Stretch regulates expression and binding of chymotrypsin-like elastase 1 in the postnatal lung
Stretch regulates expression and binding of chymotrypsin-like elastase 1 in the postnatal lung
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DOI：
10.1096/fj.15-277350
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发表时间：
2016-02-01
期刊：
影响因子：
4.8
通讯作者：
Varisco, Brian M.
中科院分区：
文献类型：
--
作者：
Joshi, Rashika;Liu, Sheng;Varisco, Brian M.
肺拉伸对肺的正常发育和肺切除术后的代偿性肺生长至关重要，但应变诱导基质重塑的机制尚不清楚。我们之前的工作证明了凝乳胰蛋白酶样弹性酶1 （Cela1）与肺弹性蛋白重塑的关联，并且该菌株引发了近乎瞬时的弹性蛋白重塑反应。我们试图确定拉伸是否调节Cela1的表达以及Cela1与肺弹性蛋白的结合。在C57BL/6J小鼠中，Cela1蛋白在肺形态发生过程中增加了176倍。Cela1与丝氨酸肽酶抑制剂，分支A，成员1共价结合，导致肺匀浆中的分子质量比胰腺匀浆高。pnx后，Cela1mRNA增加6倍，蛋白增加3倍，cela1阳性细胞增加2倍。Cela1主要在胚胎肺的肺泡II型细胞中表达，并主要在出生后的cd90阳性肺成纤维细胞中表达。在代偿性肺生长期间，Cela1在非增殖性间充质细胞中被诱导表达。在离体小鼠肺切片中，拉伸使Cela1与肺组织的结合增加了46%。可溶性弹性蛋白的竞争性抑制完全消除了这种增加。拉伸诱导的弹性酶活性区域和Cela1结合区域共定位。Cela1的拉伸依赖性表达和结合动力学表明在发育和再生过程中外周肺的拉伸依赖性重塑中起重要作用。
Lung stretch is critical for normal lung development and for compensatory lung growth after pneumonectomy (PNX), but the mechanisms by which strain induces matrix remodeling are unclear. Our prior work demonstrated an association of chymotrypsin-like elastase 1 (Cela1) with lung elastin remodeling, and that strain triggered a near-instantaneous elastin-remodeling response. We sought to determine whether stretch regulates Cela1 expression and Cela1 binding to lung elastin. In C57BL/6J mice, Cela1 protein increased 176-fold during lung morphogenesis. Cela1 was covalently bound to serpin peptidase inhibitor, clade A, member 1, resulting in a higher molecular mass in lung homogenate compared to pancreas homogenate. Post-PNX, Cela1mRNA increased 6-fold, protein 3-fold, and Cela1-positive cells 2-fold. Cela1 was expressed predominantly in alveolar type II cells in the embryonic lung and predominantly in CD90-positive lungfibroblasts postnatally. During compensatory lung growth, Cela1 expression was induced in non-proliferative mesenchymal cells. In ex vivo mouse lung sections, stretch increased Cela1 binding to lung tissue by 46%. Competitive inhibition with soluble elastin completely abrogated this increase. Areas of stretch-induced elastase activity and Cela1 binding colocalized. The stretch-dependent expression and binding kinetics of Cela1 indicate an important role in stretch-dependent remodeling of the peripheral lung during development and regeneration.