Objective: To investigate the therapeutic effects of givinostat, a histone deacetylase inhibitor (HDACI), on the development of chronic asthma with airway inflammation, airway remodeling and airway hyperresponsiveness (AHR). Methods: BALB/C mice were randomly divided into control group, asthma group, dexamethasone group and givinostat group (n=12 per group). AHR was assessed. Total cell numbers and differential counts, interleukin-4(IL-4), interleukin-5(IL-5) and interferon-γ (IFNγ) levels in the bronchoalveolar lavage fluid (BALF) were measured in the above 4 groups. The pathology of lung tissue was evaluated. Immunohistochemical (IHC) staining and Western blot were used to detect α smooth muscle actin(α-SMA) and transforming growth factor-β1(TGFβ1). Results: Compared with the asthma only group, givinostat treatment relieved airway resistance (2.96±1.01 vs 6.50±0.79, P<0.05). Total inflammatory cells [(33.04±5.62)×10(4)/ml vs (98.04±9.27)×10(4)/ml, P<0.01], eosinophil cells [(9.17±2.33)×10(4)/ml vs(37.64±6.98)×10(4)/ml, P<0.01], IL-4 [(10.12±2.98)ng/ml vs (16.88±2.78)ng/ml, P<0.05] and IL-5 [(27.09±3.62)ng/ml vs (37.86±7.34)ng/ml, P<0.05] levels were all reduced in givinostat group, while IFNγ [(91.86±23.73)pg/ml vs (60.49±11.88)pg/ml, P>0.05] was enhanced in BALF. Inflammatory cell infiltration around the airway was reduced, with decreased inflammatory cell score[(1.60±0.69)points vs (3.40±0.68) points, P<0.01] and inflammatory cell number (111.65±31.41 vs 601.25±186.85, P<0.01). The goblet cell metaplasia [(26.36±2.33)% vs (57.21±11.56)%] and collagen deposition area [(52.77±7.58)μm(2)/μm vs (111.81±12.40)μm(2)/μm] were obviously reduced (P<0.01). The expressions of α-SMA and TGFβ1 in the lung tissue were both significantly decreased (P<0.01). Conclusion: Givinostat treatment can reduce airway inflammation, airway remodeling and airway hyperresponsiveness in chronic asthma. Its effect is comparable to that of glucocorticoid hormone treatment.
目的：探讨组蛋白去乙酰化酶抑制剂givinostat对支气管哮喘(以下简称哮喘)小鼠气道炎症、气道重塑和气道高反应的干预作用。方法： BALB/C小鼠按随机数字表法随机分为健康对照组、哮喘组、地塞米松干预组和givinostat干预组，每组12只。测4组小鼠气道高反应性；计数4组小鼠支气管肺泡灌洗液(BALF)中细胞总数和分类细胞数，以及IL－4、IL－5和IFNγ水平；取4组小鼠肺组织，观察病理改变；免疫组化和Western blot检测转化生长因子－β1(TGFβ1)和α－平滑肌肌动蛋白(α－SMA)表达。结果：与哮喘组比，givinostat干预组小鼠气道反应性降低(2.96±1.01比6.50±0.79，P<0.05)；BALF中炎性细胞总数[(33.04±5.62)×10(4)/ml比(98.04±9.27)×10(4)/ml]和嗜酸性粒细胞数[(9.17±2.33)×10(4)/ml比(37.64±6.98)×10(4)/ml]减少(P<0.01)，IL－4[(10.12±2.98)ng/ml比(16.88±2.78)ng/ml]和IL－5[(27.09±3.62)ng/ml比(37.86±7.34)ng/ml]水平下降(P<0.05)，IFNγ[(91.86±23.73)pg/ml比(60.49±11.88)pg/ml]水平升高(P>0.05)；肺组织气道周围炎性细胞浸润减轻，炎症评分[(1.60±0.69)分比(3.40±0.68)分]及炎性细胞数[(111.65±31.41)个比(601.25±186.85)个]降低(P<0.01)；杯状细胞化生减少[(26.36±2.33)%比(57.21±11.56)%，P<0.01]，胶原沉积面积减少[(52.77±7.58)μm(2)/μm比(111.81±12.40)μm(2)/μm，P<0.01]；肺组织中α－SMA和TGFβ1表达下降(P<0.01)。结论： givinostat能缓解哮喘气道炎症、气道重塑和气道高反应，且疗效与糖皮质激素相似。.
Keywords: Airway resistance; Asthma; Histone deacetylase inhibitor; Inflammation.