelial PAR-1 localization was responsible for resulting in airway EMT. These results demonstrate that dietary kaempferol alleviated fibrotic airway remodeling via bronchial EMT by modulating PAR1 activation. Therefore, kaempferol may be a potential therapeutic agent targeting asthmatic airway constriction.

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• Glucose increases renal tubular epithelial induction of vimentin, α-SMA and FSP-1. • Glucose enhances renal EMT by blocking tubular epithelial E-cadherin expression. • Chrysin inhibits tubular EMT-mediated tubulointerstitial fibrosis in mouse kidneys. • Chrysin restores renal tubular induction of ZO-1 and occludin downregulated in diabetic mice. • Chrysin blocks glucose-induced renal tubular cell migration with reducing MMP-2 activity.

BackgroundFibrotic remodeling of airway and lung parenchymal compartments is attributed to pulmonary dysfunction with an involvement of reactive oxygen species (ROS) in chronic lung diseases such as idiopathic pulmonary fibrosis and asthma.MethodsThe in vitro study elucidated inhibitory effects of astragalin, kaempferol-3-O-glucoside from leaves of persimmon and green tea seeds, on oxidative stress-induced airway fibrosis. The in vivo study explored the demoting effects of astragalin on epithelial to mesenchymal transition in BALB/c mice sensitized with ovalbumin (OVA).ResultsThe exposure of 20 μM H2O2 for 72 h accelerated E-cadherin loss and vimentin induction in airway epithelial BEAS-2B cells, which was reversed by non-toxic astragalin at 1–20 μM. Astragalin allayed the airway tissue levels of ROS and vimentin enhanced by OVA challenge. Collagen type 1 production increased in H2O2–exposed epithelial cells and collagen fiber deposition was observed in OVA-challenged mouse airways. This study further investigated that the oxidative stress-triggered autophagic regulation was responsible for inducing airway fibrosis. H2O2 highly enhanced the expression induction of the autophagy-related beclin-1 and light chains 3A/B (LC3A/B) within 4 h and astragalin blocked such induction by H2O2. This compound deterred the ROS-promoted autophagosome formation in BEAS-2B cells. Consistently, in OVA-sensitized mice the expression of beclin-1 and LC3A/B was highly induced, and oral administration of astragalin suppressed the autophagosome formation with inhibiting the induction of these proteins in OVA-challenged airway subepithelium. Induction of autophagy by spermidine influenced the epithelial induction of E-cadherin and vimentin that was blocked by treating astragalin.ConclusionThese results demonstrate that astragalin can be effective in allaying ROS-promoted bronchial fibrosis through inhibiting autophagosome formation in airways.