Amelioration of joint disease in a rat model of collagen‐induced arthritis by M40403, a superoxide dismutase mimetic

Salvemini, Daniela; Mazzon, Emanuela; Dugo, Laura; Serraino, Ivana; Sarro, Angela De; Caputi, Achille P.; Cuzzocrea, Salvatore

doi:10.1002/1529-0131(200112)44:12<2909::aid-art479>3.0.co;2-#

Cited by 88 publications

(65 citation statements)

References 54 publications

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“…57 In other acute and chronic inflammation models, SOD mimics reduced PARP immunofluorescence, providing further evidence of a role for SOD in inhibition of apoptosis and inflammation. 58,59 Similarly, treatment with SOD mimics reduces the magnitude of ovalbumin-induced airway hyperresponsiveness to methacholine in murine models of asthma. 60 Based on this study and others, we propose that loss of SOD activity in asthma occurs, in part, as a consequence of MnSOD protein modifications in the oxidative and nitric oxide-rich environment of the asthmatic airway, and that SOD inactivation and oxidant stress trigger apoptosis and loss of airway epithelial cells, which contributes significantly to airway remodeling and hyperreactivity of asthma.…”

Section: Discussionmentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

175

149

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Airway hyperresponsiveness and remodeling are defining features of asthma. We hypothesized that impaired superoxide dismutase (SOD) antioxidant defense is a primary event in the pathophysiology of hyperresponsiveness and remodeling that induces apoptosis and shedding of airway epithelial cells. Mechanisms leading to apoptosis were studied in vivo and in vitro. Asthmatic lungs had increased apoptotic epithelial cells compared to controls as determined by terminal dUTP nick-end labeling-positive cells. Apoptosis was confirmed by the finding that caspase-9 and -3 and poly (ADP-ribose) polymerase were cleaved. On the basis that SOD inactivation triggers cell death and low SOD levels occur in asthma, we tested whether SOD inactivation plays a role in airway epithelial cell death. SOD inhibition increased cell death and cleavage/activation of caspases in bronchial epithelial cells in vitro. Asthma is commonly diagnosed using physiological measures, but alterations in airway structure are the defining features of asthma. Damage to airway epithelium, eosinophil infiltration, smooth muscle hyperplasia, thickening and aberrant collagen, and protein composition of the basement membrane are well established elements of the asthmatic airway. 1,2 The injury to the bronchial epithelium in asthma is marked by loss of columnar epithelial cells. Extensive loss of cells and denuded basement membrane with few basal cells remaining on the airway surface are noted in severe asthma, but shedding of airway epithelium is present even in clinically mild asthma. 2,3 Physical loss of epithelial lining cells is considered one proximate cause of the airway hyperresponsiveness to inhaled mediators, and has been speculated to contribute to asthmatic airway remodeling, in particular abnormal collagen synthesis. Evidence from organ culture systems supports the concept of an epithelial-mesenchymal unit in which loss of epithelium leads to mucosal myofibroblast and fibroblast proliferation, and collagen deposition. 2,4 -6 Thus, if the epithelial injury and loss could be understood and prevented in asthma, the clinical symptoms of airway hyperresponsiveness and long-term progressive sequelae in the airways, which contribute to fixed airflow limitation, might be prevented.Several reports have proposed that loss of epithelial cells is because of apoptosis based on immunostaining for the proteins that regulate apoptosis, or by detection of DNA strand breaks by immunostaining with the terminal dUTP nick-end labeling (TUNEL) assay. 7-11 However, not all reports have confirmed increased TUNEL positivity in airways. 9 Furthermore, if airway epithelial cells are undergoing increased cell death, it is unclear whether this is because of an inherent cell defect or a response to the asthmatic airway environment. Although nonspecific events related to increased levels of reactive oxygen and

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Section: Discussionmentioning

confidence: 99%

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Comhair

Ghosh

et al. 2005

The American Journal of Pathology

175

149

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“…However, we detected neither TNF-a nor IL-6 in the DA rats with arthritis. Previous studies [22,23] have reported increased levels of TNF-a and IL-1b in Wistar or Lewis rats with type II collagen-induced arthritis. We were unable to elucidate the reason underlying the inability to detect cytokines in arthritic DA rats.…”

Section: Serum Levels Of Tnf-a Il-6 and Crp In Arthritic Ratsmentioning

confidence: 99%

Effects of exposure to hyperbaric oxygen on oxidative stress in rats with type II collagen-induced arthritis

Nagatomo

Fujino

et al. 2009

Clin Exp Med

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Arthritis was induced in 9-week-old female Dark Agouti rats by injecting type II collagen. Serum levels of the derivatives of reactive oxygen metabolites (dROMs), which are oxidative stress markers, and C-reactive protein (CRP) in arthritic rats that were exposed to a pressure of 1.25 atmospheres absolute and an oxygen concentration of 36% for 3 weeks (arthritis + HBO group) were compared to those of control rats (control group) and arthritic rats that were not exposed to hyperbaric oxygen (arthritis group). The body weights of the arthritis and arthritis + HBO groups were lower than that of the control group, whereas no difference in the body weight was observed between the arthritis and arthritis + HBO groups. The serum levels of dROMs and CRP in the arthritis group were higher than those in the control and arthritis + HBO groups. No difference in the serum level of CRP was observed between the control and arthritis + HBO groups. These results indicate that the conditions of hyperbaric oxygen exposure used in this study are effective for reducing the levels of reactive oxygen species, which are overproduced during arthritis.

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“…Furthermore, substantial evidence provided by the utility of PARP inhibitors exists to support that PARP activation is important in inflammation (Virag and Szabó, 2002). SOD mimetics of the M40403 class reduce PARP activation in models of acute and chronic inflammation (Salvemini et al, 2001), supporting the role of superoxide in this pathway. Here we have found that PARP was in fact activated in the paw at the time of maximal hyperalgesia, and this was blocked by M40403, suggesting that the antihyperalgesic effect of M40403 is derived partly by the inhibition of superoxide-driven PARP activation.…”

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confidence: 93%

“…1a, inhibition of the inflammatory response closely correlated with inhibition of hyperalgesia. The observation that M40403 inhibits cytokine release is consistent with data obtained in other models of acute (Salvemini et al, 1999) and chronic inflammation (Salvemini et al, 2001). A mechanism by which M40403 blocks cytokine release is by preventing the activation of redox-sensitive transcription factors, including nuclear factor-B and activator protein-1, by superoxide, which in turn regulates the genes that encode (among numerous things) various proinflammatory and pronociceptive cytokines (Gius et al, 1999;Matata and Galinanes, 2002).…”

mentioning

confidence: 94%

A Newly Identified Role for Superoxide in Inflammatory Pain

Wang¹,

Porreca

Cuzzocrea

et al. 2004

J Pharmacol Exp Ther

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354

361

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Novel classes of pain-relieving molecules are needed to fill the void between nonsteroidal anti-inflammatory agents and narcotics. Our studies have identified superoxide as a novel mediator of hyperalgesia (clinically defined as an augmented sensitivity to painful stimuli) and have exposed potential pathways through which this radical modulates the hyperalgesic response. The role of superoxide in pain was elucidated using a superoxide dismutase mimetic, M40403 [a manganese(II) complex with a bis(cyclo-hexylpyridine-substituted) macrocyclic ligand]. Intraplantar injection of carrageenan in rats led to timedependent development of peripheral inflammation [measured parameters of inflammation included paw edema, cytokine release in the paw exudates, nitrotyrosine formation (a marker of peroxynitrite formation and oxidative stress), and poly-ADPribose-polymerase activation (the nuclear enzyme activated by superoxide/peroxynitrite)] and hyperalgesia. M40403 blocked all measured parameters of inflammation and hyperalgesia. Furthermore, when given therapeutically (2 h after the induction of hyperalgesia) either by intravenous or intrathecal administration, M40403 but not its inactive congener M40404 inhibited hyperalgesia with a rapid onset of action. Our results also show that, at the level of the spinal cord and time of peak hyperalgesia, endogenous manganese superoxide dismutase was nitrated and subsequently deactivated, losing its capacity to remove superoxide. The antihyperalgesic effects of M40403 were not reversed by naloxone excluding the potential involvement of an opiate pathway. Collectively, these studies have unraveled a critical role for superoxide in the nociceptive signaling cascade both peripherally and centrally. The discovery of this pathway opens a new therapeutic strategy for the development of novel nonnarcotic antihyperalgesic agents.

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Amelioration of joint disease in a rat model of collagen‐induced arthritis by M40403, a superoxide dismutase mimetic

Cited by 88 publications

References 54 publications

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Superoxide Dismutase Inactivation in Pathophysiology of Asthmatic Airway Remodeling and Reactivity

Effects of exposure to hyperbaric oxygen on oxidative stress in rats with type II collagen-induced arthritis

A Newly Identified Role for Superoxide in Inflammatory Pain

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