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β1整合素功能的变构调节诱导肺组织修复。

Allosteric modulation of beta1 integrin function induces lung tissue repair.

作者信息

Aljamal-Naylor Rehab, Wilson Linda, McIntyre Susan, Rossi Fiona, Harrison Beth, Marsden Mark, Harrison David J

机构信息

Avipero Ltd., 5th Floor, 125 Princes Street, Edinburgh EH2 4AD, UK.

出版信息

Adv Pharmacol Sci. 2012;2012:768720. doi: 10.1155/2012/768720. Epub 2012 Feb 26.

DOI:10.1155/2012/768720
PMID:22505883
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3299389/
Abstract

The cellular cytoskeleton, adhesion receptors, extracellular matrix composition, and their spatial distribution are together fundamental in a cell's balanced mechanical sensing of its environment. We show that, in lung injury, extracellular matrix-integrin interactions are altered and this leads to signalling alteration and mechanical missensing. The missensing, secondary to matrix alteration and cell surface receptor alterations, leads to increased cellular stiffness, injury, and death. We have identified a monoclonal antibody against β1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of β1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung.

摘要

细胞细胞骨架、黏附受体、细胞外基质组成及其空间分布共同构成了细胞对其环境进行平衡机械感知的基础。我们发现，在肺损伤中，细胞外基质与整合素的相互作用发生改变，这会导致信号改变和机械感知错误。继发于基质改变和细胞表面受体改变的感知错误会导致细胞硬度增加、损伤和死亡。我们鉴定出一种针对β1整合素的单克隆抗体，它能引起基质重塑并提高细胞存活率。该抗体作为β1整合素的变构双激动剂/拮抗剂调节剂。有趣的是，在肺部退行性疾病的动物模型中，这种抗体逆转了功能性和结构性组织损伤。

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