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Published ahead of print on June 22, 2006, doi:10.1165/rcmb.2006-0135OC

Am. J. Respir. Cell Mol. Biol., Volume 35, Number 5, November 2006, 565-570

A more recent version of this article appeared on November 1, 2006
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Submitted on April 5, 2006
Revised on June 19, 2006

Airway Hyperreactivity in Exacerbation of Chronic Asthma is Independent of Eosinophilic Inflammation

Jessica S Siegle1, Nicole Hansbro2, Cristan Herbert1, Ming Yang2, Paul S Foster3, and Rakesh K Kumar1*

1 Department of Pathology, School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia, 2 School of Biomedical Sciences, University of Newcastle, Newcastle, NSW, Australia, 3 School of Biomedical Sciences, University of Newcastle, Newcastle, NSW, Australia; Division of Molecular Biosciences, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia

* To whom correspondence should be addressed. E-mail: r.kumar{at}unsw.edu.au.

We have developed an animal model to investigate the mechanisms underlying an acute exacerbation of chronic asthma. Sensitized BALB/c mice were exposed to aerosolized ovalbumin, either as chronic low-level challenge (mass concentration ~=3 mg/m3) for 4 weeks, a single moderate-level challenge (~=30 mg/m3), or chronic low-level followed by single moderate-level challenge (the acute exacerbation group). Compared to animals receiving chronic challenge alone, mice in the acute exacerbation group exhibited a more marked inflammatory response, with involvement of intrapulmonary airways and lung parenchyma, and increased numbers of lymphocytes and eosinophils in bronchoalveolar lavage fluid. They also developed airway hyperreactivity (AHR) to methacholine, demonstrable as increased transpulmonary resistance and decreased compliance. This pattern of AHR was absent in chronically challenged animals, but was also present in animals given single moderate-level challenge. However, compared to animals receiving a single moderate-level challenge, inflammation and AHR were induced more rapidly in the acute exacerbation group. Eosinophil-deficient GATA1 {Delta}dbl mice exhibited undiminished AHR in the acute exacerbation model. We conclude that in mice with pre-existing airway lesions resembling mild chronic asthma, exposure to a moderately high concentration of inhaled antigen induces features of an acute exacerbation. The inflammatory response involves distal airways and is associated with a distinct pattern of AHR, which develops independent of the enhanced eosinophilic inflammation.




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