The TGF-beta-Pseudoreceptor BAMBI is strongly expressed in COPD lungs and regulated by nontypeable Haemophilus influenzae
The TGF-beta-Pseudoreceptor BAMBI is strongly expressed in COPD lungs and regulated by nontypeable Haemophilus influenzae
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DOI：
10.1186/1465-9921-11-67
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发表时间：
2010-05-31
影响因子：
5.8
通讯作者：
Goldmann, Torsten
中科院分区：
文献类型：
--
作者：
Droemann, Daniel;Rupp, Jan;Goldmann, Torsten
背景资料：无法分型的流感嗜血杆菌（NTHI）可能在慢性阻塞性肺疾病（COPD）的发病机制中起感染性触发作用。关于急性和持续性感染对组织重塑和修复因子（如转化生长因子（TGF）-β）的影响，很少有数据可供使用。方法：从COPD患者和对照组获得的肺组织中的NTHI感染进行了研究，在体内和使用体外模型。用两种不同的临床分离株进行感染实验。使用原位杂交（ISH）在未刺激的和体外感染的肺组织中进行NTHI检测。为了表征TGF-β信号传导分子，进行转录组阵列。TGF-假受体BMP和激活素膜结合抑制剂（BAMBI）的表达采用免疫组织化学（IHC）、ISH和PCR进行分析。结果：COPD患者NTHI感染率为38%，对照组为0%（p <0.05），COPD患者NTHI感染率为38%（p < 0.05）。转录组阵列显示TGF-β受体1和2以及Smad-3表达没有显著变化，而证明了COPD肺组织体外感染后BAMBI的强表达和上调。BAMBI在肺泡巨噬细胞（AM）上广泛表达，在肺泡上皮细胞（AEC）上表达程度较低。肺组织上清液中细胞因子浓度的测量揭示了TGF-β表达的降低（p < 0.05）以及强烈的促炎反应（p < 0.01）。结论：我们首次显示了TGF假受体BAMBI在人肺中的表达，其在体内和体外COPD肺组织中响应于NTHI感染而上调。NTHI介导的促炎细胞因子的诱导和TGF-β表达的抑制的组合可以影响炎症诱导的组织重塑。
Background: Nontypeable Haemophilus influenzae (NTHI) may play a role as an infectious trigger in the pathogenesis of chronic obstructive pulmonary disease (COPD). Few data are available regarding the influence of acute and persistent infection on tissue remodelling and repair factors such as transforming growth factor (TGF)-beta.Methods: NTHI infection in lung tissues obtained from COPD patients and controls was studied in vivo and using an in vitro model. Infection experiments were performed with two different clinical isolates. Detection of NTHI was done using in situ hybridization (ISH) in unstimulated and in in vitro infected lung tissue. For characterization of TGF-beta signaling molecules a transcriptome array was performed. Expression of the TGF-pseudoreceptor BMP and Activin Membrane-bound Inhibitor (BAMBI) was analyzed using immunohistochemistry (IHC), ISH and PCR. CXC chemokine ligand (CXCL)-8, tumor necrosis factor (TNF)-alpha and TGF-beta expression were evaluated in lung tissue and cell culture using ELISA.Results: In 38% of COPD patients infection with NTHI was detected in vivo in contrast to 0% of controls (p < 0.05). Transcriptome arrays showed no significant changes of TGF-beta receptors 1 and 2 and Smad-3 expression, whereas a strong expression of BAMBI with upregulation after in vitro infection of COPD lung tissue was demonstrated. BAMBI was expressed ubiquitously on alveolar macrophages (AM) and to a lesser degree on alveolar epithelial cells (AEC). Measurement of cytokine concentrations in lung tissue supernatants revealed a decreased expression of TGF-beta (p < 0.05) in combination with a strong proinflammatory response (p < 0.01).Conclusions: We show for the first time the expression of the TGF pseudoreceptor BAMBI in the human lung, which is upregulated in response to NTHI infection in COPD lung tissue in vivo and in vitro. The combination of NTHI-mediated induction of proinflammatory cytokines and inhibition of TGF-beta expression may influence inflammation induced tissue remodeling.