Epigallocatechin-3-Gallate Reduces Allergen-Induced Asthma-Like Reaction in Sensitized Guinea Pigs

Abstract

In this study, we have evaluated the effects of the polyphenol epigallocatechin-3-gallate (EGCG), an antioxidant molecule that also enhances constitutive nitric-oxide synthase (NOS) activity, on antigen-induced asthma-like reaction in sensitized guinea pigs. For comparison, we used epicatechin, which shares antioxidant but not NOS-modulating properties with EGCG. Ovalbumin-sensitized guinea pigs placed in a respiratory chamber were challenged with ovalbumin. EGCG (25 mg/kg b.wt.) or epicatechin (25 mg/kg b.wt.) was given i.p. 20 min before ovalbumin challenge. We analyzed latency time for the onset of respiratory abnormalities, cough severity, duration of dyspnea, lung tissue histopathology, mast cell activation (by granule release), leukocyte/eosinophilic infiltration (by major basic protein and myeloperoxidase), oxygen free radical-mediated injury (by nitrotyrosine and 8-hydroxy-2-deoxyguanosine and superoxide dismutase), NOS activity, and bronchial inflammatory response [by tumor necrosis factor-␣ in bronchoalveolar lavage (BAL)]. In the sensitized animals, severe respiratory abnormalities appeared soon after the antigen challenge, accompanied by bronchoconstriction, alveolar inflation, and a marked increase in the assayed parameters of inflammatory cell recruitment, free radical lung injury, and release of proinflammatory molecules in BAL fluid. This was associated with marked depression of constitutive NOS activity. Pretreatment with EGCG, but not epicatechin, significantly reduced all the above parameters and sustained endothelial-type NOS activity. These findings provide evidence that EGCG, probably by modulating NOS activity, can counteract allergic asthma-like reaction in sensitized guinea pigs and suggest its possible future use for the treatment of asthma.Asthma is a common inflammatory airway disease whose prevalence is ever-increasing, especially among children (Kitch et al., 2000), and whose major pathophysiological hallmarks are mast cell activation, increased endothelial expression of adhesion molecules, and enhanced leukocyte recruitment (Maddox and Schwartz, 2002). The therapy mainly relies on ␤ 2 -agonists for acute episodes and glucocorticoids for long-term treatment (Von Mutius, 2000). Understanding the factors regulating transition between acute and chronic asthma and airway remodeling, or perpetuation of any of these states, may help identification of new targets for asthma therapy.In many cell types, nitric oxide (NO) is generated by three NO synthase (NOS) isoenzymes. The neuronal-type (nNOS) and the endothelial-type (eNOS) isoforms are Ca 2ϩ /calmodulin-dependent and expressed constitutively. The inducible NOS (iNOS) is Ca 2ϩ /calmodulin-independent and is expressed mainly on inflammation (Moncada et al., 1991). Induction of iNOS transcription is mediated by early events, including the activation of nuclear factor B by lipopolysaccharide, interleukin 1␤, and tumor necrosis factor (TNF)-␣, as well as of signal transducer and activator of transcription 1 by interferon-␥. Constitut...

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“…It is well known that MDA production is a suitable index of membrane lipid peroxidation and cell damage [7,8] and that consumption of endogenous antioxidant enzymes, like SOD, is a typical effect of oxidative stress [5]. In our experiments, antigen challenge signifi cantly increased MDA production (Fig.…”

“…; Harlan, Milan, Italy). The experimental protocol was the same used previously for similar purposes [5]. It complied with the recommendations of the European Economic Community (86/609/CEE) for the care and use of laboratory animals and was approved by the animal care committee of the University of Florence (Florence, Italy).…”

“…All guinea pigs were placed in a whole body respiratory chamber and challenged with an aerosol of OV (5 mg/ml in water) for 10 s, as previously described [5].…”

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