Suplatast tosilate inhibits goblet-cell metaplasia of airway epithelium in sensitized mice.
BACKGROUND
IL-4 and IL-13 play a putative role in mucus hypersecretion in asthma. Suplatast tosilate prevents the synthesis of T(H2) cytokines.


OBJECTIVE
Because suplatast tosilate inhibits T(H2) cytokines but does not inhibits IFN-gamma production, we examined the effect of suplatast on IL-4- or IL-13- and ovalbumin (OVA)-induced mucin synthesis in NCI-H292 cells in vitro and in bronchi of pathogen-free BALB/c mice in vivo.


METHODS
In vitro, NCI-H292 cells were preincubated with suplatast tosilate (0.1-100 microgram/mL) 1 hour before adding human recombinant IL-4 (10 ng/mL). In vivo, mouse recombinant IL-4 or IL-13 (250 ng per/mouse) was instilled intranasally in mice pretreated with suplatast tosilate (50 mg.kg(-1).d(-1)). Mucous glycoconjugates were stained with Alcian blue (AB)/periodic acid-Schiff (PAS) stain. To evaluate effects of suplatast tosilate on goblet-cell metaplasia in OVA-sensitized mice, animals were pretreated with suplatast tosilate (1-50 mg.kg(-1).d(-1)) intragastrically. IL-4 and IL-13 were measured, and allergic inflammatory cells were analyzed in bronchoalveolar lavage fluid of OVA-sensitized mice.


RESULTS
Pretreatment with suplastast did not prevent IL-4- or IL-13-induced increase in mucous glycoconjugate production in NCI-H292 cells or in mice. OVA sensitization increased AB/PAS-stained area of the epithelium (48.1% +/- 2.4%, P <.01 compared with control mice). Suplatast tosilate inhibited OVA-induced goblet-cell metaplasia in airway epithelium in a dose-dependent fashion; 50 mg.kg(-1).d(-1) decreased the AB/PAS area to 22.7% +/- 2.7% (P <.05 compared with OVA sensitization alone). Pretreatment with suplatast tosilate also prevented OVA-induced increase in IL-4 and IL-13 levels and decreased the number of lymphocytes and eosinophils in bronchoalveolar lavage fluid (P <.05 compared with values of mice given OVA alone).


CONCLUSIONS
These results indicate that suplatast tosilate prevents allergen-induced goblet-cell metaplasia and the recruitment of eosinophils and lymphocytes into the airways. These results suggest that this effect is due to the prevention of the production of T(H2) cytokines in airways.
Shim
J J
JJ
Cardiovascular Research Institute, Department of Medicine, University of California San Francisco, USA.
Dabbagh
K
K
Takeyama
K
K
Burgel
P R
PR
Dao-Pick
T P
TP
Ueki
I F
IF
Nadel
J A
JA
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001190:Arylsulfonates / Q000494:pharmacology*; D001980:Bronchi / Q000187:drug effects*; D002460:Cell Line; D020397:Goblet Cells / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007114:Immunization; D015847:Interleukin-4 / Q000494:pharmacology; D008297:Male; D008679:Metaplasia; D051379:Mice; D008807:Mice, Inbred BALB C; D009077:Mucins / Q000096:biosynthesis / Q000187:drug effects; D010047:Ovalbumin / Q000494:pharmacology; D013452:Sulfonium Compounds / Q000494:pharmacology*
D018926:Anti-Allergic Agents; D001190:Arylsulfonates; D009077:Mucins; D013452:Sulfonium Compounds; D015847:Interleukin-4; D010047:Ovalbumin; C073028:suplatast tosilate