Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on α-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts
Bronchoalveolar lavage fluid concentrations of transforming growth factor (TGF)-β1, TGF-β2, interleukin (IL)-4 and IL-13 after segmental allergen challenge and their effects on α-smooth muscle actin and collagen III synthesis by primary human lung fibroblasts
复制标题
DOI：
10.1111/j.1365-2222.2004.01885.x
复制
发表时间：
2004-03-01
影响因子：
6.1
通讯作者：
Peters, SP
中科院分区：
文献类型：
--
作者：
Batra, V;Musani, AI;Peters, SP
哮喘气道重塑以肌成纤维细胞增生和基底膜下胶原沉积为特征。我们假设，在哮喘患者的支气管肺泡灌洗液（BAL）中，在节段性变应原激发（SAC）后，与哮喘气道重塑有关的细胞因子和生长因子增加，并且这些生长因子和细胞因子增加α-平滑肌肌动蛋白（α-SMA）。方法转化生长因子（TGF）-β 1，TGF-β 2，分别在基线、SAC后1天、1周和2周检测10例哮喘患者和9例非哮喘对照者BAL液中IL-4和IL-13水平。通过外源性添加TGF-β 1、TGF-β 2、IL-4或IL-13（浓度范围为0.01-10 ng/mL）刺激HLF融合培养物48 h。胶原蛋白III测定培养上清液和α-SMA细胞裂解物通过Western blot.Results在基线时，有哮喘和对照组之间的TGF-β 1，IL-4和IL-13的BAL液浓度没有差异，但是，非哮喘有较高的总TGF-β 2的浓度。在哮喘患者中，SAC后1天BAL液中所有四种因子的浓度均显著增加。SAC后1周，TGF-β 1、TGF-β 2和IL-13浓度恢复至基线水平，但BAL液IL-4浓度至少在2周内保持升高。TGF-β 1、TGF-β 2和IL-4显著增加成纤维细胞中的α-SMA，但只有IL-4引起胶原III合成的相应增加。IL-13对Ⅲ型胶原合成和α-SMA表达无直接影响。结论IL-4可剂量依赖性地促进α-SMA和Ⅲ型胶原合成，可能是哮喘气道重塑的重要细胞因子。TGF-β 1和TGF-β 2也可能通过刺激成纤维细胞向肌成纤维细胞的表型变化在气道重塑中发挥作用。此外，III型胶原的合成似乎不依赖于肌成纤维细胞的表型，并且明显受到不同生长因子和细胞因子的调节。
Rationale Asthmatic airway remodelling is characterized by myofibroblast hyperplasia and subbasement membrane collagen deposition. We hypothesized that cytokines and growth factors implicated in asthmatic airway remodelling are increased in bronchoalveolar lavage (BAL) fluid of asthmatics after segmental allergen challenge (SAC), and that these growth factors and cytokines increase alpha-smooth muscle actin (alpha-SMA) and collagen III synthesis by human lung fibroblasts (HLFs).Methods Transforming growth factor (TGF)-beta1, TGF-beta2, IL-4 and IL-13 levels were measured in BAL fluid from 10 asthmatics and 9 non-asthmatic controls at baseline and then 1 day, 1 week and 2 weeks after SAC. Confluent cultures of HLFs were stimulated by exogenous addition of TGF-beta1, TGF-beta2, IL-4 or IL-13 (concentration range 0.01-10 ng/mL) over 48 h. Collagen III was measured in culture supernates and alpha-SMA in cell lysates by Western blot.Results At baseline, there was no difference in BAL fluid concentrations of TGF-beta1, IL-4 and IL-13 between asthmatics and controls; however, non-asthmatics had higher concentrations of total TGF-beta2. In asthmatics, BAL fluid concentrations of all four factors increased significantly 1 day after SAC. TGF-beta1, TGF-beta2 and IL-13 concentrations returned to baseline by 1 week after SAC, but BAL fluid IL-4 concentration remained elevated for at least 2 weeks. TGF-beta1, TGF-beta2 and IL-4 significantly increased alpha-SMA in fibroblasts, but only IL-4 caused corresponding increases in collagen III synthesis. IL-13 had no direct effects on collagen III synthesis and alpha-SMA expression.Conclusions Because IL-4 caused a dose-dependent increase in alpha-SMA and collagen III synthesis, it may be an important cytokine mediating asthmatic airway remodelling. TGF-beta1 and TGF-beta2 may also play a role in airway remodelling by stimulating phenotypic change of fibroblasts to myofibroblasts. Additionally, collagen III synthesis appears to be independent of myofibroblast phenotype and is apparently regulated by different growth factors and cytokines.