Intratracheal administration of anaphylatoxin C5a potentiates antigen-induced pulmonary reactions through the prolonged production of cysteinyl-leukotrienes

The effects of intratracheal administration of anaphylatoxin C5a on airway inflammation have been studied using two sources of material, zymosan activ ated serum (ZAS) and purified rat C5a des Arg, in order to determine the in fluence of complement activation on allergic airway disorders. The intratracheal administration of ovalbumin (OA) to OA-sensitized rats ge nerated two phases of airway response, an immediate airway response (IAR) o ccurring within 15 min and a late airway response (LAR) beginning 4-6 h aft er the allergen challenge. The simultaneous administration of ZAS and OA in to the trachea generated a sustained elevation of airway resistance (Raw) f ollowing IAR, while that of OA or ZAS alone resulted in Raw returning nearl y to the baseline just after the IAR. The elevation of Raw after the combin ed challenge of OA and ZAS was significantly inhibited by pretreatment with a CysLT(1) receptor antagonist, pranlukast 30 mg/kg, but after that OA or ZAS alone was not significantly inhibited by pranlukast. The intratracheal administration of purified C5a produced an airway response that was similar to, but higher than, that evoked by ZAS. Namely, the challenge with OA plu s C5a resulted in a higher IAR than OA plus ZAS, and also caused an early a nimal death up to 6 h, which was prevented by a combined pretreatment with pranlukast and the H-1 receptor antagonist, diphenhydramine. A histological examination at 6 h after the OA challenge identified an infi ltration of inflammatory cells into the bronchial submucosal tissue, with a predominance of neutrophils and fewer eosinophils. On the other hand, a hi stological examination after the OA and ZAS challenge showed more severe in filtration of granulocytes into the bronchial submucosal tissue than that w ith OA or ZAS alone. The challenge with OA plus C5a was associated with sev ere perivascular leakage in the lungs and the combined pretreatment with bo th the antagonists led to a marked reduction in perivascular leakage. The q uantitation of N-acetyl-leukotriene E-4 (N-Ac-LTE4), a major metabolite of cysteinyl-leukotrienes (cysLTs), in the bile indicated a significantly grea ter and longer excretion of cysLTs, from 1 to 6 h after the combined challe nge, than that after either OA or ZAS alone. This suggested a prolonged gen eration of cysLTs in the lung by the combined challenge. In conclusion, our findings suggest that anaphylatoxin C5a may mediate the airway inflammatory response induced by a specific antigen challenge partly through a prolonged production of cysLTs and the release of histamine. (C) 2000 Elsevier Science B.V. All rights reserved.