The effects of antisense interleukin-4 gene transferred by recombinant adeno-associated virus vector on the airway remodeling in allergic rats

Abstract

Background: Th2-derived cytokines, including interleukin-4 (IL-4), are considered to play an important role in the development of airway remodeling of asthma. Objectives: Our previous study has demonstrated that a recombinant adeno-associated virus containing antisense against IL-4 gene (rAAV-asIL4) vector could significantly suppress the expression of IL-4 protein and airway inflammation in the rat models of allergic asthma. In this study, we applied the rAAV-asIL4 vector to allergic rats to investigate the effects of anti-IL4 therapy on airway remodeling in allergic asthma. Methods: rAAV-asIL4 was used to infect the ovalbumin (OVA)-sensitized and challenged rats by tail-vein injection. IL-4 protein in bronchoalveolar lavage fluid (BALF) was detected by enzyme-linked immunosorbent assay. The number of eosinophils in BALF was counted. Transforming growth factor-beta1 (TGF-beta1) and TGF-beta2-positive cells in the peribronchial space were detected by immunohistochemical staining, and collagen deposition beneath the basement membrane was detected by Sirius red stain. The lung tissues were collected for histologic analysis of total bronchial wall area (W_At) and airway smooth muscle area (W_Am). Results: rAAV-asIL4 significantly decreased IL-4 protein in BALF of OVA-sensitized and challenged rats. The number of eosinophils in BALF, the TGF-beta1 and TGF-beta2-positive cells in the peribronchial space were also suppressed. Moreover, the rAAV-asIL4 treatment inhibited the area of Sirius red staining in airways and the increase in W_At and W_Am. Conclusion: These results suggest that rAAV-asIL4 may attenuate the airway remodeling process relevant to the inhibition of airway inflammation. This study provides elementary evidence for the potential utility of rAAV-asIL4 as an approach to gene therapy for asthmatic airway remodeling.

• asthma
• airway remodeling
• interleukin-4
• recombinant adeno-associated virus
• gene therapy

ACKNOWLEDGMENTS

This work was supported by the National Natural Science Foundation of China (No. 30300144 and No. 30900647).

This manuscript was revised in English phrased sentences/wording by Kathleen Keefe (Experimental Pathology Section, Cell and Cancer Biology Branch, CCR, NCI, NIH, Bethesda, MD, USA).