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Age-specific effects on rat lung glutathione and antioxidant enzymes after inhaling ultrafine soot.

ABSTRACT: Vehicle exhaust is rich in polycyclic aromatic hydrocarbons (PAHs) and is a dominant contributor to urban particulate pollution (PM). Exposure to PM is linked to respiratory and cardiovascular morbidity and mortality in susceptible populations, such as children. PM can contribute to the development and exacerbation of asthma, and this is thought to occur because of the presence of electrophiles in PM or through electrophile generation via the metabolism of PAHs. Glutathione (GSH), an abundant intracellular antioxidant, confers cytoprotection through conjugation of electrophiles and reduction of reactive oxygen species. GSH-dependent phase II detoxifying enzymes glutathione peroxidase and glutathione S-transferase facilitate metabolism and conjugation, respectively. Ambient particulates are highly variable in composition, which complicates systematic study. In response, we have developed a replicable ultrafine premixed flame particle (PFP)-generating system for in vivo studies. To determine particle effects in the developing lung, 7-day-old neonatal and adult rats inhaled 22 ?g/m(3) PFP during a single 6-hour exposure. Pulmonary GSH and related phase II detoxifying gene and protein expression were evaluated 2, 24, and 48 hours after exposure. Neonates exhibited significant depletion of GSH despite higher initial baseline levels of GSH. Furthermore, we observed attenuated induction of phase II enzymes (glutamate cysteine ligase, glutathione reductase, glutathione S-transferase, and glutathione peroxidase) in neonates compared with adult rats. We conclude that developing neonates have a limited ability to deviate from their normal developmental pattern that precludes adequate adaptation to environmental pollutants, which results in enhanced cytotoxicity from inhaled PM.

SUBMITTER: Chan JK

PROVIDER: S-EPMC3547088 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Age-specific effects on rat lung glutathione and antioxidant enzymes after inhaling ultrafine soot.

Chan Jackie K W JK Kodani Sean D SD Charrier Jessie G JG Morin Dexter D Edwards Patricia C PC Anderson Donald S DS Anastasio Cort C Van Winkle Laura S LS

American journal of respiratory cell and molecular biology 20121011 1

Vehicle exhaust is rich in polycyclic aromatic hydrocarbons (PAHs) and is a dominant contributor to urban particulate pollution (PM). Exposure to PM is linked to respiratory and cardiovascular morbidity and mortality in susceptible populations, such as children. PM can contribute to the development and exacerbation of asthma, and this is thought to occur because of the presence of electrophiles in PM or through electrophile generation via the metabolism of PAHs. Glutathione (GSH), an abundant in ...[more]

PMID: 23065132

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Project description:BACKGROUND:Urban particulate matter (PM) has been epidemiologically correlated with multiple cardiopulmonary morbidities and mortalities, in sensitive populations. Children exposed to PM are more likely to develop respiratory infections and asthma. Although PM originates from natural and anthropogenic sources, vehicle exhaust rich in polycyclic aromatic hydrocarbons (PAH) can be a dominant contributor to the PM2.5 and PM0.1 fractions and has been implicated in the generation of reactive oxygen species (ROS). OBJECTIVES:Current studies of ambient PM are confounded by the variable nature of PM, so we utilized a previously characterized ethylene-combusted premixed flame particles (PFP) with consistent and reproducible physiochemical properties and 1) measured the oxidative potential of PFP compared to ambient PM, 2) determined the ability of PFPs to generate oxidative stress and activate the transcription factor using in vitro and ex vivo models, and 3) we correlated these responses with antioxidant enzyme expression in vivo. METHODS:We compared oxidative stress response (HMOX1) and antioxidant enzyme (SOD1, SOD2, CAT, and PRDX6) expression in vivo by performing a time-course study in 7-day old neonatal and young adult rats exposed to a single 6-hour exposure to 22.4 ?g/m3 PFPs. RESULTS:We showed that PFP is a potent ROS generator that induces oxidative stress and activates Nrf2. Induction of the oxidative stress responsive enzyme HMOX1 in vitro was mediated through Nrf2 activation and was variably upregulated in both ages. Furthermore, antioxidant enzyme expression had age and lung compartment variations post exposure. Of particular interest was SOD1, which had mRNA and protein upregulation in adult parenchyma, but lacked a similar response in neonates. CONCLUSIONS:We conclude that PFPs are effective ROS generators, comparable to urban ambient PM2.5, that induce oxidative stress in neonatal and adult rat lungs. PFPs upregulate a select set of antioxidant enzymes in young adult animals, that are unaffected in neonates. We conclude that the inability of neonatal animals to upregulate the antioxidant response may, in part, explain enhanced their susceptibility to ultrafine particles, such as PFP.

Project description:Advanced age at the time of spinal cord injury (SCI) exacerbates damage from reactive oxygen species (ROS). Mechanisms underlying this age-dependent response are not well understood and may arise from decreased antioxidant defense. We investigated how spinal cord levels of the antioxidant glutathione (GSH), and its regulation, change with age and SCI. GSH is used by GSH peroxidase to sequester ROS and is recycled by GSH reductase. Male and female, 4- and 14-month-old (MO) mice received a 60 kDyn contusion SCI, and the levels of GSH and its regulatory enzymes were evaluated at one and three days post-injury (dpi). The mice with SCI were treated with N-acetylcysteine-amide (NACA; 150 mg/kg), a cysteine supplement that increases GSH, to determine effects on functional and histological outcomes. GSH was decreased with older age in sham mice, and an SCI-dependent depletion was observed in 4-MO mice by three dpi. Neither age nor injury affected the abundance of proteins regulating GSH synthesis or recycling. GSH peroxidase activity, however, increased after SCI only in 4-MO mice. In contrast, GSH peroxidase activity was increased in 14-MO sham mice, indicating that spinal cords of older mice have an elevated oxidative state. Indeed, 14-MO sham mice had more oxidized protein (3-nitrotyrosine [3-NT]) within their spinal cords compared with 4-MO sham mice. Only 4-MO mice had significant injury-induced increases in 3-NT at three dpi. NACA treatment restored GSH and improved the redox environment in injured 4- and 14-MO mice at one dpi; however, three days of NACA delivery did not improve motor, sensory, or anatomical deficits at 28 dpi in 4-MO mice and trended toward toxicity in all outcomes in 14-MO mice. Our observation suggests that GSH levels at acute stages of SCI play a minimal role in age-dependent outcomes reported after SCI in mice. Collective results implicate elements of injury occurring after three dpi, such as inflammation, as key regulators of age-dependent effects.

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Age-specific effects on rat lung glutathione and antioxidant enzymes after inhaling ultrafine soot.

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Age-specific effects on rat lung glutathione and antioxidant enzymes after inhaling ultrafine soot.

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