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Published ahead of print on November 14, 2003, doi:10.1165/rcmb.2003-0066OC

Am. J. Respir. Cell Mol. Biol., Volume 30, Number 5, May 2004, 651-661

A more recent version of this article appeared on May 1, 2004
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Submitted on March 3, 2003
Revised on November 12, 2003

Immunostimulatory DNA inhibits TGF-{beta} expression and airway remodeling

Jae Y Cho1, Marina Miller1, Kwang J Baek1, Ji W Han1, Jyothi Nayar1, Monica Rodriguez1, Sook Y Lee1, Kirsti McElwain1, Shauna McElwain1, Eyal Raz1, and David H Broide1*

1 Medicine, University of California San Diego, La Jolla, California, USA

* To whom correspondence should be addressed. E-mail: dbroide{at}ucsd.edu.

Immunostimulatory sequences of DNA (ISS) inhibit eosinophilic airway inflammation, Th2 responses and airway hyperreactivity (AHR) in mouse models of acute OVA induced airway inflammation. To determine whether ISS inhibits airway remodeling, we developed a mouse model of airway remodeling in which OVA sensitized mice were repeatedly exposed to intranasal OVA administration for 1-6 months. Mice chronically exposed to OVA developed sustained eosinophilic airway inflammation and sustained AHR to methacholine compared to control mice. In addition, the mice chronically exposed to OVA developed features of airway remodeling including thickening of the peribronchial smooth muscle layer, peribronchial myofibroblast accumulation, expression of the pro-fibrotic growth factor TGF-{beta}, and subepithelial collagen deposition (assessed by quantitation of the area of peribronchial trichome staining using image analysis, and immunostaining with anti-collagen V antibodies). Administration of ISS systemically every other week significantly inhibited the development of AHR, eosinophilic inflammation, airway mucus production, and importantly airway remodeling in mice chronically exposed to OVA for 3-6 months. In addition, ISS significantly reduced bronchoalveolar lavage and lung levels of the pro-fibrotic cytokine TGF-{beta}. These studies demonstrate that ISS not only prevents Th2 mediated airway inflammation in response to acute allergen challenge, but also airway remodeling associated with chronic allergen challenge.




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