HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text (PDF) All Versions of this Article: 19/7/840 04-2691fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Birrell, M. A. Articles by Belvisi, M. G. Search for Related Content PubMed PubMed Citation Articles by Birrell, M. A. Articles by Belvisi, M. G.

Resveratrol, an extract of red wine, inhibits lipopolysaccharide induced airway neutrophilia and inflammatory mediators through an NF-B-independent mechanism

Respiratory Pharmacology,
^* Thoracic Medicine, National Heart and Lung Institute, Imperial College London, London, UK

¹ Correspondence: Respiratory Pharmacology Group, Department of Airway Diseases, National Heart and Lung Institute, Dovehouse St., London SW3 6LY, UK. E-mail: m.belvisi{at}imperial.ac.uk

SPECIFIC AIMS

Consumption of resveratrol, particularly through drinking moderate amounts of red wine, has been suggested to have beneficial health effects. Over the last decade a great deal of research has been performed on this naturally occurring compound and it has been shown to possess anti-inflammatory properties in vitro.

The initial aim of this study was to determine what effect resveratrol would have in a preclinical in vivo model of airway neutrophilia. The secondary aim was to attempt to elucidate how this molecule was affecting cellular inflammation by measuring a range of reported "resveratrol-sensitive" mediators and parameters known to be involved in the inflammatory response.

PRINCIPAL FINDINGS

1. Resveratrol inhibited airway tissue neutrophilia
Administration of resveratrol into the airway before exposure to aerosolized LPS resulted in a dose-related reduction in airway tissue neutrophilia to a similar extent as that produced by the clinically relevant glucocorticoid, budesonide (Fig. 1 ).

View larger version (11K): [in this window] [in a new window]   Figure 1. Effect of resveratrol and budesonide on inflammatory cell numbers in the lung tissue. Rats were dosed with vehicle (0.5% methylcellulose and 0.2% Tween 80 in saline, 1 mL/kg), resveratrol (1, 3, 10, or 30 mg/kg) or budesonide (0.3, 1, 3, and 10 mg/kg) intratracheally under halothane (4% in oxygen for 4 min). 90 min later, the rats were exposed to aerosolized saline or LPS (0.3 mg/mL). 6 h later, challenge lung samples were collected and white cells extracted by enzymatic digest. Numbers of neutrophils in the cell pellet were determined by differential counting under light microscopy. Results are expressed as mean ± SEM of 8 animals. Statistical analysis was assessed using one-way ANOVA and the appropriate posttest. (+P<0.05, denoting significant difference to the saline-challenged vehicle group; *P<0.05, denoting significant difference to the LPS-challenged vehicle group).

2. Inflammatory mediators were inhibited by resveratrol
The reduction in airway neutrophilia by resveratrol treatment was associated with a reduction in some LPS-induced inflammatory mediators such as TNF-, IL-1ß, CINC-1, and PGE₂ (Fig. 2 ), suggesting a causative link.

View larger version (26K): [in this window] [in a new window]   Figure 2. Effect of resveratrol and budesonide on levels of mediators in the lung tissue. Rats were dosed with vehicle (0.5% methylcellulose and 0.2% Tween 80 in saline, 1 mL/kg), resveratrol (1, 3, 10, or 30 mg/kg) or budesonide (0.3, 1, 3, and 10 mg/kg) intratracheally under halothane (4% in oxygen for 4 min). 90 min later, the rats were exposed to aerosolized saline or LPS (0.3 mg/ml). 6 h later, lung tissue samples were collected. Levels of mediators in the lung tissue homogenate were determined by ELISA-IL-1ß (A), TNF- (B) and CINC-1 (C) or by PGE2 RIA (D). Results are expressed as mean ± SEM of 8 animals. Statistical analysis was assessed using one-way ANOVA and the appropriate posttest. (+P<0.05, denoting significant difference to the saline-challenged vehicle group; *P<0.05, denoting significant difference to the LPS-challenged vehicle group).

3. The inhibition of inflammatory mediators by resveratrol was independent of effects on NF-B activity or gene expression
Recent in vitro studies have suggested that the effect of resveratrol on inflammation is due to its impact on the NF-B pathway and subsequent reduction in gene expression. In this preclinical model, it was shown that resveratrol did not reduce LPS-induced increase in p65 levels, a marker of NF-B activation, or expression of genes linked to the activity of NF-B, iNOS, and COX-2, which suggests resveratrol was not affecting NF-B activation. Indeed, none of the inflammatory proteins that were reduced by resveratrol had altered gene expression levels, suggesting the effect of resveratrol is posttranscriptional on these proteins.

CONCLUSIONS AND SIGNIFICANCE

This is the first study to demonstrate anti-inflammatory effects of resveratrol in an in vivo model of airway inflammation. We have also shown that the inhibition of inflammatory mediators is through an NF-B-independent mechanism. These results suggest that this naturally occurring molecule may possess anti-inflammatory properties via a novel mechanism (Fig. 3 ). Elucidation of this mechanism of action may lead to potential new therapies for the treatment of chronic inflammation.

View larger version (21K): [in this window] [in a new window]   Figure 3. Schematic diagram illustrating how resveratrol could be exerting its anti-inflammatory effects in this preclinical model. This diagram depicts the simplified production of inflammatory mediators from stimuli to the recruitment of airway neutrophilia. The dotted line indicates previous hypothesized in vitro mechanisms of action of this naturally occurring compound. In this preclinical in vivo model, it appears that resveratrol has not affected NF-B activity or gene expression to reduce the production of inflammatory mediators. The unbroken arrows indicate possible mechanisms of action of the molecule.

Recently, there have been many well-publicized links between drinking moderate amounts of red wine and beneficial health effects. This study reveals an exciting and highly promising prospect for a possible new anti-inflammatory agent. These findings are doubly exciting because resveratrol is a naturally occurring molecule that is ingested by many, which suggests the possibility of minimal toxic side effects. This study also may have highlighted a compound with a potential novel mechanism of action. This in turn may lead to new avenues of research in the quest for novel therapies for chronic inflammation.

FOOTNOTES

To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-2691fje;

This article has been cited by other articles:

				M. A. Birrell, J. De Alba, M. C. Catley, E. Hardaker, S. Wong, M. Collins, D. L. Clarke, S. N. Farrow, T. M. Willson, J. L. Collins, et al. Liver X Receptor Agonists Increase Airway Reactivity in a Model of Asthma via Increasing Airway Smooth Muscle Growth J. Immunol., September 15, 2008; 181(6): 4265 - 4271. [Abstract] [Full Text] [PDF]

				A. Nadeem, A. Masood, and N. Siddiqui Review: Oxidant--antioxidant imbalance in asthma: scientific evidence, epidemiological data and possible therapeutic options Therapeutic Advances in Respiratory Disease, August 1, 2008; 2(4): 215 - 235. [Abstract] [PDF]

				H. Yao, S.-R. Yang, I. Edirisinghe, S. Rajendrasozhan, S. Caito, D. Adenuga, M. A. O'Reilly, and I. Rahman Disruption of p21 Attenuates Lung Inflammation Induced by Cigarette Smoke, LPS, and fMLP in Mice Am. J. Respir. Cell Mol. Biol., July 1, 2008; 39(1): 7 - 18. [Abstract] [Full Text] [PDF]

				D. D. C. Miranda, D. P. Arcari, J. Pedrazzoli Jr, P. d. O. Carvalho, S. M. Cerutti, D. H. M. Bastos, and M. L. Ribeiro Protective effects of mate tea (Ilex paraguariensis) on H2O2-induced DNA damage and DNA repair in mice Mutagenesis, July 1, 2008; 23(4): 261 - 265. [Abstract] [Full Text] [PDF]

				A. Kode, S. Rajendrasozhan, S. Caito, S.-R. Yang, I. L. Megson, and I. Rahman Resveratrol induces glutathione synthesis by activation of Nrf2 and protects against cigarette smoke-mediated oxidative stress in human lung epithelial cells Am J Physiol Lung Cell Mol Physiol, March 1, 2008; 294(3): L478 - L488. [Abstract] [Full Text] [PDF]

				A. Sharafkhaneh, S. Velamuri, V. Badmaev, C. Lan, and N. Hanania Review: The potential role of natural agents in treatment of airway inflammation Therapeutic Advances in Respiratory Disease, December 1, 2007; 1(2): 105 - 120. [Abstract] [PDF]

				M. A. Birrell, M. C. Catley, E. Hardaker, S. Wong, T. M. Willson, K. McCluskie, T. Leonard, S. N. Farrow, J. L. Collins, S. Haj-Yahia, et al. Novel Role for the Liver X Nuclear Receptor in the Suppression of Lung Inflammatory Responses J. Biol. Chem., November 2, 2007; 282(44): 31882 - 31890. [Abstract] [Full Text] [PDF]

				H. Gradisar, M. M. Keber, P. Pristovsek, and R. Jerala MD-2 as the target of curcumin in the inhibition of response to LPS J. Leukoc. Biol., October 1, 2007; 82(4): 968 - 974. [Abstract] [Full Text] [PDF]

				J. R. Cortes, M. Perez-G, M. D. Rivas, and J. Zamorano Kaempferol Inhibits IL-4-Induced STAT6 Activation by Specifically Targeting JAK3 J. Immunol., September 15, 2007; 179(6): 3881 - 3887. [Abstract] [Full Text] [PDF]

				A. P. Kumar, S. Bhaskaran, M. Ganapathy, K. Crosby, M. D. Davis, P. Kochunov, J. Schoolfield, I-T. Yeh, D. A. Troyer, and R. Ghosh Akt/cAMP-Responsive Element Binding Protein/Cyclin D1 Network: A Novel Target for Prostate Cancer Inhibition in Transgenic Adenocarcinoma of Mouse Prostate Model Mediated by Nexrutine, a Phellodendron Amurense Bark Extract Clin. Cancer Res., May 1, 2007; 13(9): 2784 - 2794. [Abstract] [Full Text] [PDF]

				A. Mouihate, T. F. Horn, and Q. J. Pittman Oxyresveratrol dampens neuroimmune responses in vivo: a selective effect on TNF-{alpha} Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1215 - R1221. [Abstract] [Full Text] [PDF]

				I. Rahman and I. M. Adcock Oxidative stress and redox regulation of lung inflammation in COPD. Eur. Respir. J., July 1, 2006; 28(1): 219 - 242. [Abstract] [Full Text] [PDF]

				A. J. Pantuck, J. T. Leppert, N. Zomorodian, W. Aronson, J. Hong, R. J. Barnard, N. Seeram, H. Liker, H. Wang, R. Elashoff, et al. Phase II Study of Pomegranate Juice for Men with Rising Prostate-Specific Antigen following Surgery or Radiation for Prostate Cancer. Clin. Cancer Res., July 1, 2006; 12(13): 4018 - 4026. [Abstract] [Full Text] [PDF]

				M. A. Birrell, S. Wong, E. L. Hardaker, M. C. Catley, K. McCluskie, M. Collins, S. Haj-Yahia, and M. G. Belvisi I{kappa}B Kinase-2-Independent and -Dependent Inflammation in Airway Disease Models: Relevance of IKK-2 Inhibition to the Clinic Mol. Pharmacol., June 1, 2006; 69(6): 1791 - 1800. [Abstract] [Full Text] [PDF]

				M. A. Birrell, S. Wong, K. McCluskie, M. C. Catley, E. L. Hardaker, S. Haj-Yahia, and M. G. Belvisi Second-Generation Inhibitors Demonstrate the Involvement of p38 Mitogen-Activated Protein Kinase in Post-Transcriptional Modulation of Inflammatory Mediator Production in Human and Rodent Airways J. Pharmacol. Exp. Ther., March 1, 2006; 316(3): 1318 - 1327. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) All Versions of this Article: 19/7/840 04-2691fjev1    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Birrell, M. A. Articles by Belvisi, M. G. Search for Related Content PubMed PubMed Citation Articles by Birrell, M. A. Articles by Belvisi, M. G.