Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury.
Progressive fibrotic diseases involving diverse organ systems are associated with the persistence of fibroblasts/myofibroblasts in injured tissues. Activation of focal adhesion kinase (FAK) and protein kinase B (PKB/Akt) by transforming growth factor-beta1 mediate stable induction of myofibroblast differentiation and survival. In this report, we demonstrate that transforming growth factor-beta1-induced activation of both PKB/Akt and FAK are dose dependently inhibited by the protein kinase inhibitor, AG1879, in cultured human lung fibroblasts. In a murine model of intratracheal bleomycin-induced lung fibrosis, regions of active fibrogenesis demonstrate elevated expression of PKB/Akt and FAK phosphorylation in vivo, effects that are attenuated in mice receiving daily intraperitoneal injections of AG1879 (bleomycin-AG1879) versus a chemically inactive analog (bleomycin-control). PKB/Akt and FAK phosphorylation are elevated in fibroblasts isolated from lungs of bleomycin-injured mice, effects that are inhibited in bleomycin-AG1879 mice. Accumulation of alpha-smooth muscle actin-expressing myofibroblasts is markedly reduced in lungs of bleomycin-AG1879 mice. The numbers of recruited inflammatory cells were not significantly different between these groups. Bleomycin-AG1879 mice are protected from lung fibrosis as evidenced by histopathology, trichrome staining, and biochemical analysis for collagen. Thus, targeting of prosurvival signaling pathways in fibroblasts/myofibroblasts may provide a novel and effective strategy for anti-fibrotic therapy of treatment-unresponsive fibrotic disorders.
Vittal
Ragini
R
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, 6301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, MI 48109, USA. vjt@umich.edu
Horowitz
Jeffrey C
JC
Moore
Bethany B
BB
Zhang
Hengmin
H
Martinez
Fernando J
FJ
Toews
Galen B
GB
Standiford
Theodore J
TJ
Thannickal
Victor J
VJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D002470:Cell Survival; D017364:Collagenases / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000378:metabolism*; D005355:Fibrosis; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D007150:Immunohistochemistry; D007249:Inflammation; D008168:Lung / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009130:Muscle, Smooth / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines / Q000494:pharmacology; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D019061:src-Family Kinases / Q000037:antagonists & inhibitors
C412373:AG 1879; D000199:Actins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496051:Ptk2 protein, mouse; D019061:src-Family Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D017364:Collagenases