Bustos Martha L, Mura Marco, Hwang David, Ludkovski Olga, Wong Amy P, Keating Armand, Waddell Thomas K
Latner Thoracic Surgery Research Laboratories and McEwen Centre for Regenerative Medicine, University of Toronto, Toronto General Hospital, Toronto Medical Discovery Tower, Toronto, Ontario, Canada.
Department of Pathology, Princess Margaret Hospital, Toronto, Ontario, Canada.
Mol Ther. 2015 Mar;23(3):561-9. doi: 10.1038/mt.2014.223. Epub 2014 Nov 20.
The contribution of bone marrow cells (BMC) in lung repair is controversial. We previously reported a subpopulation of BMC that express Clara cell secretory protein (CCSP). To determine the contribution of endogenous CCSP(+) BMC to airway regeneration, we performed bone marrow transplantation studies using the CCtk mouse, which expresses a thymidine kinase suicide gene under regulation of the CCSP promoter. Mice were transplanted with wild-type or CCtk BMC and treated with ganciclovir to eliminate CCSP(+) cells. After airway injury using naphthalene, mice depleted of CCSP(+) BMC had more inflammatory cells in lung and decreased levels of oxygen in arterial blood. They also had reduced expression of airway epithelial genes and less Clara cells compared to control mice that had intact CCSP(+) BMC and bone marrow derived CCSP(+) cells in the airways. After naphthalene injury, administration of CCSP reproduced the beneficial effect of CCSP(+) BMC by improving recovery of airway epithelium, reducing lung inflammation and increasing oxygen in arterial blood from mice depleted of CCSP(+) BMC. Our data demonstrate that ablation of CCSP(+) BMC delays airway recovery and suggests the beneficial effect of CCSP(+) BMC in lung recovery is in part due to production of CCSP itself.
骨髓细胞（BMC）在肺修复中的作用存在争议。我们之前报道过表达克拉拉细胞分泌蛋白（CCSP）的BMC亚群。为了确定内源性CCSP(+) BMC对气道再生的作用，我们使用CCtk小鼠进行了骨髓移植研究，该小鼠在CCSP启动子的调控下表达胸苷激酶自杀基因。将小鼠移植野生型或CCtk BMC，并用更昔洛韦处理以消除CCSP(+)细胞。使用萘造成气道损伤后，CCSP(+) BMC耗竭的小鼠肺内炎症细胞增多，动脉血氧水平降低。与气道中CCSP(+) BMC完整且有骨髓来源的CCSP(+)细胞的对照小鼠相比，它们气道上皮基因的表达也减少，克拉拉细胞也更少。萘损伤后，给予CCSP可改善CCSP(+) BMC耗竭小鼠的气道上皮恢复、减轻肺部炎症并提高动脉血氧水平，从而重现CCSP(+) BMC的有益作用。我们的数据表明，CCSP(+) BMC的消融会延迟气道恢复，并提示CCSP(+) BMC在肺恢复中的有益作用部分归因于CCSP自身的产生。
