Original contributionInhibition of airway inflammation and hyperreactivity by an antioxidant mimetic
Introduction
Asthma is a chronic disease associated with airway obstruction. Airway inflammation is a major factor in the pathogenesis of asthma and bronchial hyperresponsiveness, as well as an important factor in determining the severity and progression of the disease. It is believed that oxidative stress plays an important role in the pathogenesis of airway inflammation [1], [2].
Evidence from recent studies suggests that elevated levels of oxidative stress are associated with asthma. Urine concentration of F2-isoprostanes was reported to increase following allergen challenges [3]. Plasma levels of lipid peroxides were also significantly increased in patients with asthma [4]. Levels of exhaled nitric oxide (NO) and exhaled carbon monoxide were significantly increased in non-steroid-treated asthmatic patients as compared to these levels in healthy subjects [5], [6]. Loss of superoxide dismutase (SOD) activity in epithelial lining fluid occurred in response to segmental antigen instillation into the lungs of individuals with atopic asthma [7]. In addition, the concentrations of ascorbic acid (vitamin C) and alpha-tocopherol (vitamin E) in lung lining fluid have been reported to be low in patients with mild asthma [8]. Low dietary intake of vitamin C and manganese was found to be associated with increased risks of bronchial activity [9]. Dietary supplements of vitamin C and vitamin E to asthmatics have been shown to decrease the severity of pollutant-induced bronchial responsiveness [10].
Our laboratory has reported previously that mammalian airways have unusually high levels of extracellular superoxide dismutase (EC-SOD) [11] and that EC-SOD regulates NO bioavailability [12]. Increased NO exhalation is a common phenomenon in asthmatic patients [6]. We postulate that the high levels of exhaled NO in asthmatic patients are associated with a pro-oxidant activity in the airway walls, resulting in lipid peroxidation and protein nitration. Since this pathway may be mediated by high rates of production of superoxide (O2•−), EC-SOD in airway walls would be critical for inhibiting the inflammatory cascade following NO production [13]. Augmentation of SOD activity in the extracellular milieu of airways would, therefore, be a potential treatment for asthma.
The catalytic antioxidant AEOL 10113, chemical name Manganese (III) Meso-Tetrakis-(N-Methylpyridinium-2-yl) porphyrin, exhibits a high SOD activity [14]. It also contains catalase activity and inhibits lipid peroxidation. It carries a 5+ charge and is believed to partition, primarily, in the extracellular spaces. Manganic porphyrins have been shown to protect cells against a variety of oxidative stresses both in vitro and in vivo [15], including the protection of bleomycin- or paraquat-induced lung injury [16], [17]. In the current study, AEOL 10113 was instilled into the lungs of mice during ovalbumin (OVA)-induced airway inflammation to test the hypothesis that antioxidant augmentation can be used as a treatment for antigen-induced airway hyperreactivity and inflammation.
Section snippets
Reagents
All reagents and chemicals were obtained from Sigma Chemical (St. Louis, MO, USA) unless otherwise noted. The catalytic antioxidant AEOL 10113 was provided by Incara Pharmaceuticals, Inc. (Research Triangle Park, NC, USA).
Animals
Six week old male Balb/c mice (Harlan Sprague-Daley, Inc.; San Diego, CA, USA) were used for the studies. Airway inflammation was induced with OVA immunization and challenges [18]. Briefly, mice were given an intraperitoneal (i.p.) injection of 10 μg OVA and 1 mg alum in 100
Airway inflammation
Mice that were immunized but not challenged with OVA did not develop airway inflammation and were used as negative controls in this study. Approximately one half million cells were recovered from each control mouse. There was a 5-fold increase in the total number of BAL cells recovered from OVA-immunized and -challenged mice when compared to nonchallenged controls (Fig. 1). AEOL 10113 did not have an effect on control mice that were immunized but not challenged with OVA. When mice were given
Discussion
Airway inflammation and hyperreactivity in asthma likely involves an oxidative stress to the lung. Evidence suggests that oxidative stress markers are increased and antioxidant reserves are decreased in asthmatic patients. The findings in this study, that OVA-induced mouse lung recruitment of inflammatory cells was inhibited by treatment of mice with the catalytic antioxidant AEOL 10113 during OVA challenges, support this hypothesis.
The eosinophil is well recognized as a central effector cell
Acknowledgements
The authors would like to express their gratitude to Mr. Joseph D. Rice, Mr. Michael E. Nicks, and Mrs. Karen R. Dockstader for their expert technical assistance. AEOL 10113 was provided by Incara Pharmaceuticals, Inc. (Research Triangle Park, NC). Drs. Chang and Crapo serve as consultants for Incara Pharmaceuticals, Inc., and Dr. Crapo holds equity in this company. The research described in this study was funded by NIH Grants PO1 HL31992-19 and PO1 HL42444.
References (41)
- et al.
Oxygen radicals, inflammation, and tissue injury
Free Radic. Biol. Med.
(1988) Human disease, free radicals, and the oxidant/antioxidant balance
Clin. Biochem.
(1993)- et al.
Evidence of oxidative stress in asthma and COPDpotential inhibitory effect of theophylline
Respir. Med.
(2000) - et al.
Rapid loss of superoxide dismutase activity during antigen-induced asthmatic response
Lancet
(2000) - et al.
Altered lung antioxidant status in patients with mild asthma
Lancet
(1999) - et al.
Extracellular superoxide dismutase in vessels and airways of humans and baboons
Free Radic. Biol. Med.
(1996) - et al.
Modulation of nitric oxide responses in asthma by extracellular antioxidants
J. Allergy Clin. Immunol.
(1999) - et al.
The ortho effect makes manganese(III) meso-tetrakis(N-methylpyridinium- 2-yl)porphyrin a powerful and potentially useful superoxide dismutase mimic
J. Biol. Chem.
(1998) - et al.
Metalloporphyrin class of therapeutic catalytic antioxidants
Trends Pharmacol. Sci.
(1999) - et al.
A metalloporphyrin superoxide dismutase mimetic protects against paraquat-induced lung injury in vivo
Toxicol. Appl. Pharmacol.
(1996)
The trials and tribulations of IL-5, eosinophils, and allergic asthma
J. Allergy Clin. Immunol.
Pulmonary T cells and eosinophilscoconspirators or independent triggers of allergic respiratory pathology?
J. Allergy Clin. Immunol.
Eosinophil peroxidase oxidation of thiocyanate. Characterization of major reaction products and a potential sulfhydryl-targeted cytotoxicity system
J. Biol. Chem.
The role of lymphocytes in allergic disease
J. Allergy Clin. Immunol.
Important roles for L-selectin and ICAM-1 in the development of allergic airway inflammation in asthma
Pulm. Pharmacol. Ther.
Vascular endothelial growth factor expression of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E- selectin through nuclear factor-kappa B activation in endothelial cells
J. Biol. Chem.
NF- kappa B independent suppression of endothelial vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 gene expression by inhibition of flavin binding proteins and superoxide production
J. Mol. Cell. Cardiol.
Involvement of superoxide and nitric oxide on airway inflammation and hyperresponsiveness induced by diesel exhaust particles in mice
Free Radic. Biol. Med.
Assessment of oxidant stress in allergic asthma by measurement of the major urinary metabolite of F2-isoprostane, 15-F2t-IsoP (8-iso-PGF2alpha)
Clin. Exp. Allergy
Raised levels of exhaled carbon monoxide are associated with an increased expression of heme oxygenase-1 in airway macrophages in asthmaa new marker of oxidative stress
Thorax
Cited by (88)
Reduction of peroxynitrite by some manganoporphyrins of AEOL series: DFT approach with dispersion correction and NBO analysis
2021, Journal of Inorganic BiochemistryCitation Excerpt :In this paper, we calculated the electronic structures of some AEOL compounds (AEOL-10113, AEOL-10150, AEOL-11114 and AEOL-11203) and the association complexes between each of those and peroxynitrite in water to compare their relative activity for reductive oxygen atom cleavage from ONOO− to form NO2 (ONOO− reduction, simply) by using DFT with dispersion correction and natural bond orbital (NBO) analysis. To our best knowledge, there have been several studies on biofunctional properties of AEOL compounds [10–15], but no report on DFT computations for their electronic structures and ONOO− reduction activities. We selected four AEOL compounds (AEOL-10113, AEOL-10150, AEOL-11114 and AEOL-11203 on Fig. 1) as AEOL models for catalytic reduction of ONOO− in DFT computations, because the previous researches showed that they (especially, AEOL-10150) can be good candidates for SOD mimic and catalytic antioxidant [10].
Antioxidant MnTBAP does not protect adult mice from neonatal hyperoxic lung injury
2020, Respiratory Physiology and NeurobiologyCitation Excerpt :However, AHR was not significantly different from hyperoxic mice at 12 weeks, suggesting the absence of protective effects of MnTBAP on AHR. Intratracheal AEOL-10113, a catalytic antioxidant decreased ovalbumin-induced AHR to methacholine and reduced airway inflammation as evidenced by a reduced number of neutrophils, eosinophils, and lymphocytes in BAL (Chang and Crapo, 2002). Neutrophils (McGovern et al., 2015) and eosinophils (Sverrild et al., 2017) play an important role in the pathophysiology of asthma and allergic AHR.
Impact of combined ultrasound-microwave treatment on structural and functional properties of golden threadfin bream (Nemipterus virgatus) myofibrillar proteins and hydrolysates
2020, Ultrasonics SonochemistryCitation Excerpt :SOD is responsible for converting superoxide anions to less reactive hydrogen peroxide, which is then further degraded to water by CAT [44]. Excess ROS induced by H2O2 consumed large amounts of antioxidant enzymes, which reduced the functioning of the antioxidant defence system [45]. In the present study, MP peptides could be taken up by individual cells, which contributed to mitigating oxidative stress by scavenging ROS.
Bilirubin nanoparticles ameliorate allergic lung inflammation in a mouse model of asthma
2017, BiomaterialsCitation Excerpt :Reactive oxygen species (ROS) are known to play a crucial role in the pathogenesis and progression of a variety of acute and chronic inflammatory diseases [21,22]. In fact, it has been shown that administration of antioxidants such as AEOL 10,113 and bilirubin can attenuate OVA-induced airway inflammation by scavenging ROS [4,23]. Thus, we investigated whether BRNPs were capable of scavenging ROS in CD4+ T cells.
Oxidative signaling in chronic obstructive airway diseases
2017, Immunity and Inflammation in Health and Disease: Emerging Roles of Nutraceuticals and Functional Foods in Immune SupportMolecular mechanisms of reactive oxygen species-related pulmonary inflammation and asthma
2013, Molecular ImmunologyCitation Excerpt :In relation to ROS, EC-SOD will break down superoxide anion into hydrogen peroxide, which can then be reduced to water (Leopold and Loscalzo, 2005). EC-SOD is an enzyme most prevalently found in the matrix surrounding pulmonary vessels and airways (Oury et al., 1994) and EC-SOD mimics have proven to diminish airway inflammation in asthma animal models (Chang and Crapo, 2002). Modifications of biologically significant proteins can be initiated by an increase in ROS.