Strain Differences in a Murine Model of Air Pollutant–induced Nonatopic Asthma and Rhinitis

Harkema, Jack R.; Hotchkiss, Lucas A.; Vetter, Nicholas A.; Jackson-Humbles, Daven; Lewandowski, Ryan P.; Wagner, James G.

doi:10.1177/0192623316674274

Cited by 12 publications

(9 citation statements)

References 46 publications

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“…The mucous cell metaplasia observed in the surface epithelium lining the proximal axial airway (G5) in the ILC-sufficient mice after repeated 9-day exposure was also similar in character and magnitude to the ozone-induced metaplastic responses that we have previously observed in the nasal (Kumagai et al 2016;Ong et al 2016) and pulmonary airways (Harkema et al 2017) of similarly exposed C57BL/6 mice. Mucous cell metaplasia is a commonly reported nasal epithelial response to repeated daily ozone exposures in rats (Cho, Hotchkiss, and Harkema 1999;Harkema et al 1999) as well as in nonhuman primates Harkema, Plopper, Hyde, St George, Wilson, et al 1987).…”

Section: Discussionsupporting

confidence: 72%

“…We have recently reported that the magnitude of ozone-induced mucous cell metaplasia in the proximal pulmonary airway is strain dependant (Harkema et al 2017). In this previous study, we found that C57BL/6 male mice exhibit greater metaplasia than BALB/c male mice, even though both strains of mice were of similar age and exposed to the same exposure regimen (0.8 ppm ozone, 4 hr/day, for 9 consecutive weekdays, as in the present study).…”

Section: Discussionmentioning

confidence: 99%

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Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone

et al. 2017

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Exposure to elevated levels of ambient ozone in photochemical smog is associated with eosinophilic airway inflammation and nonatopic asthma in children. In the present study, we determined the role of innate lymphoid cells (ILCs) in the pathogenesis of ozone-induced nonatopic asthma by using lymphoid cell-sufficient C57BL/6 mice, ILC-sufficient Rag2 mice (devoid of T and B cells), and ILC-deficient Rag2Il2rg mice (depleted of all lymphoid cells including ILCs). Mice were exposed to 0 or 0.8 parts per million ozone for 1 day or 9 consecutive weekdays (4 hr/day). A single exposure to ozone caused neutrophilic inflammation, airway epithelial injury, and reparative DNA synthesis in all strains of mice, irrespective of the presence or absence of ILCs. In contrast, 9-day exposures induced eosinophilic inflammation and mucous cell metaplasia only in the lungs of ILC-sufficient mice. Repeated ozone exposures also elicited increased messenger RNA expression of transcripts associated with type 2 immunity and airway mucus production in ILC-sufficient mice. ILC-deficient mice repeatedly exposed to ozone had no pulmonary pathology or increased gene expression related to type 2 immunity. These results suggest a new paradigm for the biologic mechanisms underlying the development of a phenotype of childhood nonatopic asthma that has been linked to ambient ozone exposures.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone

et al. 2017

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“…In the present study, repeated daily exposures, but not a single-day exposure, to ozone caused type 2 immune responses with associated eosinophilic inflammation in the nasal airways of ILC-sufficient Rag2 À/À and C57BL/6 mice, but not Rag2 À/À Il2rg À/À mice. Though we have reported similar findings previously, 1,3,17 our current study is the first to document ozone-induced influx (mucosal distribution and density) and persistence (postexposure) of GATA-3þ lymphoid cells in the nasal airways of ILC-sufficient, but T-cell and B-cell-deficient Rag2 À/À mice and ILC-, T-cell-and B-cell-sufficient C57BL/6 mice, as well as the absence of these lymphoid cells in air-or ozone-exposed ILC-, T-cell-, and B-cell-deficient Rag2 À/À Il2rg À/À mice.…”

Section: Discussionsupporting

confidence: 90%

Influx, Persistence, and Recall of Eosinophils and GATA-3+ Innate Lymphoid Cells in the Nasal Mucosa of Mice Exposed and Reexposed to the Gaseous Air Pollutant Ozone

et al. 2019

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Mice exposed to the air pollutant ozone develop eosinophilic rhinitis that is mediated by group 2, GATA-3+, innate lymphoid cells (ILC2s). In the present study, we determined the influx, persistence, and recall of nasal ILC2s and eosinophils in ozone-exposed mice. C57BL/6 (T/B cell sufficient, ILC sufficient), Rag2−/− (T/B cell deficient, ILC sufficient), and Rag2−/−Il2rg−/− (T/B cell deficient, ILC deficient) mice were exposed to 0 or 0.8 ppm ozone for 1 or 9 weekdays and killed 1 or 17 days postexposure. GATA-3+ lymphocytes were sparse in nasal tissue of air-exposed ILC-sufficient mice and absent in ILC-deficient mice. Nine-day, but not 1-day, ozone exposures induced nasal influxes of eosinophils and GATA-3+ lymphocytes in C57BL/6 and Rag2−/− mice but not in Rag2−/−Il2rg−/− mice. Eosinophils waned 17 days postexposure in ILC-sufficient strains of mice. GATA-3+ lymphocytes in C57BL/6 mice also attenuated after exposure but not in ILC-sufficient Rag2−/− mice. Eosinophils, but not GATA-3+ cells, increased rapidly with reexposure in ILC-sufficient mice. Type 2 immune-related messenger RNA expression correlated with cellular responses to ozone. These new findings in mice further elucidate the role of ILC2s in ozone-induced eosinophilic rhinitis and support epidemiologic associations between ozone exposure and eosinophilic inflammation in children.

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“…These O 3induced airway alterations are mediated by ILC2s, rather than by the more classical T and B lymphoid cells that are important in adaptive immune responses typically associated with allergic rhinitis and allergic asthma (103). Furthermore, repeated exposure to O 3 induces ILC2-mediated airway type 2 immunity, eosinophilic inflammation, and mucous cell metaplasia in the pulmonary airways (104,105). Thus, repeated O 3 exposures may induce a nonatopic asthma phenotype characterized by innate type 2 immunity, eosinophilic inflammation, and mucous cell metaplasia.…”

Section: A Mechanism For Nonatopic Asthmamentioning

confidence: 99%

Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report

Thurston¹,

Balmes²,

Garcia³

et al. 2020

Annals ATS

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153

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Although it is well accepted that air pollution exposure exacerbates preexisting airway disease, it has not been firmly established that long-term pollution exposure increases the risk of new-onset asthma or chronic obstruction pulmonary disease (COPD). This Workshop brought together experts on mechanistic, epidemiological, and clinical aspects of airway disease to review current knowledge regarding whether air pollution is a causal factor in the development of asthma and/or COPD. Speakers presented recent evidence in their respective areas of expertise related to air pollution and new airway disease incidence, followed by interactive discussions. A writing committee summarized their collective findings. The Epidemiology Group found that long-term exposure to air pollution, especially metrics of traffic-related air pollution such as nitrogen dioxide and black carbon, is associated with onset of childhood asthma. However, the evidence for a causal role in adultonset asthma or COPD remains insufficient. The Mechanistic Group concluded that air pollution exposure can cause airway remodeling, which can lead to asthma or COPD, as well as asthma-like phenotypes that worsen with long-term exposure to air pollution, especially fine particulate matter and ozone. The Clinical Group concluded that air pollution is a plausible contributor to the onset of both asthma and COPD. Available evidence indicates that long-term exposure to air pollution is a cause of childhood asthma, but the evidence for a similar determination for adult asthma or COPD remains insufficient. Further research is needed to elucidate the exact biological mechanism underlying incident childhood asthma, and the specific air pollutant that causes it.

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Strain Differences in a Murine Model of Air Pollutant–induced Nonatopic Asthma and Rhinitis

Cited by 12 publications

References 46 publications

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone

Innate Lymphoid Cells Mediate Pulmonary Eosinophilic Inflammation, Airway Mucous Cell Metaplasia, and Type 2 Immunity in Mice Exposed to Ozone

Influx, Persistence, and Recall of Eosinophils and GATA-3+ Innate Lymphoid Cells in the Nasal Mucosa of Mice Exposed and Reexposed to the Gaseous Air Pollutant Ozone

Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report

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