Date Published: February 26, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Rehab AlJamal-Naylor, Linda Wilson, Susan McIntyre, Fiona Rossi, Beth Harrison, Mark Marsden, David J. Harrison.
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.
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.
In this paper we have investigated the role of β1 integrin in lung injury and repair in emphysema. We demonstrated that β1 integrin becomes allosterically activated in epithelial-mesenchymal cells, with the corollary that allosteric modulation inhibited elastase-induced injury. We further demonstrate a potential cellular mechanism for this β1 integrin-mediated effect. In order to do so, we established an in vitro model system which replicated features of elastase-induced emphysema in vivo. We identified that allosteric modulation of β1 integrin inhibited caspase activation, F-actin aggregate formation, and abnormal fluctuations in cellular ATP levels, under conditions in which the total β1 expression was changed and activation inhibited. The key finding of our investigation was that, by direct allosteric modulation of β1 integrin with a specific monoclonal antibody, both functional and structural reversal of elastase-induced tissue injury was induced in vivo. Our findings support the notion that cytomechanics are important determinants of cell fate and effect repair.