Intranasal administration of recombinant progranulin inhibits bronchial smooth muscle hyperresponsiveness in mouse allergic asthma.
Am J Physiol Lung Cell Mol Physiol
; 314(1): L215-L223, 2018 01 01.
Article
em En
| MEDLINE
| ID: mdl-28982738
ABSTRACT
Progranulin (PGRN) is a growth factor with multiple biological functions and has been suggested as an endogenous inhibitor of Tumor necrosis factor-α (TNF-α)-mediated signaling. TNF-α is believed to be one of the important mediators of the pathogenesis of asthma, including airway hyperresponsiveness (AHR). In the present study, effects of recombinant PGRN on TNF-α-mediated signaling and antigen-induced hypercontractility were examined in bronchial smooth muscles (BSMs) both in vitro and in vivo. Cultured human BSM cells (hBSMCs) and male BALB/c mice were used. The mice were sensitized and repeatedly challenged with ovalbumin antigen. Animals also received intranasal administrations of recombinant PGRN into the airways 1 h before each antigen inhalation. In hBSMCs, PGRN inhibited both the degradation of IκB-α (an index of NF-κB activation) and the upregulation of RhoA (a contractile machinery-associated protein that contributes to the BSM hyperresponsiveness) induced by TNF-α, indicating that PGRN has an ability to inhibit TNF-α-mediated signaling also in the BSM cells. In BSMs of the repeatedly antigen-challenged mice, an augmented contractile responsiveness to acetylcholine with an upregulation of RhoA was observed both the events were ameliorated by pretreatments with PGRN intranasally. Interestingly, a significant decrease in PGRN expression was found in the airways of the repeatedly antigen-challenged mice rather than those of control animals. In conclusion, exogenously applied PGRN into the airways ameliorated the antigen-induced BSM hyperresponsiveness, probably by blocking TNF-α-mediated response. Increasing PGRN levels might be a promising therapeutic for AHR in allergic asthma.
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MEDLINE
Assunto principal:
Hipersensibilidade Respiratória
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Asma
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Proteínas Recombinantes
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Brônquios
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Hiper-Reatividade Brônquica
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Peptídeos e Proteínas de Sinalização Intercelular
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Músculo Liso
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article