Rosiglitazone, a ligand of the peroxisome proliferator-activated receptor-γ, reduces acute inflammation

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Abstract

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. The PPAR-γ receptor subtype appears to play a pivotal role in the regulation of cellular proliferation and inflammation. The thiazolidinedione rosiglitazone (Avandia) is a peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist, that was recently approved by the Food and Drug Administration for treatment of type II diabetes mellitus. In the present study, we have investigated the effects of rosiglitazone in animal models of acute inflammation (carrageenan-induced paw oedema and carrageenan-induced pleurisy). We report here for the first time that rosiglitazone (given at 1, 3 or 10 mg/kg i.p. concomitantly with carrageenan injection in the paw oedema model, or at 3, 10 or 30 mg/kg i.p. 15 min before carrageenan administration in the pleurisy model) exerts potent anti-inflammatory effects (e.g. inhibition of paw oedema, pleural exudate formation, mononuclear cell infiltration and histological injury) in vivo. Furthermore, rosiglitazone reduced: (1) the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase (PARP), (2) the expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), intercellular adhesion molecules-1 (ICAM-1) and P-selectin in the lungs of carrageenan-treated rats. In order to elucidate whether the protective effect of rosiglitazone is related to activation of the PPAR-γ receptor, we also investigated the effect of a PPAR-γ antagonist, bisphenol A diglycidyl ether (BADGE), on the protective effects of rosiglitazone. BADGE (30 mg/kg i.p.) administered 30 min prior to treatment with rosiglitazone significantly antagonized the effect of the PPAR-γ agonist and thus abolished the anti-inflammatory effects of rosiglitazone. We propose that rosiglitazone and other potent PPAR-γ agonists may be useful in the therapy of inflammation.

Introduction

The inflammatory process is invariably characterised by a production of prostaglandins, leukotrienes, histamine, bradykinin, platelet-activating factor (PAF) and by a release of chemicals from tissues and migrating cells (Tomlinson et al., 1994). Carrageenan-induced local inflammation is commonly used to evaluate non-steroidal anti-inflammatory drugs (NSAID). Therefore, carrageenan-induced local inflammation (paw oedema or pleurisy) is a useful model to asses the contribution of mediators involved in vascular changes associated with acute inflammation.

In particular, the initial phase of inflammation (oedema, 0–1 h) which is not inhibited by NSAID such us indomethacin or aspirin, has been attributed to the release of histamine, 5-hydroxytryptamine and bradykinin, followed by a late phase (1–6 h) mainly sustained by prostaglandin release and more recently has been attributed to the induction of inducible cyclo-oxygenase (COX-2) in the tissue (Nantel et al., 1999). It appears that the onset of the carrageenan local inflammation has been linked to neutrophil infiltration and the production of neutrophil-derived free radicals, such as hydrogen peroxide, superoxide and hydroxyl radical, as well as to the release of other neutrophil-derived mediators (Salvemini et al., 1996).

Furthermore, there is a large amount of evidence that the production of reactive oxygen species (ROS) such as hydrogen peroxide, superoxide and hydroxyl radicals at the site of inflammation contribute to tissue damage Dawson et al., 1999, Cuzzocrea et al., 1997. Inhibitors of nitric oxide synthase (NOS) activity reduce the development of carrageenan-induced inflammation and support a role for nitric oxide (NO) in the pathophysiology associated with this model of inflammation Cuzzocrea et al., 1997, Wei et al., 1995. In addition to NO, peroxynitrite is also generated in carrageenan-induced inflammation (Cuzzocrea et al., 1997).

Peroxisome proliferator activated receptors (PPAR) are ligand activated transcription factors belonging to the nuclear hormone receptor superfamily, which includes the classical steroid, thyroid, and retinoid hormone receptors as well as many orphan receptors. So far, three PPAR isotypes have been identified and are commonly designated PPARα, PPARß and PPARγ. The actions of PPAR were originally thought to be limited to the control of lipid metabolism and homeostasis. Recent studies, however, showed that PPAR activation can regulate inflammatory responses and cellular proliferation and differentiation as well as apoptosis Escher and Wahli, 2000, Corton et al., 2000. Therefore, it is possible that PPAR-γ trans-represses the expression of pro-inflammatory mediators at the transcriptional level by inhibiting NF-κB, STAT-1 and activation protein-1 (AP-1) signalling (Ricote et al., 1998). There is also evidence to support a role of PPARγ in various physiopathological conditions including cancer, atherosclerosis and diabetes. Synthesized ligands, thiazolidinedione derivatives (TZD), such as rosiglitazone, pioglitazone and roglitazone, are used as oral antihyperglycemic agents in the therapy of non-insulin-dependent diabetes mellitus Vamecq and Latruffe, 1999, Kadowaki, 2000. One such compound, rosiglitazone binds with a high affinity to PPARγ (Lehmann et al., 1995) All TZD tested to date, i.e., rosiglitazone, pioglitazone, and troglitazone, bind and activate the PPARγ isotype with Kd that parallel their antidiabetic activity in vivo Lehmann et al., 1995, Willson et al., 1996. In addition to TZD, other synthetic compounds have been identified as PPARγ activators. It has been also shown that several NSAID, such as indomethacin, ibuprofen, fenoprofen, and flufenamic acid, bind and activate PPARγ and promote adipocyte differentiation (Lehmann et al., 1997). In addition, recent studies have also shown that PPARγ may participate in control of inflammation, especially, in modulating the production of inflammatory mediators Jiang et al., 1998, Ricote et al., 1998. Recent studies have shown that bisphenol A diglycidyl ether (BADGE) is a PPAR-γ antagonist in various cell line including 3T3-L1 and 3T3-F442A cells (Wright et al., 2000). Therefore, our research group have recently, demonstrated in vivo that BADGE is able to revert the protective effect of rosiglitazone (Cuzzocrea et al., in press). In the present study, we have investigated the effects of rosiglitazone on paw oedema and lung injury associated with carrageenan-induced pleurisy. In particular, we have investigated the effect of the PPAR-γ agonist rosiglitazone on (i) PMN infiltration [myeloperoxidase (MPO) activity], (ii) lipid peroxidation [malondialdehyde (MDA) levels], (iii) COX-2 expression (by immunohistochemistry), (iv) the nitration of tyrosine residues (an indicator of the formation of peroxynitrite) (by immunohistochemistry), (v) poly (ADP-ribose) polymerase (PARP) activation, (vi) iNOS expression and (vii) lung damage (histology). Finally, in order to elucidate whether the protective effects of rosiglitazone is related to the activation of the PPAR-γ receptor, we have also investigated if BADGE, the PPAR-γ antagonist, is able to attenuate the protective effects of rosiglitazone.

Section snippets

Animals

Male Sprague–Dawley rats (300–350 g; Charles River; Milan; Italy, used for the paw oedema study) and Sprague–Dawley rats (140–160 g, Harlan, Milan; Italy, used for the pleurisy study) were housed in a controlled environment and provided with standard rodent chow and water. Animal care was in compliance with Italian regulations on protection of animals used for experimental and other scientific purpose (D.M. 116192) as well as with the EEC regulations (O.J. of E.C. L 358/1 12/18/1986).

Paw oedema

Paw oedema

Effects of rosiglitazone on the course of the carrageenan-induced paw oedema

Carrageenan injection caused a time-dependent increase of paw volume with a peak occurring at 4 h (Fig. 1). Rosiglitazone (3, 10 or 30 mg/kg/i.p.) significantly inhibited the oedema caused by carrageenan in a dose-related fashion. The inhibitory effect of rosiglitazone (30 mg/kg/i.p.) was completely reversed by the administration of 30 mg/kg/i.p. BADGE (Fig. 1). Treatment of rats with BADGE alone (30 mg/kg) did not modify oedema formation (data not shown).

Effects of rosiglitazone on carrageenan-induced pleurisy

Histological examination of lung

Discussion

Peroxisome proliferator-activated receptors (PPARS) are members of the nuclear hormone receptor superfamily. These receptors which exist in three different isoforms (PPAR-α, PPAR-γ and PPAR-Δ). has been detected in various species whit a tissue-specific differential expression (Youssef and Badr, 2001). PPARs regulate a variety of physiological processes including adipogenesis, glucose metabolism and placental function Tomlinson et al., 1994, Vane, 1994. Therefore, only recent studies have

Acknowledgments

This study was supported by grant from 40%. The authors would like to thank Giovanni Pergolizzi and Carmelo La Spada for their excellent technical assistance during this study, Mrs. Caterina Cutrona for secretarial assistance and Miss Valentina Malvagni for editorial assistance with the manuscript. CT is a Senior Fellow of the British Heart Foundation (FS 96/018) and PKC was supported by The National Kidney Research Fund (R41/2/2000).

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