FK506 aerosol locally inhibits antigen-induced airway inflammation in Guinea pigs.
BACKGROUND
Eosinophilic airway inflammation is a common pathological feature of asthma. It has been shown that FK506 given systemically suppresses antigen-induced airway inflammation in animal models. However, it is unknown whether inhaled FK506 can suppress the airway allergic inflammation/immune response and whether it acts locally or systemically.


METHODS
We tested the effects of oral FK506 and inhaled FK506 on antigen-induced airway inflammation in guinea pigs. The tissue and blood concentrations of FK506 given via both routes were compared. The effect of inhaled FK506 on the expression of cytokine mRNA in lung and bronchoalveolar lavage fluid (BALF) cells was also tested.


RESULTS
Both routes of administration of FK506 suppressed the airway eosinophilia in egg albumin (EA)-sensitized and -challenged animals. The effect of three inhaled puffs was almost equal to that of 1 mg/kg administered by the oral route. Following inhalation of three puffs, FK506 concentration in blood (AUC(0-24 h)) was approximately 1/21 of that following oral FK506 (1 mg/kg). After EA challenge, mRNA expression of interleukin (IL)-5, eotaxin and IL-1beta in BALF cells and IL-5 in the lung increased significantly. FK506 aerosol markedly inhibited IL-5 mRNA expression in the lung. In situ hybridization indicated that in the BALF IL-5 mRNA expression by lymphocyte-like cells was inhibited by FK506 aerosol. In addition, anti-IL-5 antibody injected intratracheally almost completely abolished eosinophilia in this model.


CONCLUSIONS
Inhaled FK506 can suppress airway inflammation in guinea pigs, where the local action, presumably the inhibition of T-cell activation/function in the lung and airways, was primarily important.
Morishita
Yoshihiko
Y
Department of Inflammation, Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan. yoshihiko_morishita@po.fujisawa.co.jp
Hirayama
Yoshitaka
Y
Miyayasu
Kikuo
K
Tabata
Kenji
K
Kawamura
Akio
A
Ohkubo
Yoshitaka
Y
Mutoh
Seitaro
S
D000280:Administration, Inhalation; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004804:Eosinophils / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D006168:Guinea Pigs; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy*; D015848:Interleukin-5 / Q000276:immunology; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D012137:Respiratory System / Q000187:drug effects*; D016559:Tacrolimus / Q000097:blood / Q000494:pharmacology*
D000906:Antibodies; D016207:Cytokines; D007166:Immunosuppressive Agents; D015848:Interleukin-5; D012333:RNA, Messenger; D016559:Tacrolimus