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Complement C3a Regulates Late Asthmatic Response and Airway Hyperresponsiveness in Mice¹

Nobuaki Mizutani^2,*, Takeshi Nabe and Shin Yoshino^*

^* Department of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan; and Department of Pharmacology, Kyoto Pharmaceutical University, Kyoto, Japan

Allergic asthma is a chronic inflammatory disorder of the airways characterized by biphasic airway obstruction and airway hyperresponsiveness. In this study, we attempted to elucidate the contribution of the complement C3a to these asthmatic symptoms. BALB/c mice sensitized by i.p. injections of OVA plus alum were challenged with OVA intratracheally four times. The fourth challenge caused a biphasic asthmatic response peaking at 10 min and 3–4 h, as well as airway hyperresponsiveness to methacholine. Histological examination revealed increased expression of C3a receptors in the lung on the fourth challenge. Additionally, the C3 level in serum 4 h after the fourth challenge was significantly reduced compared with that before the challenge. When a C3a receptor antagonist, SB290157, was administered i.p. 30 min before the fourth challenge, the late-phase asthmatic response and airway hyperresponsivness induced by the fourth challenge were significantly inhibited, although the early-phase response was not influenced. In bronchoalveolar lavage fluid, neutrophil infiltration 24 h after the fourth challenge was reduced by the treatment. On the other hand, SB290157 suppressed the increased expression of IL-1β in the lung in this model, and the intratracheal administration of IL-1β induced airway obstruction, airway hyperresponsiveness, and neutrophil infiltration in normal mice. These results illustrate that C3a is involved in the development of the late asthmatic response and airway hyperresponsiveness. The mechanism leading to the development of these symptoms may correlate with the recruitment of neutrophils and/or the production of IL-1β induced by C3a.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported in part by a Grant-in-Aid for Young Scientists (B) (20790121) from the Ministry of Education, Science, Sport, and Culture of Japan.

² Address correspondence and reprint requests to Dr. Nobuaki Mizutani, Department of Pharmacology, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe 658-8558, Japan. E-mail address: mizutani{at}kobepharma-u.ac.jp

³ Abbreviations used in this paper: BALF, bronchoalveolar lavage fluid; MCh, methacholine; PAS, periodic acid-Schiff; sRaw, specific airway resistance.