Interleukin-5 Expression in the Lung Epithelium of Transgenic Mice Leads to Pulmonary Changes Pathognomonic of Asthma

Abstract

We have generated transgenic mice that constitutively express murine interleukin (IL)-5 in the lung epithelium. Airway expression of this cytokine resulted in a dramatic accumulation of peribronchial eosinophils and striking pathologic changes including the expansion of bronchusassociated lymphoid tissue (BALT), goblet cell hyperplasia, epithelial hypertrophy, and focal collagen deposition. These changes were also accompanied by eosinophil infiltration of the airway lumen. In addition, transgenic animals displayed airway hyperresponsiveness to methacholine in the absence of aerosolized antigen challenge. These findings demonstrate that lung-specific IL-5 expression can induce pathologic changes characteristic of asthma and may provide useful models to evaluate the efficacy of potential respiratory disease therapies or pharmaceuticals.

Peroxisome proliferator–activated receptor γ is expressed in airways and inhibits features of airway remodeling in a mouse asthma model☆

“…38 Similarly, IL-4, IL-5, and IL-9 caused extensive mucus metaplasia, whereas IL-9 and IL-5 induced subepithelial fibrosis and AHR. [39][40][41] In our previous study we showed that ciglitazone treatment reduced the pulmonary eosinophilia and the production of cytokines associated with inflammation (IL-6), eosinophilia (IL-5), and T H 2-driven humoral immune responses (IL-4 and IL-13) in lung extracts. 29 Expression of these cytokines is in part under the control of known ubiquitously expressed PPAR-c targets, such as MAP kinases, c-jun and c-fos, or nuclear factor jB.…”

Marked Airway Eosinophilia Prevents Development of Airway Hyper-responsiveness During an Allergic Response in IL-5 Transgenic Mice

“…In the study by Lee et al (10) the promotor for the Clara cell secretory protein CC10 was used, resulting in a dramatic increase in airway IL-5 compared with our study (269,000 Ϯ 37,000 pg/lavage (10) vs 74 Ϯ 21 pg/ml (our study)). Their markedly increased IL-5 levels may have contributed to both the peribronchial eosinophilia and the striking structural changes in the airways, including the expansion of bronchus-associated lymphoid tissue, epithelial hypertrophy, and focal collagen deposition (10). These pathologic changes probably resulted in AHR without Ag sensitization and challenge (10).…”

“…Their markedly increased IL-5 levels may have contributed to both the peribronchial eosinophilia and the striking structural changes in the airways, including the expansion of bronchus-associated lymphoid tissue, epithelial hypertrophy, and focal collagen deposition (10). These pathologic changes probably resulted in AHR without Ag sensitization and challenge (10). Therefore, this previous study was not able to study the effects of airway eosinophilia on the development of AHR induced by allergen challenge and perhaps by a factor(s) produced by T cells, such as IL-13.…”

“…Recently, anti-IL-5 mAb only partially decreased airway tissue eosinophilia, making interpretation of the roles of IL-5 and eosinophils in human asthma even more difficult (8). In mice neutralization of IL-5 prevented allergen-induced AHR (9), and overproduction of IL-5 in the airways led to AHR (10). However, previous results, suggesting that AHR was prevented in IL-5 knockout mice (11), but was not prevented in mice treated with anti-IL-5 mAb, were conflicting (12).…”

Critical Role for T Cells in Sephadex-Induced Airway Inflammation: Pharmacological and Immunological Characterization and Molecular Biomarker Identification

“…Evidence for a role for IL-5 has emanated from in vivo work in animal models of allergic inflammation. Thus, transgenic mice overexpressing the IL-5 gene exhibit evidence of airway remodeling and the induction of AHR (38) and administration of neutralizing anti-IL-5 mAbs has been demonstrated to inhibit the eosinophilia induced by nematode infection or Ag exposure in sensitized animals (39 -41). Likewise, exposure of IL-5 gene knockout mice to aerosolized Ags caused an ablated eosinophil recruitment into the lungs (42).…”