Effects of Ozone and Endotoxin Coexposure on Rat Airway Epithelium: Potentiation of Toxicant-Induced Alterations

Wagner, James G.; Hotchkiss, Jon A.; Harkema, Jack R.

doi:10.2307/3454675

Cited by 9 publications

(7 citation statements)

References 28 publications

(34 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This acute supplementation regimen was apparently sufficient for pulmonary γT to block any acute oxidant or inflammatory stimuli induced by inhalation with ozone. We have previously described the requirement for neutrophils in the initiation and progression of ozone-induced MCM in a non-allergic model [33], as well as associations of eosinophils and neutrophils with MCM in allergic models [34]. In the present study, eosinophilic infiltrates that were dramatically increased in BALF by allergen were attenuated by supplementation with γT.…”

Section: Discussionsupporting

confidence: 59%

Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

Wagner

Jiang

Harkema

et al. 2007

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

Ozone is a commonly encountered environmental oxidant which has been linked to asthma exacerbation in epidemiological studies. Ozone induces airway inflammation and enhances response to inhaled allergen. It has been suggested that antioxidant therapy may minimize the adverse effects of ozone in asthma. We have previously shown that the antioxidant gammatocopherol (γT), an isoform of vitamin E, also has anti-inflammatory effects. We employed a Brown Norway rat model of ozone-enhanced allergic responses to test the therapeutic effects of γT on O 3 -induced airway inflammation. Ovalbumin (OVA) -sensitized rats were intranasally challenged with 0 or 0.5% OVA on Days 1 and 2, and exposed to 0 or 1 ppm ozone (8h/day) on Days 4 and 5. Rats were also given 0 or 100 mg/kg γT on Days 2 through 5. Pulmonary tissue and bronchoalveolar lavage fluid (BALF) were collected on Day 6. OVA challenge caused increased total cells (267% increase) and eosinophils (4000%) in BALF that was unaffected by ozone exposure. Morphometric evaluation of lung tissue revealed increases in intraepithelial mucosubstances (IM) (300%) and subepithelial eosinophils (400%) in main axial airways. Ozone exposure of allergic rats enhanced IM increases in proximal axial airways (200%), induced cysleukotrienes, MCP-1 and IL-6 production in BALF, and upregulated expression of IL-5 and IL-13 mRNA. γT treatment had no effect on IM increases by allergen, but blocked enhancement by ozone. γT attenuated both OVA-or ozone -stimulated eosinophilic infiltration, and increases of BALF cys-leukotrienes, MCP-1 and IL-6, as well as IL-5 and IL-13 mRNA. These data Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript demonstrate broad anti-inflammatory effects of a γT and suggest it may be an effective therapy of allergic airway inflammation.

show abstract

Section: Discussionsupporting

confidence: 59%

Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

Wagner

Jiang

Harkema

et al. 2007

Free Radical Biology and Medicine

Self Cite

View full text Add to dashboard Cite

show abstract

“…Toxicant-induced mucous cell hyperplasia is a potential concern in long-term outcomes of chlorine toxicity. Mucous cell hyperplasia was shown to occur in response to bacterial endotoxin (47), and is potentiated by additional exposures to ozone (27,48,49). The increase in mucous cells is not associated with an increase in epithelial cell density, and may be attributable to the loss of serous cells.…”

Section: Discussionmentioning

confidence: 98%

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

Fanucchi¹,

Bracher

Doran

et al. 2012

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

We assessed the safety and efficacy of combined intravenous and aerosolized antioxidant administration to attenuate chlorine gasinduced airway alterations when administered after exposure. Adult male Sprague-Dawley rats were exposed to air or 400 parts per million (ppm) chlorine (a concentration likely to be encountered in the vicinity of industrial accidents) in environmental chambers for 30 minutes, and returned to room air, and they then received a single intravenous injection of ascorbic acid and deferoxamine or saline. At 1 hour and 15 hours after chlorine exposure, the rats were treated with aerosolized ascorbate and deferoxamine or vehicle. Lung antioxidant profiles, plasma ascorbate concentrations, airway morphology, and airway reactivity were evaluated at 24 hours and 7 days after chlorine exposure. At 24 hours after exposure, chlorine-exposed rats had significantly lower pulmonary ascorbate and reduced glutathione concentrations. Treatment with antioxidants restored depleted ascorbate in lungs and plasma. At 7 days after exposure, in chlorineexposed, vehicle-treated rats, the thickness of the proximal airways was 60% greater than in control rats, with twice the amount of mucosubstances. Airway resistance in response to methacholine challenge was also significantly elevated. Combined treatment with intravenous and aerosolized antioxidants restored airway morphology, the amount of airway mucosubstances, and airway reactivity to control levels by 7 days after chlorine exposure. Our results demonstrate for the first time, to the best of our knowledge, that severe injury to major airways in rats exposed to chlorine, as characterized by epithelial hyperplasia, mucus accumulation, and airway hyperreactivity, can be reversed in a safe and efficacious manner by the postexposure administration of ascorbate and deferoxamine.Keywords: epithelial injury; epithelial repair; mucosubstances; ascorbate; deferoxamine; aerosol Chlorine is essential to global industry and to global public health. According to the World Chlorine Council (http://www. worldchlorine.org), 14.4 million metric tons were produced in North America in 2008, and 62.8 million metric tons were produced globally. Water treatment makes up only 5% of the world's use of chlorine. The majority of chlorine is used in the production of plastics such as polyvinyl chloride (1). It is also used as a bleaching agent for pulp and paper production, as feedstock in the production of chlorinated solvents used in metalworking, in dry cleaning, in electronics, and in pharmaceutical production (1-6).Only 20 American states contain facilities that produce chlorine, but every American state has facilities that use chlorine. This results in the shipping of chlorine by railcar, and increases the potential for large-scale accidents. According to the Environmental Protection Agency, chlorine gas was related to 518 serious accidents over a 5-year period during the 1990s (1). Multiple-casualty exposures to chlorine have resulted from industrial accidents involving chlorine ta...

show abstract

“…Acute exposure to ozone causes nasal epithelial and inflammatory responses in laboratory animals (Nikasinovic, Momas, and Seta 2003) and induces epithelial hyperplasia and MCM in the transitional and respiratory epithelium of both rats (Harkema et al 1989) and monkeys. Neutrophil influx is required for the rapid induction of MCM by ozone, suggesting a critical role for acute inflammation in this process (Wagner, Hotchkiss, and Harkema 2001; Wagner et al 2001). …”

Section: Introductionmentioning

confidence: 99%

γ-Tocopherol Attenuates Ozone-induced Exacerbation of Allergic Rhinosinusitis in Rats

et al. 2009

Self Cite

View full text Add to dashboard Cite

Compared to healthy subjects, individuals with allergic airway disease (e.g., asthma, allergic rhinitis) have enhanced inflammatory responses to inhaled ozone. We created a rodent model of ozone-enhanced allergic nasal responses in Brown Norway rats to test the therapeutic effects of the dietary supplement g-tocopherol (γT). Ovalbumin (OVA)-sensitized rats were intranasally challenged with 0% or 0.5% OVA (in saline) on Days 1 and 2, and then exposed to 0 or 1 ppm ozone (eight hours/day) on Days 4 and 5. Rats were also given 0 or 100 mg/kg γT (p.o., in corn oil) on days 2 through 5, beginning twelve hours after the last OVA challenge. On Day 6, nasal tissues were collected for histological evaluation and mor-phometric analyses of intraepithelial mucosubstances (IM) and eosinophilic inflammation. Nasal septal tissue was microdissected and analyzed by reverse transcriptase polymerase chain reaction (RT-PCR) for mucin glycoprotein 5AC (MUC5AC) expression levels. Histological analysis revealed mild to moderate eosinophil influx in the mucosa lining the nasal airways and maxillary sinus of OVA-challenged rats (eosinophilic rhinosinusitis). Ozone exposure of allergic rats further increased eosinophils in the maxillary sinus (400%), nasolacrimal duct (250%), and proximal midseptum (150%). Storage of intraepithelial mucosubstances (IM) was not significantly affected by OVA challenge in filtered air-exposed rats, but it was increased by ozone in the septum (45%) and maxillary sinus (55%) of allergic compared to control rats. Treatment with γT attenuated the ozone/ OVA-induced synergistic increases in IM and mucosal eosinophils in both nasal and paranasal airways. γ-Tocopherol also blocked OVA and ozone-induced MUC5AC gene expression. Together, these data describe a unique model of ozone enhancement of allergic rhinosinusitis and the novel therapeutic efficacy of a common supplement, γT, to inhibit ozone exacerbation of allergic airway responses.

show abstract

Effects of Ozone and Endotoxin Coexposure on Rat Airway Epithelium: Potentiation of Toxicant-Induced Alterations

Cited by 9 publications

References 28 publications

Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

Ozone enhancement of lower airway allergic inflammation is prevented by γ-tocopherol

Post-Exposure Antioxidant Treatment in Rats Decreases Airway Hyperplasia and Hyperreactivity Due to Chlorine Inhalation

γ-Tocopherol Attenuates Ozone-induced Exacerbation of Allergic Rhinosinusitis in Rats

Contact Info

Product

Resources

About