Role of interleukin‐13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma

Kumar, Rakesh K.; Herbert, Cristan; Yang, Ming; Koskinen, Aulikki; McKenzie, Andrew N. J.; Foster, Paul S.

doi:10.1046/j.1365-2222.2002.01420.x

Cited by 162 publications

(141 citation statements)

References 42 publications

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“…2), which was consistent with our previous observations in these mice at 18 hours post-exposure (Kumar et al, 2002). Surprisingly, however, there was strong expression of eotaxin both by tracheal epithelial cells and by plasma cells in the lamina propria in these animals (Fig.…”

Section: Eosinophil Recruitment and Eotaxin Expression In Il-13 ؊/؊ Micesupporting

confidence: 92%

Eotaxin Expression by Epithelial Cells and Plasma Cells in Chronic Asthma

Kumar

Thomas

Seetoo

et al. 2002

Laboratory Investigation

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SUMMARY:Chemoattractants such as eotaxin are believed to play an important role in the recruitment of eosinophils into the airways in asthma. We investigated expression of eotaxin in the airway wall in a model of chronic human asthma, in which systemically sensitized mice were exposed to low mass concentrations of aerosolized antigen for 6 weeks. In these animals, the number of intraepithelial eosinophils in the airways was significantly increased 3 hours after exposure and declined by 24 hours. In parallel, immunoreactivity for eotaxin was strikingly up-regulated in airway epithelial cells and in inflammatory cells in the lamina propria. The latter were identified as plasma cells by double immunofluorescent labeling. Increased expression of eotaxin by epithelial cells and plasma cells was also demonstrated in a case of fatal human asthma. In contrast, sensitized mice that received a single exposure to a high mass concentration of aerosolized antigen exhibited delayed eosinophil recruitment, which did not correlate with eotaxin expression. Furthermore, in sensitized chronically exposed interleukin-13-deficient mice there was virtually no recruitment of eosinophils into the airways, although eotaxin expression was greater than or equal to that in wild-type mice. These results indicate that there are striking differences between acute and chronic exposure models in the time course of eotaxin expression and eosinophil recruitment. Although high eotaxin levels alone are not sufficient to cause recruitment of eosinophils into the airways, recurrent exposure may generate or up-regulate additional signals required for eosinophil chemotaxis. (Lab Invest 2002, 82:495-504).

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Section: Eosinophil Recruitment and Eotaxin Expression In Il-13 ؊/؊ Micesupporting

confidence: 92%

Eotaxin Expression by Epithelial Cells and Plasma Cells in Chronic Asthma

Kumar

Thomas

Seetoo

et al. 2002

Laboratory Investigation

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“…AHR and subepithelial remodeling have also been shown to develop in N6 IL-13 Ϫ/Ϫ mice in a chronic model of asthma (32). These observations are in contrast to those reported by Walter et al (23), who showed that IL-13 was critical for the development of allergen-induced AHR in N7 IL-13 Ϫ/Ϫ mice.…”

Section: Discussionmentioning

confidence: 55%

Polymorphisms in IL-4Rα Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13−/− Mice

Webb

Matthaei

Cai

et al. 2004

The Journal of Immunology

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The development of airways hyperreactivity in allergic IL-13−/− mice is controversial and appears to correlate with the number of times that the original 129 × C57BL/6 founder strain has been crossed to the BALB/c background. In this investigation, we compared allergic responses in founder IL-13−/− mice crossed for either 5 (N5) or 10 (N10) generations to BALB/c mice. Whereas allergic N5 IL-13−/− mice developed airways hyperreactivity, tissue eosinophilia, elevated IgE, and pulmonary expression of Ym proteins, these processes were attenuated in N5 IL-13−/− mice treated with an IL-4-neutralizing Ab, and in N10 IL-13−/− mice. These data showed that IL-4 was more effective in regulating allergic responses in N5 IL-13−/− mice than in N10 IL-13−/− mice. To elucidate the mechanism associated with these observations, we show by restriction and sequence analysis that N5 IL-13−/− mice express the C57BL/6 form of IL-4Rα and N10 IL-13−/− mice express the BALB/c form. Despite the near identical predicted molecular mass of these isoforms, IL-4Rα from N5 IL-13−/− mice migrates with a slower electrophoretic mobility than IL-4Rα from N10 IL-13−/− mice, suggesting more extensive posttranslational modification of the N5 form. The Thre49Ile polymorphism in the extracellular domain of BALB/c IL-4Rα has been demonstrated to disrupt N-linked glycosylation of Asn47 and increase the dissociation rate of the IL-4Rα/IL-4 interaction. Collectively, these data show that polymorphisms in IL-4Rα, which have been shown to affect the interaction with IL-4, correlate with the ability of IL-4 to regulate allergic responses in IL-13−/− mice.

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“…Human studies reveal an association between severity of remodeling and AHR in asthma (Chetta et al, 1996;Hoshino et al, 1998), as well as a correlation between increasing subepithelial fibrosis and progression from asymptomatic AHR to asthma (Laprise et al, 1999). However, our previous studies using this experimental model suggest that remodeling and development of AHR can be uncoupled in IL-5-deficient animals, which develop significant airway wall remodeling but not AHR , as well as in IL-13-deficient animals, which do not exhibit remodeling but continue to be hyperreactive to methacholine (Kumar et al, 2002a).…”

Section: Foster Et Almentioning

confidence: 81%

CD4+ T-Lymphocytes Regulate Airway Remodeling and Hyper-Reactivity in a Mouse Model of Chronic Asthma

Foster

Yang

Herbert

et al. 2002

Laboratory Investigation

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SUMMARY:Asthma is an acute-on-chronic inflammatory disease of the airways, characterized by airflow obstruction and hyper-reactivity of the airways to a variety of stimuli. Chronic asthma is associated with remodeling of the airway wall, which may contribute to hyper-reactivity and fixed airflow obstruction. We used an improved mouse model of chronic asthma to investigate the role of CD4 ϩ T-lymphocytes in airway remodeling and hyper-reactivity. Animals functionally depleted of CD4 ϩ T-lymphocytes by repeated administration of a monoclonal antibody exhibited markedly decreased airway responsiveness. In addition, these mice had greatly diminished subepithelial fibrosis, epithelial thickening, and mucous cell hyperplasia/metaplasia. Chronic inflammation in the airway wall was moderately reduced, with a marked decrease in the accumulation of immunoglobulinsynthesizing plasma cells. However, intraepithelial accumulation of eosinophils was not significantly inhibited and airway epithelial expression of eotaxin was undiminished. This work provides the first experimental evidence that CD4 ϩ T-lymphocytes play a crucial role in the pathogenesis of the lesions of chronic asthma and lends support to the notion that functional inhibition of these cells may be an important therapeutic target. (Lab Invest 2002, 82:455-462).

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Role of interleukin‐13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma

Cited by 162 publications

References 42 publications

Eotaxin Expression by Epithelial Cells and Plasma Cells in Chronic Asthma

Eotaxin Expression by Epithelial Cells and Plasma Cells in Chronic Asthma

Polymorphisms in IL-4Rα Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13−/− Mice

CD4+ T-Lymphocytes Regulate Airway Remodeling and Hyper-Reactivity in a Mouse Model of Chronic Asthma

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