%0 Journal Article
%T Allosteric Modulation of Beta1 Integrin Function Induces Lung Tissue Repair
%A Rehab AlJamal-Naylor
%A Linda Wilson
%A Susan McIntyre
%A Fiona Rossi
%A Beth Harrison
%A Mark Marsden
%A David J. Harrison
%J Advances in Pharmacological Sciences
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/768720
%X 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 ¦Â1 integrin which caused matrix remodelling and enhancement of cell survival. The antibody acts as an allosteric dual agonist/antagonist modulator of ¦Â1 integrin. Intriguingly, this antibody reversed both functional and structural tissue injury in an animal model of degenerative disease in lung. 1. Introduction Tissue regeneration comprises dedifferentiation of adult cells into a stem cell state and the development of these cells into new remodelled tissue, identical to the lost one. Tissue repair is defined as replacement of normal tissue by fibrous tissue and integrins are crucial in these processes. Integrins are membrane spanning proteins facilitating the two-way communication between the inside and outside of a cell. Integrins have the capacity to bind a multitude of molecules both inside and outside of the cell. The binding of these molecules results in the transmission of information into and out of the cell, which can influence a host of different cellular functions, including the cells metabolic activity. Of the many types of integrin receptors, the ¦Â1 integrin is by far the most ubiquitous allowing cells to detect a vast array of stimuli ranging between toxins, protein hormones, neurotransmitters, and macromolecules. There have been numerous publications documenting a potential role of ¦Â1 integrin in tissue development and repair in several tissue types (reviewed in [1]). It is clear that ¦Â1 integrin plays a crucial role during postnatal skin development and wound healing, with the loss of epithelial ¦Â1 integrin causing extensive skin blistering and wound healing defects. More recently, there has been active interest in the cosmeceutical development of ¦Â1 integrin targeting formulations. One such example is following the discovery of fucoidans from Fucus vesiculosus and its effect on skin scarring and ageing [2, 3] which was later found to be mainly attributed to alpha2 and ¦Â1 integrin [4]. Integrins in general, including ¦Â1 integrin, exhibit global structural rearrangement and exposure of ligand binding sites
%U http://www.hindawi.com/journals/aps/2012/768720/