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Published ahead of print on September 18, 2003, doi:10.1164/rccm.200306-739OC

Am. J. Respir. Crit. Care Med., Volume 168, Number 11, December 2003, 1333-1341

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Submitted on June 4, 2003
Accepted on September 8, 2003

Inhibition of Complement Activation Decreases Airway Inflammation and Hyperresponsiveness

Erwin W Gelfand1*, Christian Taube1, Yeong-Ho Rha1, Katsuyuki Takeda1, Jung Won Park1, Anthony Joetham1, Annette Balhorn1, Azzeddine Dakhama1, Patricia C Giclas1, and V. Michael Holers2

1 Pediatrics, National Jewish Medical and Research Center, Denver, CO, USA, 2 Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO, USA

* To whom correspondence should be addressed. E-mail: gelfande{at}njc.org.

Studies in murine models have suggested the involvement of the complement anaphylatoxins (C3a and C5a) in the development of allergic asthma. We investigated the effects of inhibiting complement activation after sensitization but prior to allergen challenge on the development of allergic airway inflammation and airway hyperresponsiveness (AHR). To prevent complement activation, we used a recombinant soluble form of the mouse membrane complement inhibitor Crry (complement receptor-related gene y) fused to the IgG1 hinge, CH2 and CH3 domains (Crry-Ig), which has decay-accelerating activity for both the classical and alternative pathways of complement as well as cofactor activity for factor I-mediated cleavage of C3b and C4b. C57BL/6 mice were sensitized (days 1 and 14) and challenged (days 24-26) with ovalbumin (OVA). Crry-Ig was administered after allergen sensitization either as an intraperitoneal injection or by nebulization prior to allergen challenge. Crry-Ig significantly prevented the development of AHR, decreased airway and lung eosinophilia as well as the numbers of lung lymphocytes, decreased levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid and decreased serum OVA-specific IgE and IgG1. These results suggest that prevention of complement activation may have a therapeutic role in the treatment of allergic airway inflammation and asthma in sensitized individuals.
Key words: mouse model, lung function, lymphocytes, cytokines




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