RSV感染活化TLR3/TRIF信号通路在HSCT后闭塞性毛细支气管炎发生及发展中的作用机制研究

闭塞性毛细支气管炎（BO）是造血干细胞移植后常见的肺部并发症，主要表现为不可逆的气道阻塞，其发生率高预后差，严重影响移植患者的长期生存及生活质量。研究发现，移植后呼吸道合胞病毒(RSV)感染可导致显著的气流下降及BO的发生，但其发生的机制尚不清楚。RSV感染可上调TLR3的表达，通过TRIF途径最终导致 NF-κB和IRF3 的活化, 启动TNF-α、IL-8等的转录和翻译，引起抗病毒免疫应答。而研究发现TNF-α及IL-8等在导致BO气道重构中起着重要的作用。故我们提出假设：RSV感染造血干细胞移植受者后，通过激活TLR3/TRIF通路，触发或加重BO的发生及发展。本研究将通过RSV感染小鼠同种异体骨髓移植模型、TLR3基因敲除小鼠移植模型等以及临床标本研究，明确RSV感染活化TLR3/TRIF信号通路在移植后BO发生中所起的作用。研究结果，将为移植后BO的预防及治疗提供新的方向及靶点。

Bronchiolitis obliterans (BO) is a late, non-infectious pulmonary complication which is commonly seen in patients who underwent the hematopoietic stem cell transplantation (HSCT). It manifests as irreversible airflow obstruction with high morbidity and poor prognosis, and will seriously influence the long- term survival and life quality of hematopoietic stem cell transplant recipients. Previous studies indicated that the respiratory syncytial virus (RSV) infection after HSCT would lead to significant decreased pulmonary airflow and BO, however, the mechanism was still unclear. It was believed the infection of RSV would upregulate the expression of TLR3, and activate the NF-κB and IRF3 through TRIF pathway, then activate the transcription and translation of corresponding inflammatory factors and cytokines (such as IL-8, TNF-α), finally resulted in antiviral immune response. Other studies had also found that TNF-α and IL-8 played an important role in airway remodeling which would lead to BO. So we hypotheses that RSV infection could induce the BO incidence in HSCT recipients by activating TLR3/TRIF signaling pathways. In this research, we will use RSV infected allogeneic bone marrow transplantation mice model and TLR3 gene knockout mice transplanted model, and also detect clinical specimens, to clarify the role of TLR3/TRIF signaling pathway activated by RSV in occurrence and development of bronchiolitis obliterans after HSCT. The results would provide a new direction and target for the prevention and treatment of bronchiolitis obliterans, and would hopefully improve the survival rate and life quality of these patients.