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 activated serum (ZAS) and purified rat C5a des Arg, in order to determine the influence of complement activation on allergic airway disorders.The intratracheal administration of ovalbumin (OA) to OA-sensitized rats generated two phases of airway response, an immediate airway response (IAR) occurring within 15 min and a late airway response (LAR) beginning 4-6 h after the allergen challenge. The simultaneous administration of ZAS and OA into the trachea generated a sustained elevation of airway resistance (Raw) following IAR, while that of OA or ZAS alone resulted in Raw returning nearly to the baseline just after the IAR. The elevation of Raw after the combined 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 plus C5a resulted in a higher IAR than OA plus ZAS, and also caused an early animal 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 infiltration of inflammatory cells into the bronchial submucosal tissue, with a predominance of neutrophils and fewer eosinophils. On the other hand, a histological examination after the OA and ZAS challenge showed more severe infiltration of granulocytes into the bronchial submucosal tissue than that with OA or ZAS alone. The challenge with OA plus C5a was associated with severe perivascular leakage in the lungs and the combined pretreatment with both the antagonists led to a marked reduction in perivascular leakage. The quantitation of N-acetyl-leukotriene E(4) (N-Ac-LTE(4)), a major metabolite of cysteinyl-leukotrienes (cysLTs), in the bile indicated a significantly greater and longer excretion of cysLTs, from 1 to 6 h after the combined challenge, than that after either OA or ZAS alone. This suggested a prolonged generation 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.
Kodani
M
M
Department of Pharmacology, School of Pharmaceutical Sciences, Fukuoka University, 814-0180, Fukuoka, Japan.
Sakata
N
N
Takano
Y
Y
Kamiya
H
H
Katsuragi
T
T
Hugli
T E
TE
Abe
M
M
D000403:Airway Resistance / Q000276:immunology; D000818:Animals; D000941:Antigens / Q000008:administration & dosage* / Q000276:immunology; D001646:Bile / Q000378:metabolism; D002867:Chromones / Q000008:administration & dosage; D015936:Complement C5a / Q000008:administration & dosage*; D015937:Complement C5a, des-Arginine / Q000008:administration & dosage; D003545:Cysteine / Q000096:biosynthesis* / Q000502:physiology; D004155:Diphenhydramine / Q000008:administration & dosage; D006634:Histamine H1 Antagonists / Q000008:administration & dosage; D006969:Hypersensitivity, Immediate / Q000276:immunology; D018836:Inflammation Mediators / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D007442:Intubation, Intratracheal; D020024:Leukotriene Antagonists; D017998:Leukotriene D4 / Q000378:metabolism; D017999:Leukotriene E4 / Q000031:analogs & derivatives* / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis* / Q000502:physiology; D008168:Lung / Q000276:immunology* / Q000473:pathology; D008297:Male; D008565:Membrane Proteins; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011914:Rats, Inbred BN; D018077:Receptors, Leukotriene; D015054:Zymosan / Q000008:administration & dosage
D000941:Antigens; D002867:Chromones; D015937:Complement C5a, des-Arginine; D006634:Histamine H1 Antagonists; D018836:Inflammation Mediators; D020024:Leukotriene Antagonists; D015289:Leukotrienes; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; C112381:cysteinyl-leukotriene; D017998:Leukotriene D4; D017999:Leukotriene E4; C047630:N-acetylleukotriene E4; D015936:Complement C5a; D004155:Diphenhydramine; D010047:Ovalbumin; D015054:Zymosan; C412375:cysteinyl leukotriene receptor 2; D003545:Cysteine; C083169:leukotriene D4 receptor; C047681:pranlukast