JOURNAL ARTICLE

Modulation of prosurvival signaling in fibroblasts by a protein kinase inhibitor protects against fibrotic tissue injury

Ragini Vittal, Jeffrey C Horowitz, Bethany B Moore, Hengmin Zhang, Fernando J Martinez, Galen B Toews, Theodore J Standiford, Victor J Thannickal
American Journal of Pathology 2005, 166 (2): 367-75
15681821
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.

Full Text Links

Find Full Text Links for this Article

Discussion

You are not logged in. Sign Up or Log In to join the discussion.

Related Papers

Remove bar
Read by QxMD icon Read
15681821
×

Save your favorite articles in one place with a free QxMD account.

×

Search Tips

Use Boolean operators: AND/OR

diabetic AND foot
diabetes OR diabetic

Exclude a word using the 'minus' sign

Virchow -triad

Use Parentheses

water AND (cup OR glass)

Add an asterisk (*) at end of a word to include word stems

Neuro* will search for Neurology, Neuroscientist, Neurological, and so on

Use quotes to search for an exact phrase

"primary prevention of cancer"
(heart or cardiac or cardio*) AND arrest -"American Heart Association"