新生儿急性肾损伤诱导的肺损伤中HMGB1调控CXCL1趋化中性粒细胞浸润的致病机制研究

新生儿急性肾损伤（AKI）高病死率常与伴发肾外脏器衰竭有关。部分新生儿AKI早期仅表现为肾损伤，随病情进展，出现急性肺损伤（ALI），乃至多脏器衰竭。本项目聚焦的科学问题是：新生儿AKI诱导ALI的关键病理机制和干预策略。预实验显示AKI新生儿血清中高迁移率族蛋白B1（HMGB1）明显高于对照组；尤以并发ALI患儿更甚；体内外实验发现HMGB1和其特异受体RAGE及趋化因子CXCL1在以中性粒细胞炎症为特征的急性肾缺血/再灌注（IRI）新生大鼠肺组织显著上调，抗体中和HMGB1可缓解肾IRI诱导的肺损伤。项目组拟明晰HMGB1在新生儿AKI诱导肺损伤中的调控作用；解析HMGB1结合肺微血管内皮和肺泡上皮细胞RAGE受体激活核因子NF-κB上调CXCL1介导肺损伤的机制；明确HMGB1中和抗体对肺损伤的保护作用，藉此探索形成靶向干预HMGB1防治AKI诱导ALI、降低新生儿病死率的新策略。

Neonatal acute kidney injury (AKI) is associated with high mortality. Dysfunction of other organs is an important cause of poor outcomes from AKI. In some neonates with AKI, only renal injury occurs in the early stage; acute lung injury (ALI), and even multiple organ failure, occurs subsequently along with disease progress. This proposed research project attempts to address the scientific question: pathological mechanism and intervention strategy of neonatal AKI induced ALI. In our preliminary study conducted in neonates, we found that the concentration of serum high mobility group box 1 (HMGB1) in critically ill neonates with AKI was significantly higher as compared with non-AKI controls, and the highest serum HMGB1 concentration was observed in AKI neonates who developed ALI during neonatal intensive care unit stay. Our preliminary experiments conducted in vivo and in vitro showed that renal ischemia reperfusion injury (IRI) induced lung injury characterized by neutrophil infiltration, and the protein expression of HMGB1, the receptor for advanced glycation end-products (RAGE), and chemokine C-X-C motif chemokine ligand 1 (CXCL1) was increased in the lung of the newborn rats following renal IRI. Moreover, anti-HMGB1 neutralizing antibody attenuated lung injury induced by renal IRI..The goals of this study are to investigate the role of HMGB1 in neonatal AKI induced lung injury; elucidate the mechanism of HMGB1 mediated lung injury induced by neonatal AKI via binding to its receptor RAGE expressed in pulmonary microvascular endothelium and alveolar epithelial cells, activating nuclear factor kappa B (NF-κB), and regulating CXCL1; and evaluate whether anti-HMGB1 neutralizing antibody may have protective effects on neonatal AKI induced lung injury. The data gained will provide new insights into understanding of the molecular mechanisms related to neonatal AKI induced ALI and provide a potential therapeutic target to improve outcomes of neonatal AKI.