协同刺激分子B7-H3在拮抗中性粒细胞凋亡和促进LPS诱导肺损伤中的作用

急性肺损伤（ALI）/急性呼吸窘迫综合症（ARDS）的防治仍是临床亟待解决的问题。中性粒细胞激活和凋亡延迟在ALI发病过程中起了关键作用，但所涉及的分子生物学机制尚有待进一步确定。 本课题前期发现协同刺激分子B7-H3经TLR信号调控固有免疫应答，最近又发现ARDS患者中性粒细胞表达B7-H3受体且B7-H3可延迟中性粒细胞凋亡。因此，我们推测B7-H3拮抗中性粒细胞凋亡在ALI进程中可能发挥关键作用。 鉴此，本课题拟进一步分析B7-H3在ARDS患者体内表达的临床意义及其与中性粒细胞凋亡相关性；以B7-H3阻断性单抗为干预手段，研究B7-H3在激活和拮抗中性粒细胞凋亡中的生物学作用以及涉及的凋亡信号分子机制；采用野生型和TLR2/ TLR4基因敲除小鼠构建ALI动物模型， 探讨B7-H3拮抗中性粒细胞凋亡促进ALI病程进展与TLR信号的相关性及机制，为免疫干预治疗提供新的理论基础。

The prevention and treatment of acute lung injury (ALI)/adult respiratory distress syndrome (ARDS) continue to be a major clinical challenge, particularly in intensive care units. The activation and delayed apoptosis of polymorphonuclear neutrophils (PMNs) possess a key role in the pathogenesis of ALI/ARDS, but the precise molecular mechanism involved has not been fully elucidated. Our previously published work has demonstarted that B7-H3, a newly discovered co-stimulatory member of the B7 superfamily, augments the innate immunity-initiated inflammatory response via both a TLR2 and TLR4-mediated signal transduction pathway. We recently discovered that PMNs from ARDS patients exhibited upregulated expression of B7-H3 receptor and treatment with B7-H3 resulted in a delayed PMN apoptosis. Thus, we hypothesized that B7-H3 contributes to the development of ALI/ARDS via its impact on prevention of PMN apoptosis. The specific objectives of this research proposal are: 1) to determine whether B7-H3 levels in the clinical samples from patients with ALI/ARDS correlates to the disease stage, thus functioning as the prognosis marker during the development of ALI/ARDS; 2) to examine whether B7-H3 exerts a stimulatory effects on PMN that cause PMN activation and simultaneously prevent PMN apoptosis, and the possible downstream signal molecules involved by using a specific anti-B7-H3 blocking mAb; 3) to clarify whether B7-H3 contributes to the development of ALI/ARDS and whether this occurs via a TLR2/TLR4-dependent signal pathway, by establishing ALI model in both wild-type and TLR2/TLR4-deficient mice. Thus, we aim to identify the clinical importance, biological functions, and molecular mechanisms of B7-H3 during the development of ALI/ARDS and to evaluate the potential of targeting B7-H3 in the management of clinical ALI/ARDS.