Abstract
Recent clinical evidence indicates that the non-eosinophilic subtype of severe asthma is characterized by fixed airway obstruction, which may be related to emphysema. Transgenic studies have demonstrated that high levels of IFN-γ in the airways induce emphysema. Fibroblast growth factor 2 (FGF2), which is the downstream mediator of TGF-β, is important in wound healing. We investigated the role of FGF2 in IFN-γ-induced emphysema and the therapeutic effects of recombinant FGF2 in the prevention of emphysema in a severe non-eosinophilic asthma model. To evaluate the role of FGF2 in IFN-γ-induced emphysema, lung targeted IFN-γ transgenic mice were cross-bred with FGF2-deficient mice. A severe non-eosinophilic asthma model was generated by airway application of LPS-containing allergens twice a week for 4 weeks. To evaluate protective effects of FGF2, recombinant FGF2 (10 μg) was injected subcutaneously during allergen challenge in the severe asthma model. We found that non-eosinophilic inflammation and emphysema induced by transgenic overexpression of IFN-γ in the airways were aggravated by the absence of FGF2. Airway challenge with LPS-containing allergens induced more inflammation in mice sensitized with LPS-containing allergens compared to challenge with allergens alone. In addition, LPS-induced lung inflammation and emphysema depended on IFN-γ but not on IL-13. Interestingly, emphysema in the severe asthma model was significantly inhibited by treatment with recombinant FGF2 during allergen challenge, whereas lung inflammation was unaffected. Therefore, our present data suggest that FGF2 may help protect against IFN-γ-induced emphysema, and that recombinant FGF2 may help lessen the severity of emphysema.
Highlights
Asthma is a complex disease, which has various subtypes according to fixed airflow obstruction, the presence of airway hyperresponsiveness (AHR), and eosinophilic inflammationand (Busse and Lemanske, 2001)
The degree of emphysema, assessed by chord length, was similar in the two groups (Figure 4D). These findings suggest that severe non-eosinophilic asthma phenotypes, such as lung inflammation and emphysema, induced by airway challenge with LPScontaining allergens do not depend on IL-13
We investigated the potential role of Fibroblast growth factor 2 (FGF2) in the development of IFN-γ-induced emphysema using two emphysema models: a lung-targeted IFN-γ TG model and a severe non-eosinophilic asthma model induced by airway exposure to LPS-containing allergens
Summary
Asthma is a complex disease, which has various subtypes according to fixed airflow obstruction, the presence of airway hyperresponsiveness (AHR), and eosinophilic inflammationand (Busse and Lemanske, 2001). Asthma is classified into mild, moderate, and severe subtypes. Mild and moderate asthma are related to eosinophilic inflammation, whereas severe asthma is associated with neutrophilic (or non-eosinophilic) inflammation (Busse and Lemanske, 2001; Bateman et al, 2008). Cluster analysis to identify asthma subtypes has shown that non-eosinophilic or neutrophilic severe asthma is characterized by fixed airway obstruction, whereas the eosinophilic subtype is characterized by reversible lung function (Haldar et al, 2008; Moore et al, 2010).
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