Leukotriene B4 mediates substance P-induced granulocyte infiltration into mouse skin. Comparison with antigen-induced granulocyte infiltration.
Substance P, a potent proinflammatory peptide present in sensory neurons, causes granulocyte (neutrophil and eosinophil) infiltration into mouse skin by inducing mast cell degranulation. However, the mediator responsible for this granulocyte infiltration has not been determined. In this study, we determined which mediator from cutaneous mast cells mediates substance P-induced granulocyte infiltration in the skin by the use of two mediator antagonists; one for platelet activating factor (PAF) CV-6209 and the other for leukotriene B4 (LTB4) ONO-4057. Subcutaneous injection of substance P (10(-7)-10(-5) M) caused granulocyte infiltration in the skin of BALB/c mice in a time- and concentration-dependent fashion. Pretreatment with the LTB4 antagonist decreased substance P-induced neutrophil and eosinophil infiltration into mouse skin at 6 h to the same extent that an inhibitor of mast cell degranulation, disodium cromoglycate, decreased those responses. However, pretreatment with the PAF antagonist affected neither substance P-induced neutrophil nor eosinophil infiltration at 6 h. A LTC4/D4 antagonist ONO-1078 and a histamine H1 antagonist chlorpheniramine had no effect on the granulocyte infiltration, either. The LTB4 antagonist also decreased substance P-induced neutrophil, but not eosinophil, infiltration into mouse skin at 24 h. In contrast, the PAF antagonist inhibited Ag-induced eosinophil infiltration of mouse skin, whereas the LTB4 antagonist inhibited the Ag-induced neutrophil infiltration. We conclude that LTB4 is a major mast cell-derived chemotactic mediator for initiating substance P-induced neutrophil and eosinophil infiltration into mouse skin. Our results suggest that LTB4 antagonists might be useful in preventing such neurogenic inflammation.
Iwamoto
I
I
Second Department of Internal Medicine, Chiba University School of Medicine, Japan.
Tomoe
S
S
Tomioka
H
H
Yoshida
S
S
D000818:Animals; D015550:Cell Degranulation / Q000187:drug effects; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004804:Eosinophils / Q000502:physiology*; D007975:Leukotriene B4 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000502:physiology*; D010666:Phenylpropionates / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology; D012879:Skin Physiological Phenomena; D013373:Substance P / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D010666:Phenylpropionates; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; C053321:CV 6209; C067523:ONO-LB 457; D007975:Leukotriene B4; D013373:Substance P