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Allosteric modulation of beta1 integrin function induces lung repair in animal model of emphysema.

Rehab J. Al-Jamal¹, Linda Wilson², Chris J. Armit ¹, Susan McIntyre ¹, Mark Marsden³, Steven D. Shapiro⁴ & David J. Harrison¹

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1. Division of Pathology, University of Edinburgh, Cancer Research Centre, Crewe Road South, Edinburgh, EH4 2XR, United Kingdom
2. School of Biomedical Sciences, Hugh Robson Building, George Square, University of Edinburgh, Edinburgh EH8 9XD,United Kingdom
3. MRC Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, United Kingdom
4. Department of Medicine, University of Pittsburgh, 1218 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA

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Manuscript

Date:

Received 12 July 2007 10:54 UTC; Posted 13 July 2007

Subjects:

Pharmacology

Tags:

• tissue repair
• Integrin
• cytomechanics
• regeneration

Abstract:

Emphysema is a progressive lung disease characterised by loss of lung parenchyma with associated functional changes including decreased tissue elastance. Here we report beta1 integrin is a novel target for tissue repair and regeneration in emphysema. We show a single dose of a monoclonal antibody against beta1 integrin induced both functional and structural reversal of elastase-induced lung injury in vivo, and we found that similar matrix remodelling changes occurred in human lung tissue. We also identified a potential mechanism of action as this allosteric modulation of beta1 integrin inhibited elastase-induced caspase activation, F-actin aggregate formation and changes in cellular ATP levels. This was accompanied by maintenance of beta1?integrin levels and inhibition of caveolin-1 phosphorylation. We propose that allosteric modulation of beta1 integrin-mediated mechanosensing prevents cell death associated with lung injury and progressive emphysema, thus allowing cells to survive and for repair and regeneration to ensue.

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This document is licensed to the public under the Creative Commons Attribution 2.5 License

How to cite this document:

Al-Jamal, Rehab, Wilson, Linda, Armit , Chris J., McIntyre , Susan, Marsden, Mark, Shapiro, Steven D., and Harrison, David J.. Allosteric modulation of beta1 integrin function induces lung repair in animal model of emphysema. . Available from Nature Precedings <http://hdl.handle.net/10101/npre.2007.437.1> (2007)

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