2018年1月
Intranasal administration of recombinant progranulin inhibits bronchial smooth muscle hyperresponsiveness in mouse allergic asthma
AMERICAN JOURNAL OF PHYSIOLOGY-LUNG CELLULAR AND MOLECULAR PHYSIOLOGY
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- 巻
- 314
- 号
- 1
- 開始ページ
- L215
- 終了ページ
- L223
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1152/ajplung.00575.2016
- 出版者・発行元
- AMER PHYSIOLOGICAL SOC
Progranulin (PGRN) is a growth factor with multiple biological functions and has been suggested as an endogenous inhibitor of Tumor necrosis factor-alpha (TNF-alpha)-mediated signaling. TNF-alpha 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-alpha-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 I kappa B-alpha (an index of NF-kappa B activation) and the upregulation of RhoA (a contractile machinery-associated protein that contributes to the BSM hyperresponsiveness) induced by TNF-alpha, indicating that PGRN has an ability to inhibit TNF-alpha -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-alpha -mediated response. Increasing PGRN levels might be a promising therapeutic for AHR in allergic asthma.
- リンク情報
- ID情報
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- DOI : 10.1152/ajplung.00575.2016
- ISSN : 1040-0605
- eISSN : 1522-1504
- PubMed ID : 28982738
- Web of Science ID : WOS:000426199600006