Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1

Shore, Stephanie A.; Williams, Erin S.; Chen, Lucas; Benedito, Leandro A.P.; Kasahara, David I.; Zhu, Min

doi:10.3109/08958378.2011.622316

Cited by 16 publications

(18 citation statements)

References 87 publications

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“…Several investigators [27]–[30] have examined the effects of ozone, another powerful oxidant, in mice and rats and found that older animals showed either lesser functional decrements and lesser inflammatory responses compared to younger animals or no differences. Shore et al [27] found that levels of soluble TNF receptor 1 were increased in the older animals, and suggested that that this phenomenon might account for the decreased inflammatory response.…”

Section: Discussionmentioning

confidence: 99%

Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse

et al. 2013

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It has been proposed that the development of COPD is driven by premature aging/premature senescence of lung parenchyma cells. There are data suggesting that old mice develop a greater inflammatory and lower anti-oxidant response after cigarette smoke compared to young mice, but whether these differences actually translate into greater levels of disease is unknown. We exposed C57Bl/6 female mice to daily cigarette smoke for 6 months starting at age 3 months (Ayoung@) or age 12 months (Aold@), with air-exposed controls. There were no differences in measures of airspace size between the two control groups and cigarette smoke induced exactly the same amount of emphysema in young and old. The severity of smoke-induced small airway remodeling using various measures was identical in both groups. Smoke increased numbers of tissue macrophages and neutrophils and levels of 8-hydroxyguanosine, a marker of oxidant damage, but there were no differences between young and old. Gene expression studies using laser capture microdissected airways and parenchyma overall showed a trend to lower levels in older animals and a somewhat lesser response to cigarette smoke in both airways and parenchyma but the differences were usually not marked. Telomere length was greatest in young control mice and was decreased by both smoking and age. The senescence marker p21Waf1 was equally upregulated by smoke in young and old, but p16INK4a, another senescence marker, was not upregulated at all. We conclude, in this model, animal age does not affect the development of emphysema and small airway remodeling.

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Section: Discussionmentioning

confidence: 99%

Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse

et al. 2013

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“…For RT-PCR, RNA was extracted from lungs and cDNA generated as previously described [42]. Endothelin 1, TrkB, fractalkine, and adipsin mRNA expression were quantified by real time PCR (7300 Real-Time PCR Systems, Applied Biosystems, US) using SYBR-green detection.…”

Section: Methodsmentioning

confidence: 99%

Obesity and airway responsiveness: Role of TNFR2

Williams¹,

Chen²,

Kasahara³

et al. 2013

Pulmonary Pharmacology & Therapeutics

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Obese mice exhibit innate airway hyperresponsiveness (AHR), a feature of asthma. Tumor necrosis factor alpha (TNFα) is implicated in the disease progression and chronic inflammatory status of both obesity and asthma. TNF acts via two TNF receptors, TNFR1 and TNFR2. To examine the role of TNFR2 in the AHR observed in obese mice, we generated obese Cpefat mice that were either sufficient or deficient in TNFR2 (Cpefat and Cpefat/TNFR2−/− mice, respectively) and compared them with their lean controls (WT and TNFR2−/− mice). Compared to WT mice, Cpefat mice exhibited AHR to aerosolized methacholine (measured using the forced oscillation technique) which was ablated in Cpefat/TNFR2−/− mice. Bioplex or ELISA assay indicated significant increases in serum leptin, G-CSF, IL-7, IL-17A, TNFα, and KC in obese versus lean mice, as well as significant obesity-related increases in bronchoalveolar lavage fluid (BALF) G-CSF and IP-10, regardless of TNFR2 status. Importantly, BALF IL-17A was significantly increased over lean controls in Cpefat but not Cpefat/TNFR2−/− mice. Functional annotation clustering of significantly affected genes identified from microarray analysis comparing gene expression in lungs of Cpefat and WT mice, identified blood vessel morphogenesis as the gene ontology category most affected by obesity. This category included several genes associated with AHR, including endothelin and trkB. Obesity increased pulmonary mRNA expression of endothelin and trkB in TNFR2 sufficient but not deficient mice. Our results indicate that TNFR2 signaling is required for the innate AHR that develops in obese mice, and suggest that TNFR2 may act by promoting IL-17A, endothelin, and/or trkB expression.

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“…We used real-time PCR to quantitate IL-13 and IL-17A mRNA expression as described (Shore et al 2011). We subtracted Ct values for a housekeeping gene, 36B4 ( rplp0 ) (which codes for a ribosomal protein), from Ct values for IL-13 or IL-17A to obtain ΔCt values.…”

Section: Methodsmentioning

confidence: 99%

Augmented Pulmonary Responses to Acute Ozone Exposure in Obese Mice: Roles of TNFR2 and IL-13

Williams¹,

Mathews²,

Kasahara³

et al. 2013

Environ Health Perspect

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Background: Acute ozone (O3) exposure results in greater inflammation and airway hyperresponsiveness (AHR) in obese versus lean mice.Objectives: We examined the hypothesis that these augmented responses to O3 are the result of greater signaling through tumor necrosis factor receptor 2 (TNFR2) and/or interleukin (IL)-13.Methods: We exposed lean wild-type (WT) and TNFR2-deficient (TNFR2–/–) mice, and obese Cpefat and TNFR2-deficient Cpefat mice (Cpefat/TNFR2–/–), to O3 (2 ppm for 3 hr) either with or without treatment with anti–IL-13 or left them unexposed.Results: O3-induced increases in baseline pulmonary mechanics, airway responsiveness, and cellular inflammation were greater in Cpefat than in WT mice. In lean mice, TNFR2 deficiency ablated O3-induced AHR without affecting pulmonary inflammation; whereas in obese mice, TNFR2 deficiency augmented O3-induced AHR but reduced inflammatory cell recruitment. O3 increased pulmonary expression of IL-13 in Cpefat but not WT mice. Flow cytometry analysis of lung cells indicated greater IL-13–expressing CD4+ cells in Cpefat versus WT mice after O3 exposure. In Cpefat mice, anti–IL-13 treatment attenuated O3-induced increases in pulmonary mechanics and inflammatory cell recruitment, but did not affect AHR. These effects of anti–IL-13 treatment were not observed in Cpefat/TNFR2–/– mice. There was no effect of anti–IL-13 treatment in WT mice.Conclusions: Pulmonary responses to O3 are not just greater, but qualitatively different, in obese versus lean mice. In particular, in obese mice, O3 induces IL-13 and IL-13 synergizes with TNF via TNFR2 to exacerbate O3-induced changes in pulmonary mechanics and inflammatory cell recruitment but not AHR.

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Impact of aging on pulmonary responses to acute ozone exposure in mice: role of TNFR1

Cited by 16 publications

References 87 publications

Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse

Aging does not Enhance Experimental Cigarette Smoke-Induced COPD in the Mouse

Obesity and airway responsiveness: Role of TNFR2

Augmented Pulmonary Responses to Acute Ozone Exposure in Obese Mice: Roles of TNFR2 and IL-13

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