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Protein Kinase Inhibitors in the Treatment of Pulmonary Fibrosis

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Abstract:

Fibrosis of the lung and other organ systems is an increasing cause of morbidity and mortality worldwide. Effective anti-fibrotic agents for such disorders are currently lacking. Injury to epithelium-lined tissues in mammals is typically associated with a mesenchymal response, including the activation of myofibroblasts. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease that results from effacement of the normal alveolar architecture of the lung. Loss of lung capacity for gas-exchange and increased work of breathing eventually leads to respiratory failure and death. In cutaneous wound models, apoptosis of myofibroblasts are essential to scar-less wound healing. Recent studies indicate that acquisition of an apoptosis-resistant myofibroblast phenotype in the injured lung is associated with non-resolving and persistent fibrosis. The acquired resistance to apoptosis in myofibroblasts is mediated, at least in part, by the sustained activation of two critical pro-survival protein kinases, focal adhesion kinase (FAK) and protein kinase B (PKB/AKT). Therapeutic interventions that modulate the activity of these protein kinases with resultant alterations in the phenotype of myofibroblasts may prove to be effective anti-fibrotic therapeutic strategies. We discuss the potential roles for protein kinase inhibitors as novel drugs for fibrotic disorders. Progress in pre-clinical and clinical development of small molecule inhibitors targeting pro-survival protein kinases is reviewed.

Keywords: Fibrosis; apoptosis; epithelial cells; fibroblasts; focal adhesion kinase; protein kinase B; protein kinase inhibitors; therapeutics

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/092986708785908969

Affiliations: Division of Pulmonary and Critical Care Medicine, University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA.

Publication date: October 1, 2008

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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