Semaphorin 3A Is Effective in Reducing Both Inflammation and Angiogenesis in a Mouse Model of Bronchial Asthma
Semaphorin 3A Is Effective in Reducing Both Inflammation and Angiogenesis in a Mouse Model of Bronchial Asthma
复制标题
DOI：
10.3389/fimmu.2019.00550
复制
发表时间：
2019-03-22
影响因子：
7.3
通讯作者：
Vadasz, Zahava
中科院分区：
文献类型：
--
作者：
Adi, Sabag D.;Eiza, Nasren;Vadasz, Zahava
信号蛋白3A （sema3A）属于免疫信号蛋白亚家族，其功能是调节免疫介导的炎症。Sema3A是T调节性细胞和B调节性细胞上的膜相关分子。由于它能瞬间连接到这些细胞的表面，因此被认为是评估其功能状态的有用标记物。在早期研究中，我们发现哮喘患者血清中sema3A浓度降低以及Treg细胞表达降低与哮喘疾病严重程度相关。重组sema3A刺激Treg细胞诱导FoxP3和IL-10表达显著增加。为了了解sema3A是否对哮喘患者有益，我们在哮喘小鼠模型中评估了sema3A注射的效果。BALB\c小鼠先用卵清蛋白(OVA) +佐剂致敏15天，然后连续5天吸入OVA气雾剂。在上述每一天的气道致敏后4小时，其中15只小鼠每只腹腔注射50 μ g重组人sema3A-FR，其余15只小鼠注射类似纯化的载体。5 d后处死小鼠，收集支气管肺泡灌洗液（BAL），进行福尔马林固定肺活检。在sema3A治疗的小鼠中，只有20%的细支气管和小动脉被炎症细胞浸润，而对照组为90% （p = 0.0079）。此外，与sema3A处理小鼠相比，对照组的嗜酸性粒细胞浸润也显著增加。在sema3A处理的小鼠中，我们注意到BAL中只有少量的单核细胞和中性粒细胞，而在对照小鼠中，BAL中富含单核细胞和中性粒细胞。最后，在对照小鼠中，与sema3A处理的小鼠相比，血管生成明显增加，这可以从sema3A处理小鼠肺部微血管浓度降低中得到证明。综上所述，我们发现在该哮喘模型中，sema3A作为哮喘相关炎症的有效抑制因子，具有进一步开发作为哮喘治疗新药物的潜力。
Semaphorin 3A (sema3A) belongs to the sub-family of the immune semaphorins that function as regulators of immune-mediated inflammation. Sema3A is a membrane associated molecule on T regulatory cells and on B regulatory cells. Being transiently ligated to the cell surface of these cells it is suggested to be a useful marker for evaluating their functional status. In earlier studies, we found that reduced sema3A concentration in the serum of asthma patients as well as reduced expression by Treg cells correlates with asthma disease severity. Stimulation of Treg cells with recombinant sema3A induced a significant increase in FoxP3 and IL-10 expression. To find out if sema3A can be of benefit to asthma patients, we evaluated the effect of sema3A injection in a mouse model of asthma. BALB\c-mice were sensitized using ovalbumin (OVA) + adjuvant for 15 days followed by OVA aerosol inhalation over five consecutive days. Four hours following air ways sensitization on each of the above days- 15 of these mice were injected intraperitoneally with 50 mu g per mouse of recombinant human sema3A-FR and the remaining 15 mice were injected with a similarly purified vehicle. Five days later the mice were sacrificed, broncheo-alveolar lavage (BAL) was collected and formalin-fixed lung biopsies taken and analyzed. In sema3A treated mice, only 20% of the bronchioles and arterioles were infiltrated by inflammatory cells as compared to 90% in the control group (p = 0.0079). In addition, eosinophil infiltration was also significantly increased in the control group as compared with the sema3A treated mice. In sema3A treated mice we noticed only a small number of mononuclear and neutrophil cells in the BAL while in the control mice, the BAL was enriched with mononuclear and neutrophil cells. Finally, in the control mice, angiogenesis was significantly increased in comparison with sema3A treated mice as evidenced by the reduced concentration of microvessels in the lungs of sema3A treated mice. To conclude, we find that in this asthma model, sema3A functions as a potent suppressor of asthma related inflammation that has the potential to be further developed as a new therapeutic for the treatment of asthma.