Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis.
Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGFα in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGFα mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role.
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Satish K
SK
Madala
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Ramakrishna
R
Edukulla
Laboratory for Statistical Genomics and Systems Biology, University of Cincinnati, Cincinnati, Ohio, United States of America.
Mukta
M
Phatak
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Stephanie
S
Schmidt
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Cynthia
C
Davidson
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Thomas H
TH
Acciani
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Thomas R
TR
Korfhagen
Laboratory for Statistical Genomics and Systems Biology, University of Cincinnati, Cincinnati, Ohio, United States of America.
Mario
M
Medvedovic
Division of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Timothy D
TD
Lecras
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
Kimberly
K
Wagner
Division of Pulmonary Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.
William D
WD
Hardie
D000704:Analysis of Variance; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D015153:Blotting, Western; D004359:Drug Therapy, Combination; D006067:Gonanes / Q000494:pharmacology; D007150:Immunohistochemistry; D008168:Lung / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011658:Pulmonary Fibrosis / Q000188:drug therapy*; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D016211:Transforming Growth Factor alpha / Q000378:metabolism
C517975:AZD 6244; D001562:Benzimidazoles; D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016211:Transforming Growth Factor alpha