Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response
Tao Peng, … , Stephen Squinto, Yi Wang
Tao Peng, … , Stephen Squinto, Yi Wang
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1590-1600. https://doi.org/10.1172/JCI22906.
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Role of C5 in the development of airway inflammation, airway hyperresponsiveness, and ongoing airway response

Abstract

The role of complement component C5 in asthma remains controversial. Here we examined the contribution of C5 at 3 critical checkpoints during the course of disease. Using an mAb specific for C5, we were able to evaluate the contribution of C5 during (a) the initiation of airway inflammation, (b) the maintenance of airway hyperresponsiveness (AHR), and (c) sustainment of an ongoing airway response to allergen provocation. Our results indicate that C5 is probably activated intrapulmonarily after infections or exposures to allergen and C5 inhibition has profound effects at all 3 critical checkpoints. In contrast to an earlier report, C5-deficient mice with established airway inflammation did not have elevated AHR to nonspecific stimuli. In the presence of airway inflammation, C5a serves as a direct link between the innate immune system and the development of AHR by engaging directly with its receptors expressed in airways. Through their powerful chemotactic and cell activation properties, both C5a and C5b-9 regulate the downstream inflammatory cascade, which results in a massive migration of inflammatory cells into the bronchial airway lumen and triggers the release of multiple harmful inflammatory mediators. This study suggests that targeting C5 is a potential clinical approach for treating patients with asthma.

Authors

Tao Peng, Liming Hao, Joseph A. Madri, Xiao Su, Jack A. Elias, Gregory L. Stahl, Stephen Squinto, Yi Wang

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Airway response to OVA provocation and definition of 3 critical checkpoi...
Airway response to OVA provocation and definition of 3 critical checkpoints. (A) Representative DCP results indicating the longitudinal changes in sRaw. After aerosol challenge with 5% OVA for 10 minutes, the appearance of EAR was observed at 15 minutes, followed by the LAR at 5 hours. (B) Three critical points during the course of disease. Checkpoint 1: Anti-C5 mAb was given by i.p. injection on days 25, 29, and 31. Analysis of lower airway functions and quantification of airway inflammation were evaluated 5 hours after aerosol challenge with 5% OVA on day 32. Checkpoint 2: Anti-C5 mAb was given by i.p. injection on day 33, after recovery from the first airway response on day 32. AHR was assessed by evaluating the changes in RL and Cdyn from baseline in response to aerosol Mch challenges on day 35. Checkpoint 3: C5 inhibition was given by either i.v. or aerosol administration of BB5.1 during EAR on day 35. Lower airway function was determined during the peak of LAR, 5 hours after 5% OVA provocation.