PMID- 20042669
OWN - NLM
STAT- MEDLINE
DCOM- 20100316
LR  - 20211020
IS  - 1525-2191 (Electronic)
IS  - 0002-9440 (Print)
IS  - 0002-9440 (Linking)
VI  - 176
IP  - 2
DP  - 2010 Feb
TI  - Inhibition of PI3K by PX-866 prevents transforming growth factor-alpha-induced 
      pulmonary fibrosis.
PG  - 679-86
LID - 10.2353/ajpath.2010.090123 [doi]
AB  - 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.
FAU - Le Cras, Timothy D
AU  - Le Cras TD
AD  - Divisions of Pulmonary Biology, Cincinnati Children's Hospital Medical Center, 
      Cincinnati, OH 45229, USA.
FAU - Korfhagen, Thomas R
AU  - Korfhagen TR
FAU - Davidson, Cynthia
AU  - Davidson C
FAU - Schmidt, Stephanie
AU  - Schmidt S
FAU - Fenchel, Matthew
AU  - Fenchel M
FAU - Ikegami, Machiko
AU  - Ikegami M
FAU - Whitsett, Jeffrey A
AU  - Whitsett JA
FAU - Hardie, William D
AU  - Hardie WD
LA  - eng
GR  - R01 HL058795/HL/NHLBI NIH HHS/United States
GR  - R01 HL086598/HL/NHLBI NIH HHS/United States
GR  - R01 HL090156/HL/NHLBI NIH HHS/United States
GR  - HL90156/HL/NHLBI NIH HHS/United States
GR  - HL058795/HL/NHLBI NIH HHS/United States
GR  - HL086598/HL/NHLBI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091230
PL  - United States
TA  - Am J Pathol
JT  - The American journal of pathology
JID - 0370502
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Gonanes)
RN  - 0 (PX-866)
RN  - 0 (Phosphoinositide-3 Kinase Inhibitors)
RN  - 0 (SCGB1A1 protein, human)
RN  - 0 (Scgb1a1 protein, mouse)
RN  - 0 (Transforming Growth Factor alpha)
RN  - 9060-09-7 (Uteroglobin)
RN  - EC 2.7.11.1 (Oncogene Protein v-akt)
SB  - IM
MH  - Administration, Oral
MH  - Animals
MH  - Disease Progression
MH  - Drug Evaluation, Preclinical
MH  - Enzyme Inhibitors/administration & dosage/pharmacology/therapeutic use
MH  - Gonanes/administration & dosage/*pharmacology/*therapeutic use
MH  - Mice
MH  - Mice, Transgenic
MH  - Oncogene Protein v-akt/metabolism
MH  - *Phosphoinositide-3 Kinase Inhibitors
MH  - Phosphorylation/drug effects
MH  - Pulmonary Fibrosis/*chemically induced/*prevention & control
MH  - *Transforming Growth Factor alpha
MH  - Uteroglobin/genetics
PMC - PMC2808075
EDAT- 2010/01/01 06:00
MHDA- 2010/03/17 06:00
PMCR- 2011/02/01
CRDT- 2010/01/01 06:00
PHST- 2010/01/01 06:00 [entrez]
PHST- 2010/01/01 06:00 [pubmed]
PHST- 2010/03/17 06:00 [medline]
PHST- 2011/02/01 00:00 [pmc-release]
AID - S0002-9440(10)60382-3 [pii]
AID - 10.2353/ajpath.2010.090123 [doi]
PST - ppublish
SO  - Am J Pathol. 2010 Feb;176(2):679-86. doi: 10.2353/ajpath.2010.090123. Epub 2009 
      Dec 30.