Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts.
Caveolin-1-Derived Peptide Reduces ER Stress and Enhances Gelatinolytic Activity in IPF Fibroblasts.
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Caveolin-1 衍生肽可降低 IPF 成纤维细胞的 ER 应激并增强其明胶分解活性。
DOI：
10.3390/ijms23063316
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发表时间：
2022-03-18
影响因子：
5.6
通讯作者：
Ikebe M
中科院分区：
文献类型：
--
作者：
Komatsu S;Fan L;Idell S;Shetty S;Ikebe M
特发性肺纤维化（IPF）是一种以细胞外基质在肺组织中过度沉积为特征的致死性疾病。Caveolin-1支架结构域肽（CSP）已被发现在几种动物模型中减轻肺纤维化。然而，其在IPF中的病理生理学作用尚不清楚，理解CSP预防肺纤维化的机制仍然至关重要。我们首先研究了CSP进入细胞的递送，发现它在内质网（ER）中内化和积累。此外，CSP通过抑制转化生长因子β（TGFβ）处理的人IPF肺成纤维细胞（hIPF-Lfs）中的肌醇需要酶1 α（IRE 1 α）来降低ER应激。此外，我们发现CSP增强了TGFβ处理的hIPF-Lfs的明胶分解活性。IRE 1 α抑制剂; 4µ 8 C还增强了TGFβ处理的hIPF-Lfs的明胶溶解活性，支持CSP诱导IRE 1 α途径抑制的概念。CSP能显著提高TGFβ诱导的hIPF-Lfs中MMPs的表达，但却能降低胶原1的分泌。在PF、博来霉素（BLM）和表达组成型活性TGFβ的腺病毒（Ad-TGFβ）诱导的PF的两种临床前小鼠模型中观察到了类似的结果。我们的研究结果为肺成纤维细胞促进CSP依赖性保护以对抗肺纤维化的机制提供了新的见解。
Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role in IPF is obscure, and it remains critical to understand the mechanism by which CSP protects against pulmonary fibrosis. We first studied the delivery of CSP into cells and found that it is internalized and accumulated in the Endoplasmic Reticulum (ER). Furthermore, CSP reduced ER stress via suppression of inositol requiring enzyme1α (IRE1α) in transforming growth factor β (TGFβ)-treated human IPF lung fibroblasts (hIPF-Lfs). Moreover, we found that CSP enhanced the gelatinolytic activity of TGFβ-treated hIPF-Lfs. The IRE1α inhibitor; 4µ8C also augmented the gelatinolytic activity of TGFβ-treated hIPF-Lfs, supporting the concept that CSP induced inhibition of the IRE1α pathway. Furthermore, CSP significantly elevated expression of MMPs in TGFβ-treated hIPF-Lfs, but conversely decreased the secretion of collagen 1. Similar results were observed in two preclinical murine models of PF, bleomycin (BLM)- and adenovirus expressing constitutively active TGFβ (Ad-TGFβ)-induced PF. Our findings provide new insights into the mechanism by which lung fibroblasts contribute to CSP dependent protection against lung fibrosis.
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影响因子：
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作者：
Habiel DM;Hogaboam CM
通讯作者：
Hogaboam CM
影响因子：
2.9
作者：
Hoop, Cody L.;Sivanandam, V. N.;Kodali, Ravindra;Srnec, Matthew N.;van der Wel, Patrick C. A.
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DOI：
10.3109/08977194.2011.595714
发表时间：
2011-10
期刊：
Growth factors (Chur, Switzerland)
影响因子：
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通讯作者：
Frangogiannis NG
DOI：
10.1152/ajplung.00099.2011
发表时间：
2012-03-01
影响因子：
4.9
作者：
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通讯作者：
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影响因子：
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作者：
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