Regulation of TLR by surfactant proteins in interstitial pneumonia

慢性间质性肺炎是指预后不良的人群，包括特发性肺纤维化(IPF)。IPF患者偶尔会并发感染引发的呼吸紊乱加重，并导致死亡。其病理特征为弥漫性肺泡损伤，其分子生物学基础是肿瘤坏死因子-α引起的生物活性物质上调。因此，抑制患者肺组织中肿瘤坏死因子-α的上调，可以防止病情恶化，从而提高患者的生存率。炎性免疫细胞膜上表达的Toll样受体(Toll-like Receptor，TLR)和多种细菌成分相互作用，上调了肿瘤坏死因子-α的表达。另一方面，表面活性蛋白(SP)-A在体外具有抑制炎症反应的作用。我们首先研究了SP-A是否通过金黄色葡萄球菌衍生的肽聚糖(PGN)改变细胞反应。在生理范围内对肿瘤坏死因子-α分泌的抑制作用与SP-A浓度呈正相关。SP-A。直接与可溶性形式的重组胞外TLR2结构域(STLR2)结合。STLR2与SP-A共同孵育可显著降低sTLR2与PGN的结合。这些结果表明，SP-A与TLR2的直接相互作用改变了PGN诱导的细胞信号转导。接下来，我们研究了SP-A与肺炎支原体的相互作用。SP-A可增强病原体脂蛋白的作用，增加肿瘤坏死因子-α和一氧化氮的释放。只有转染TLR2或CD14+TLR2的细胞才能产生肿瘤坏死因子-α。这些发现直接表明SP-A、CD14和TLR2与肺炎支原体的即刻先天反应有关。

Chronic Interstitial pneumonias involve a group showing poor prognosis including idiopathic pulmonary fibrosis (IPF). Patients with IPF occasionally complicate with infection-triggered exacerbation of respiratory disturbance and result in death. Pathologic feature of the exacerbation is diffuse alveolar damage and its molecular biology is of the basis of the upregulation of bioactive materials presented by TNF-a. Therefore, to inhibit the upregulation of TNF-a in the patients' lungs may prevent the exacerbation and then bring a good survival rate. The expression of TNF-a is upregulated by the interaction with various bacterial components and Toll-like receptor (TLR) expressed in cell membrane of inflammatory immune cells. On the other hand, surfactant protein (SP)-A is known to provide an inhibitory effect on the inflammatory reaction in vitro.We firstly investigated whether SP-A alters cellular responses by Staphylococcus aureus derived peptidoglycan (PGN). The inhibitory effect on TNF-a secretion was dependent upon SP-A concentrations in physiological range. SP-A. directly bound to a soluble form of the recombinant extracellular TLR2 domain (sTLR2). Coincubation of sTLR2 with SP-A significantly reduced the binding of sTLR2 to PGN. These results indicate that the direct interaction of SP-A with TLR2 alters PGN-induced cell signaling. We next studied interaction between SP-A and, Mycoplasma pneumoniae. SP-A enhanced the action of the lipoprotein prepared from the pathogen, increasing the release of TNF-a and NO. Only cells transfected with TLR2 or CD 14 plus TLR2 produced TNF-a. These findings directly implicate SP-A, CD 14 and TLR2 in the immediate innate response to M. pneumoniae.