Department of Pulmonary and Critical Care Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Pharmacy, The Fourth Military Medical University, Xi'an, China.
PLoS One. 2013 Dec 9;8(12):e82367. doi: 10.1371/journal.pone.0082367. eCollection 2013.
Asthma is a complex and heterogeneous chronic inflammatory disorder that is associated with mucous cell metaplasia and mucus hypersecretion. Functional genomic analysis indicates that mucous cell metaplasia and mucus hypersecretion depend on members of the calcium-activated chloride channel (CLCA) gene family. It has been reported that the inhibition of CLCAs could relieve the symptoms of asthma. Thus, the mCLCA3 antibody may be a promising strategy to treat allergic diseases such as asthma.
We constructed asthmatic mouse models of OVA-induced chronic airway inflammatory disorder to study the function of the mCLCA3 antibody. Airway inflammation was measured by HE staining; goblet cell hyperplasia and mucus hypersecretion were detected by PAS staining; muc5ac, IL-13, IFN-γ levels in bronchoalveolar lavage fluid (BALF) were examined by ELISA; Goblet cell apoptosis was measured by TUNEL assay and alcian blue staining; mCLCA3, Bcl-2 and Bax expression were detected by RT-PCR, Western blotting and immunohistochemical analysis.
In our study, mice treated with mCLCA3 antibody developed fewer pathological changes compared with control mice and asthmatic mice, including a remarkable reduction in airway inflammation, the number of goblet cells and mCLCA3 expression in lung tissue. The levels of muc5ac and IL-13 were significantly reduced in BALF. We also found that the rate of goblet cell apoptosis was increased after treatment with mCLCA3 antibody, which was accompanied by an increase in Bax levels and a decrease in Bcl-2 expression in goblet cells.
Taken together, our results indicate that mCLCA3 antibody may have the potential as an effective pharmacotherapy for asthma.
哮喘是一种复杂且异质性的慢性炎症性疾病，与黏液细胞化生和黏液高分泌有关。功能基因组分析表明，黏液细胞化生和黏液高分泌依赖于钙激活氯离子通道（CLCA）基因家族的成员。据报道，CLCA 的抑制可以缓解哮喘症状。因此，mCLCA3 抗体可能是治疗哮喘等过敏性疾病的一种有前途的策略。
我们构建了 OVA 诱导的慢性气道炎症障碍哮喘小鼠模型，以研究 mCLCA3 抗体的功能。通过 HE 染色测量气道炎症；通过 PAS 染色检测杯状细胞增生和黏液高分泌；通过 ELISA 检测支气管肺泡灌洗液（BALF）中 muc5ac、IL-13、IFN-γ 水平；通过 TUNEL 检测和阿利新蓝染色测量杯状细胞凋亡；通过 RT-PCR、Western blot 和免疫组织化学分析检测 mCLCA3、Bcl-2 和 Bax 的表达。
在我们的研究中，与对照小鼠和哮喘小鼠相比，用 mCLCA3 抗体治疗的小鼠肺部组织的病理变化较少，包括气道炎症、杯状细胞数量和 mCLCA3 表达显著减少。BALF 中 muc5ac 和 IL-13 的水平明显降低。我们还发现，用 mCLCA3 抗体治疗后，杯状细胞凋亡率增加，同时杯状细胞中 Bax 水平升高，Bcl-2 表达降低。
综上所述，我们的研究结果表明，mCLCA3 抗体可能具有作为哮喘有效治疗药物的潜力。
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