肺组织修复能力不足是慢性阻塞性肺病肺气肿发生的另一重要机制，而且可能是共同通路，肺组织修复功能的调控正在成为肺气肿研究焦点。Rcn3是近年新发现的一个定位于内质网内分泌途径的蛋白，关于其生物学功能知之甚少。我们的合作者在国际上首先发现Rcn3参与呼吸系统生物学功能的调控。我们的预实验结果进一步显示Rcn3在肺气肿患者肺组织表达增加，且与肺功能FEV1/pre%呈负相关。Rcn3基因敲除小鼠肺组织胶原蛋白基因表达增加。基于此，我们提出这一假说：Rcn3可能通过调控肺组织的修复功能在肺气肿的发生中发挥作用。本研究将从肺气肿发生的组织修复功能受损为切入点，通过建立吸烟诱导的小鼠肺气肿模型和气道上皮细胞株体外培养，首次揭示Rcn3对肺组织修复功能的调控及其在肺气肿发生中的作用，为明确肺气肿的发病机制和寻找新的治疗靶点奠定基础。

The impaired repair capacity of lung tissue has been known as a new mechanism and probably the common pathway for the development of emphysema in chronic obstructive pulmonary disease (COPD). Understanding the regulation of lung repair function and repairing the damaged emphysematous lung have drawn considerable attention. Reticulocalbin3 (Rcn3), a novel number of the CREC (Cab45/Rcn/ERC45/Calumenin) family, is an endoplasmic reticulum lumen protein localized to the secretory pathway. By far, the biological function of Rcn3 is largely unknown. For the first time, our collaborator has demonstrated that Rcn3 play a role in regulating the biological functions of lung epithelia cells. Our preliminary studies further detected that in the lung tissue from emphysema patients, the expression of Rcn3 was upregulated and correlated negatively with the value of FEV1.0/pre%, which indicates the degree of airflow obstruction. In addition, the mRNA expression of both type I and type II collagen was significantly increased in lung tissue from Rcn3 knockout mouse. Therefore, we proposed that Rcn3 might participate in the development of emphysema through regulating the lung repair function. The current study will examine the role of Rcn3 in modulating lung repair capacity by utilizing the cell lines of airway epithelial cells cultured in vitro. Moreover, the role of Rcn3 in emphysema will be elucidated by establishing the cigarette smoke-induced emphysema mouse model. The accomplishment of this work will provide new insights into further understanding emphysema and identifying potential therapeutic target for emphysema.

慢性阻塞性肺病肺气肿的发病机制尚未完全阐明。修复功能受损是肺气肿发生的重要环节。Rcn3(reticulocalbin3) 是近年新发现的一个定位于内质网内分泌途径的蛋白，我们的合作者在国际上首先发现Rcn3基因敲除小鼠出生后即因呼吸窘迫死亡，进一步研究发现Rcn3基因敲除小鼠肺组织胶原蛋白基因表达增加；我们进一步首次证实Rcn3在人肺组织显著表达，在慢阻肺肺气肿患者的肺组织表达呈现显著上调的趋势。前期的研究结果提示Rcn3可能在肺气肿的发生中发挥作用。本研究建立了香烟烟雾暴露小鼠肺气肿模型，免疫组化研究显示小鼠支气管和肺泡上皮细胞及肺间质均有Rcn3表达，肺气肿小鼠肺组织表达显著增强，westernblot和实时定量PCR研究结果进一步表明肺气肿小鼠肺组织Rcn3蛋白和mRNA水平均显著升高。通过肺泡上皮细胞系A549体外培养，拟进一步研究Rcn3的作用机制，研究结果显示A549细胞Rcn3表达过低，与体内肺泡上皮存在差异，进一步建立小鼠在体肺泡上皮细胞特异性Rcn3敲除模型，为进一步研究Rcn3在肺气肿中的作用奠定基础。肺成纤维细胞体外培养研究表明香烟烟雾提取物能够刺激Rcn3表达显著上调。提示Rcn3可能通过调控肺成纤维细胞在肺气肿的发生中发挥作用。本研究结果证实Rcn3在肺气肿肺组织表达上调，肺成纤维细胞是Rcn3发挥作用的靶细胞之一，Rcn3调控肺成纤维细胞的功能值得深入探讨。可以采用小鼠在体肺泡上皮细胞特异性Rcn3敲除模型，进一步阐明Rcn3在肺气肿发生中的作用并进行机制的探讨。