Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system
Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system
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DOI：
10.1152/ajplung.00099.2011
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发表时间：
2012-03-01
影响因子：
4.9
通讯作者：
Shetty, Sreerama
中科院分区：
文献类型：
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作者：
Bhandary, Yashodhar P.;Shetty, Shwetha K.;Shetty, Sreerama
Bhandary YP，Shetty SK，Marudamuthu AS，Gyetko MR，Idell S，Gharaee-Kermani M，Shetty RS，Starcher BC，Shetty S通过纤溶系统各组分的协调表达调节肺泡上皮细胞凋亡和肺纤维化。Am J Physiol肺细胞分子Physiol 302：L463-L473,2012。2012年12月2日首次出版；DOI：10.1152/ajpeng.00099.2011-肺泡II型(ATII)细胞凋亡和促进肺泡纤维蛋白沉积的纤溶抑制与急性肺损伤(ALI)和肺纤维化(PF)的发展有关。因此，我们试图确定P53介导的对尿激酶型纤溶酶原激活物(UPA)的抑制和对纤溶酶原激活物抑制物-1(PAI-1)的诱导是否有助于先于PF发展的ATII细胞的凋亡。我们还试图确定小窝蛋白-1支架结构域肽(CSP)是否逆转了这些变化，以保护其免受ALI和PF的影响。在BLM损伤的野生型(WT)小鼠肺组织和分离的ATII细胞中，细胞凋亡、P53和PAI-1增加，uPA和uPA受体(UPAR)蛋白表达相互抑制。CSP可逆转上述作用，并保护ATII细胞免受博莱霉素(BLM)诱导的细胞凋亡，而CSP不能减少uPA缺陷小鼠ATII细胞的凋亡或降低P53或PAI-1。这些小鼠表现出更严重的肺泡炎。因此，在博莱姆诱导的ALI小鼠模型中，P53的表达增加并抑制uPA和uPAR的表达，同时增加PAI-1的表达，从而促进ATII细胞的凋亡。我们发现，CSP，一种针对这一途径的干预，通过uPA介导的对P53和PAI-1的抑制，在博莱曼诱导的肺损伤中保护肺上皮细胞免于凋亡和预防PF。
Bhandary YP, Shetty SK, Marudamuthu AS, Gyetko MR, Idell S, Gharaee-Kermani M, Shetty RS, Starcher BC, Shetty S. Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system. Am J Physiol Lung Cell Mol Physiol 302: L463-L473, 2012. First published December 2, 2012; doi:10.1152/ajplung.00099.2011.-Alveolar type II (ATII) cell apoptosis and depressed fibrinolysis that promotes alveolar fibrin deposition are associated with acute lung injury (ALI) and the development of pulmonary fibrosis (PF). We therefore sought to determine whether p53-mediated inhibition of urokinase-type plasminogen activator (uPA) and induction of plasminogen activator inhibitor-1 (PAI-1) contribute to ATII cell apoptosis that precedes the development of PF. We also sought to determine whether caveolin-1 scaffolding domain peptide (CSP) reverses these changes to protect against ALI and PF. Tissues as well as isolated ATII cells from the lungs of wild-type (WT) mice with BLM injury show increased apoptosis, p53, and PAI-1, and reciprocal suppression of uPA and uPA receptor (uPAR) protein expression. Treatment of WT mice with CSP reverses these effects and protects ATII cells against bleomycin (BLM)-induced apoptosis whereas CSP fails to attenuate ATII cell apoptosis or decrease p53 or PAI-1 in uPA-deficient mice. These mice demonstrate more severe PF. Thus p53 is increased and inhibits expression of uPA and uPAR while increasing PAI-1, changes that promote ATII cell apoptosis in mice with BLM-induced ALI. We show that CSP, an intervention targeting this pathway, protects the lung epithelium from apoptosis and prevents PF in BLM-induced lung injury via uPA-mediated inhibition of p53 and PAI-1.