Steroid-Insensitive Gene Expression of Extracellular Matrix Components and Pro-fibrotic Factors in the Lung Associated with Airway Hyperresponsiveness in Murine Asthma

• Published in: Biological & pharmaceutical bulletin 2024/01/20, Vol.47(1), pp.227-231
• Main Authors: Shimora, Hayato, Matsuda, Masaya, Takemoto, Naoki, Nomura, Miku, Hamaguchi, Junpei, Terakawa, Ryogo, Inaba, Miki, Kitatani, Kazuyuki, Nabe, Takeshi
• Format: Article
• Language: English
• Subjects: Activin; airway hyperresponsiveness; Animal models; Asthma; Dexamethasone; Drug delivery; Eosinophilia; Extracellular matrix; Fibronectin; Fibrosis; Gene expression; Genes; Glucocorticoids; Matrix metalloproteinase; Metalloproteinase; Methacholine; Ovalbumin; pro-fibrotic factor; Respiratory tract; steroid resistance; Steroids; Tissue inhibitor of metalloproteinase 1; Trachea
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b23-00768

Between 5 and 10% of asthma patients do not respond to glucocorticoid therapy. Experimental animal models are indispensable for investigating the pathogenesis of steroid-resistant asthma; however, the majority of murine asthma models respond well to glucocorticoids. We previously reported that multiple intratracheal administration of ovalbumin (OVA) at a high dose (500 µg/animal) induced steroid-insensitive airway eosinophilia and remodeling with lung fibrosis, whereas a low dose (5 µg/animal) caused steroid-sensitive responses. The aims of the present study were as follows: 1) to clarify whether airway hyperresponsiveness (AHR) in the two models is also insensitive and sensitive to a glucocorticoid, respectively, and 2) to identify steroid-insensitive genes encoding extracellular matrix (ECM) components and pro-fibrotic factors in the lung. In comparisons with non-challenged group, the 5- and 500-µg OVA groups both exhibited AHR to methacholine. Daily intraperitoneal treatment with dexamethasone (1 mg/kg) significantly suppressed the development of AHR in the 5-µg OVA group, but not in the 500-µg OVA group. Among genes encoding ECM components and pro-fibrotic factors, increased gene expressions of fibronectin and collagen types I, III, and IV as ECM components as well as 7 matrix metalloproteinases, tissue inhibitor of metalloproteinase-1, transforming growth factor-β1, and activin A/B as pro-fibrotic factors were insensitive to dexamethasone in the 500-µg OVA group, but were sensitive in the 5-µg OVA group. In conclusion, steroid-insensitive AHR developed in the 500-µg OVA group and steroid-insensitive genes encoding ECM components and pro-fibrotic factors were identified. Drugs targeting these molecules have potential in the treatment of steroid-resistant asthma.