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Published ahead of print on June 9, 2005, doi:10.1165/rcmb.2004-0372OC

Am. J. Respir. Cell Mol. Biol., Volume 33, Number 3, September 2005, 303-314

A more recent version of this article appeared on September 1, 2005
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Submitted on November 22, 2004
Revised on June 3, 2005

Gob-5 is not Essential for Mucus Overproduction in Preclinical Murine Models of Allergic Asthma

Annette Robichaud1, Stephanie A Tuck1, Stacia Kargman1, John Tam1, Elizabeth Wong1, Mark Abramovitz1, James Mortimer1, Helen E Burston1, Paul Masson1, Deborah Slipetz1, Brian Kennedy1, Gary O'Neill1, and Steven Xanthoudakis1*

1 Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, Quebec, Canada

* To whom correspondence should be addressed. E-mail: steven_xanthoudakis{at}merck.com.

Overexpression of Gob-5 has previously been linked to goblet cell metaplasia and mucin overproduction in both in vitro and in vivomodel systems. In this study, Gob-5 knockout mice were generated and their phenotype was evaluated in two established preclinical models of allergic asthma. We sought to determine whether the Gob-5-null animals could produce less mucus in response to allergic challenge and whether this would have any impact on reducing goblet cell metaplasia and airway inflammation. We found that in the absence of a proinflammatory stimulus we could not detect an overt phenotypic difference between age and gender-matched knockout and wild-type animals. Allergic challenge with ovalbumin or intranasal administration of IL-13 produced a robust allergic response that was similar regardless of genotype. In addition, siRNA-mediated knockdown of CLCA-1 in cultured lung epithelial cells failed to reduce mucin expression in vitro. Thus, in contrast to previously published reports, our findings show that Gob-5 expression is not essential for mucin overproduction in vitro or in murine models of allergic asthma. Furthermore, we have also exploited the use of gene expression array analysis to investigate the possibility that a compensatory mechanism, involving other genes, may act to override the requirement for Gob-5-mediated mucus overproduction.




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