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Published ahead of print on April 28, 2005, doi:10.1165/rcmb.2004-0347OC
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American Journal of Respiratory Cell and Molecular Biology. Vol. 33, pp. 178-185, 2005
© 2005 American Thoracic Society
DOI: 10.1165/rcmb.2004-0347OC

Expression and Regulation of CC Class Chemokines in the Dystrophic (mdx) Diaphragm

Alexandre Demoule, Maziar Divangahi, Gawiyou Danialou, Dusanka Gvozdic, Gary Larkin, Weisheng Bao and Basil J. Petrof

Meakins-Christie Laboratories, McGill University, Montreal; and Respiratory Division, McGill University Health Centre, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Basil J. Petrof, M.D., Respiratory Division, Room L411, Royal Victoria Hospital, 687 Pine Ave. West, Montreal, H3A 1A1, PQ Canada. E-mail: basil.petrof{at}mcgill.ca

In the murine (mdx) model of Duchenne muscular dystrophy, dystrophic changes are much more severe in the diaphragm than in limb muscles, and the diaphragm more closely resembles the human disease phenotype. Chemokines could play a central role in governing such phenotypic differences, as inflammation is an important disease modifier. Here we report that CC chemokine receptors (CCRs 1, 2, 3, 5) and ligands (macrophage inflammatory protein-1{alpha}, RANTES) are expressed at higher levels in dystrophic than in wild-type muscles across age groups (6, 12, and 24 wk). Moreover, chemokine ligand expression and muscle inflammation are significantly higher in dystrophic diaphragms than in limb muscles of the same animals. In vitro, CCR1 is constitutively expressed by cultured primary diaphragmatic myotubes. Stimulation of myotubes by proinflammatory cytokines (tumor necrosis factor-{alpha}, interleukin-1{alpha}, interferon-{gamma}) found within the in vivo dystrophic muscle environment, upregulates CCR1 in mdx and wild-type cultures, and also increases expression of its ligand RANTES to a significantly greater degree in the mdx group. Taken together, our results suggest that CC chemokines may play an important role in sustaining inflammation within the mdx diaphragm, which could help acount for its more severe phenotype and also offer a target for therapeutic intervention in Duchenne patients.

Key Words: chemokine receptors • Duchenne muscular dystrophy • inflammation • macrophage inflammatory protein-1{alpha} • RANTES • skeletal muscle




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