Protein kinase inhibitors in the treatment of pulmonary fibrosis

Curr Med Chem. 2008;15(25):2632-40. doi: 10.2174/092986708785908969.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Fibroblasts / cytology
  • Fibroblasts / drug effects*
  • Fibroblasts / enzymology
  • Focal Adhesion Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Focal Adhesion Protein-Tyrosine Kinases / metabolism
  • Humans
  • Lung / metabolism
  • Lung / pathology
  • Phenotype
  • Protein Kinase Inhibitors* / pharmacology
  • Protein Kinase Inhibitors* / therapeutic use
  • Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-akt / metabolism
  • Pulmonary Fibrosis / drug therapy*
  • Pulmonary Fibrosis / metabolism
  • Pulmonary Fibrosis / pathology


  • Protein Kinase Inhibitors
  • Focal Adhesion Protein-Tyrosine Kinases
  • Proto-Oncogene Proteins c-akt