Role of gob-5 in mucus overproduction and airway hyperresponsiveness in asthma.
Airway hyperresponsiveness (AHR), goblet cell metaplasia, and mucus overproduction are important features of bronchial asthma. To elucidate the molecular mechanisms behind these pulmonary pathologies, we examined for genes preferentially expressed in the lungs of a murine model of allergic asthma by using suppression subtractive hybridization (SSH). We identified a gene called gob-5 that had a selective expression pattern in the airway epithelium with AHR. Here, we show that gob-5, a member of the calcium-activated chloride channel family, is a key molecule in the induction of murine asthma. Intratracheal administration of adenovirus-expressing antisense gob-5 RNA into AHR-model mice efficiently suppressed the asthma phenotype, including AHR and mucus overproduction. In contrast, overexpression of gob-5 in airway epithelia by using an adenoviral vector exacerbated the asthma phenotype. Introduction of either gob-5 or hCLCA1, the human counterpart of gob-5, into the human mucoepidermoid cell line NCI-H292 induced mucus production as well as MUC5AC expression. Our results indicated that gob-5 may play a critical role in murine asthma, and its human counterpart hCLCA1 is therefore a potential target for asthma therapy.
Nakanishi
A
A
Discovery Research Laboratories II, Pharmaceutical Discovery Research Division, Takeda Chemical Industries Ltd., 10 Wadai, Tsukuba, Ibaraki 300-4293, Japan. Nakanishi_Atsushi@takeda.co.jp
Morita
S
S
Iwashita
H
H
Sagiya
Y
Y
Ashida
Y
Y
Shirafuji
H
H
Fujisawa
Y
Y
Nishimura
O
O
Fujino
M
M
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics / Q000378:metabolism*; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D004848:Epithelium / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009088:Mucoproteins / Q000235:genetics / Q000378:metabolism*; D009093:Mucus / Q000378:metabolism*; D010641:Phenotype; D016372:RNA, Antisense / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012137:Respiratory System / Q000378:metabolism* / Q000503:physiopathology*; D014161:Transduction, Genetic; D014162:Transfection
C492109:CLCA1 protein, human; D018118:Chloride Channels; C116464:Clca3a1 protein, mouse; D009088:Mucoproteins; D016372:RNA, Antisense; D012333:RNA, Messenger