title: Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced pulmonary fibrosis.
abstract: Transforming growth factor-alpha (TGFalpha) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3'-kinase (PI3K). We previously showed that induction of lung-specific TGFalpha expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFalpha expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFalpha induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFalpha prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFalpha/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy.
authors.affiliation: Divisions of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Le Cras
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Korfhagen
authors.forename: Cynthia
authors.initials: C
authors.lastname: Davidson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Schmidt
authors.forename: Matthew
authors.initials: M
authors.lastname: Fenchel
authors.forename: Machiko
authors.initials: M
authors.lastname: Ikegami
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
authors.forename: William D
authors.initials: WD
authors.lastname: Hardie
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D006067:Gonanes / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D051058:Oncogene Protein v-akt / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000517:prevention & control*; D016211:Transforming Growth Factor alpha; D014598:Uteroglobin / Q000235:genetics
chemical_list: D004791:Enzyme Inhibitors; D006067:Gonanes; C496788:PX-866; D000081082:Phosphoinositide-3 Kinase Inhibitors; C556389:SCGB1A1 protein, human; C556390:Scgb1a1 protein, mouse; D016211:Transforming Growth Factor alpha; D014598:Uteroglobin; D051058:Oncogene Protein v-akt