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Caveolin-1-derived peptide limits development of pulmonary fibrosis.
Science Translational Medicine ( IF 17.1 ) Pub Date : 2019-12-11 , DOI: 10.1126/scitranslmed.aat2848
Amarnath Satheesh Marudamuthu 1 , Yashodhar Prabhakar Bhandary 1 , Liang Fan 1 , Vijay Radhakrishnan 1 , BreAnne MacKenzie 2 , Esther Maier 3 , Shwetha Kumari Shetty 1 , M R Nagaraja 1 , Venkadesaperumal Gopu 1 , Nivedita Tiwari 1 , Yajie Zhang 3 , Alan B Watts 3 , Robert O Williams 3 , Gerald J Criner 4 , Sudhir Bolla 4 , Nathaniel Marchetti 4 , Steven Idell 1 , Sreerama Shetty 1
Affiliation  

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with a median 5-year survival of ~20%. Current U.S. Food and Drug Administration–approved pharmacotherapies slow progression of IPF, providing hope that even more effective treatments can be developed. Alveolar epithelial progenitor type II cell (AEC) apoptosis and proliferation, and accumulation of activated myofibroblasts or fibrotic lung fibroblasts (fLfs) contribute to the progression of IPF. Full-length caveolin-1 scaffolding domain peptide (CSP; amino acids 82 to 101 of Cav1: DGIWKASFTTFTVTKYWFYR) inhibits AEC apoptosis and fLf activation and expansion and attenuates PF in bleomycin (BLM)–induced lung injury in mice. Like full-length CSP, a seven–amino acid deletion fragment of CSP, CSP7 (FTTFTVT), demonstrated antifibrotic effects in murine models of lung fibrosis. When CSP7 was administered during the fibrotic phase in three preclinical models [single-dose BLM, repeated-dose BLM, and adenovirus expressing constitutively active transforming growth factor–β1 (Ad-TGF-β1)–induced established PF], CSP7 reduced extracellular matrix (ECM) markers characteristic of PF, increased AEC survival, and improved lung function. CSP7 is amenable to both systemic (intraperitoneal) or direct lung delivery in a nebulized or dry powder form. Furthermore, CSP7 treatment of end-stage human IPF lung tissue explants attenuated ECM production and promoted AEC survival. Ames testing for mutagenicity and in vitro human peripheral blood lymphocyte and in vivo mouse micronucleus transformation assays indicated that CSP7 is not carcinogenic. Together, these findings support the further development of CSP7 as an antifibrotic treatment for patients with IPF or other interstitial lung diseases.



中文翻译:

Caveolin-1衍生的肽限制了肺纤维化的发展。

特发性肺纤维化(IPF)是一种致命的纤维化肺部疾病,中位5年生存率约为20%。当前美国食品和药物管理局批准的药物治疗可减缓IPF的进展,希望能够开发出更有效的治疗方法。II型肺泡上皮祖细胞(AEC)的凋亡和增殖以及活化的成肌纤维细胞或纤维化肺成纤维细胞(fLfs)的积累有助于IPF的发展。全长Caveolin-1支架结构域肽(CSP; Cav1的第82至101位氨基酸:DGIWKASFTTFTVTKYWFYR)抑制AEC凋亡以及fLf活化和扩增,并减弱博来霉素(BLM)诱导的小鼠肺损伤中的PF。与全长CSP一样,CSP的七个氨基酸缺失片段CSP7(FTTFTVT)在鼠肺纤维化模型中显示出抗纤维化作用。在三种临床前模型中,在纤维化阶段施用CSP7 [单剂量BLM,重复剂量BLM和表达组成性活性转化生长因子β1(Ad-TGF-β1)诱导的已建立的PF的腺病毒]时,CSP7还原了细胞外基质(ECM)标记为PF的特征,增加的AEC存活率和改善的肺功能。CSP7既适合全身性(腹膜内)形式,也适合直接呈雾状或干粉形式的肺部递送。此外,CSP7治疗末期人类IPF肺组织外植体可减弱ECM的产生并提高AEC的存活率。Ames的致突变性测试以及体外人外周血淋巴细胞和体内小鼠微核转化试验表明CSP7不具有致癌性。一起,

更新日期:2019-12-11
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