Decrease in airway mucous gene expression caused by treatment with anti-tumor necrosis factor alpha in a murine model of allergic asthma.
Decrease in airway mucous gene expression caused by treatment with anti-tumor necrosis factor alpha in a murine model of allergic asthma.
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DOI：
10.1016/s1081-1206(10)60528-5
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Li XM
中科院分区：
文献类型：
--
作者：
Busse PJ;Zhang TF;Schofield B;Kilaru S;Patil S;Li XM
粘液分泌过多增加哮喘的发病率和死亡率。一些哮喘患者支气管肺泡液、痰液和单核细胞膜中的肿瘤坏死因子α (TNF-α)水平升高。在这些患者中，抗tnf -α降低了哮喘发作并改善了1秒内的用力呼气量。抗tnf -α是否减少粘膜细胞化生或增生尚未评估。目的探讨抗tnf -α在大鼠黏膜高分泌中的作用。腹腔致敏和气管致敏BALB/c小鼠在致敏和致敏前或仅致敏前分别给予250 μg抗tnf -α。对照组进行假治疗。肿瘤坏死因子受体（TNFR）小鼠（TNFR−/−和TNFR+/+）被相同地致敏和激发。最后一次刺激72小时后，记录气道压力时间指数（APTI），衡量气道高反应性。通过定量聚合酶链反应检测上皮细胞粘液诱导基因mucc - 5ac和支气管上皮细胞的周期性酸希夫（PAS）染色百分比，观察粘膜细胞化生。在TNF-α培养前，用NF-κB抑制剂预处理人气道细胞系（组成型表达MUC-5AC）。抗tnf -α处理BALB/c小鼠在致敏和攻毒前（4.9 [1.14],P = 0.007; 28.9% [6.8%], P < 0.001; 545.8 [104.5] cm H2O/s, P < 0.001）和单独攻毒前(9.3 [1.8],P = 0.03; 43.6% [10.7%], P = 0.009；分别为20.9[3.9]、82.4%[1.8%]和1055 [30.6]cm H2O/s, P = 0.06)。与卵清蛋白致敏或TNFR+/+致敏小鼠（18.4 [2.5],P < .001）相比，卵清蛋白致敏或TNFR - / -激发小鼠的MUC-5AC表达降低（2.41[0.4]）。TNF-α -诱导的MUC-5AC在人气道培养物中的表达在NF-κB抑制剂预处理后明显降低。在哮喘小鼠模型中，抗tnf -α治疗可减少气道粘膜细胞化生，这可能是其作为哮喘治疗的有益作用的部分基础。
Mucous hypersecretion increases asthma morbidity and mortality. Tumor necrosis factor α (TNF-α) levels are elevated in bronchoalveolar fluid, sputum, and monocyte membranes in some patients with asthma. Anti–TNF-α decreased asthma exacerbations and improved forced expiratory volume in 1 second in these patients. Whether anti–TNF-α reduces mucous cell metaplasia or hyperplasia has not been evaluated. To investigate the role of anti–TNF-α in mucous hypersecretion. BALB/c mice sensitized intraperitoneally and challenged intratracheally with ovalbumin were treated with 250 μg of anti–TNF-α before ovalbumin sensitization and challenge or before only ovalbumin challenge. Control groups were sham treated. The tumor necrosis factor receptor (TNFR) mice (TNFR−/−and TNFR+/+) were identically sensitized and challenged. Seventy-two hours after the final challenge, the airway pressure time index (APTI), which measures airway hyperresponsiveness, was recorded. Mucous cell metaplasia was accessed by quantitative polymerase chain reaction for MUC-5AC (the epithelial cell mucous–inducing gene) and the percentage of periodic acid–Schiff (PAS) staining of bronchial epithelial cells. A human airway cell line (constitutively expressing MUC-5AC) was pretreated with a NF-κB inhibitor before TNF-α culture. The mean (SE) fold change of MUC-5AC expression (compared with naive controls), the percentage of PAS-positive bronchiole epithelial cells, and the APTI decreased in BALB/c mice treated with anti–TNF-α before sensitization and challenge (4.9 [1.14], P = .007; 28.9% [6.8%], P < .001; and 545.8 [104.5] cm H2O/s, P < .001, respectively) and before challenge alone (9.3 [1.8], P = .03; 43.6% [10.7%], P = .009; and 896.8 [81.23] cm H2O/s, P = .06, respectively) compared with sham-treated mice (20.9 [3.9], 82.4% [1.8%], and 1,055 [30.6] cm H2O/s, respectively). MUC-5AC expression decreased in ovalbumin sensitized or challenged TNFR−/− (2.41 [0.4]) compared with ovalbumin sensitized or challenged TNFR+/+ mice (18.4 [2.5], P < .001). TNF-α–induced MUC-5AC expression in human airway culture significantly decreased with pretreatment of a NF-κB inhibitor. Anti–TNF-α treatment reduces airway mucous cell metaplasia in a mouse model of asthma, which may in part underlie its beneficial effect as asthma therapy.