title: Phosphatidylinositol 3-kinase isoform-specific effects in airway mesenchymal cell function.
abstract: The phosphatidylinositol 3-kinase (PI3K) signal transduction pathway is implicated in the airway remodeling associated with asthma. The class IA PI3K isoforms are known to be activated by growth factors and cytokines. Because this pathway is a possible site of pharmacological intervention for treating the disease, it is important to know which isoforms contribute to this process. Therefore, we used a pharmacological approach to investigate the roles of the three class IA PI3K isoforms (p110α, p110β, and p110δ) in airway remodeling using airway smooth muscle (ASM) cells derived from asthmatic subjects and ASM cells and lung fibroblasts from nonasthmatic subjects. These studies used the inhibitors N'-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide (PIK75) (which selectively inhibits p110α), 7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one (TGX221) (which selectively inhibits p110β), and 2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone (IC87114) (which selectively inhibits p110δ). Cells were stimulated with transforming growth factor-β (TGFβ) and/or 10% fetal bovine serum in the presence or absence of inhibitor or vehicle control (dimethyl sulfoxide). PIK75, but not TGX221 or IC87114, attenuated TGFβ-induced fibronectin deposition in all cell types tested. PIK75 and TGX221 each decreased secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic ASM cells and lung fibroblasts, whereas TGX221 was not as effective in asthmatic ASM cells. In addition, PIK75 decreased cell survival in TGFβ-stimulated asthmatic, but not nonasthmatic, ASM cells. In conclusion, specific PI3K isoforms may play a role in pathophysiological events relevant to airway wall remodeling.
authors.affiliation: Woolcock Institute of Medical Research, Sydney, Australia. lyn.moir@sydney.edu.au
authors.forename: Lyn M
authors.initials: LM
authors.lastname: Moir
authors.forename: Thomas
authors.initials: T
authors.lastname: Trian
authors.forename: Qi
authors.initials: Q
authors.lastname: Ge
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: Janette K
authors.initials: JK
authors.lastname: Burgess
authors.forename: Brian G G
authors.initials: BG
authors.lastname: Oliver
authors.forename: Judith L
authors.initials: JL
authors.lastname: Black
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000201:enzymology; D009025:Morpholines / Q000494:pharmacology; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation; D011744:Pyrimidinones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D012137:Respiratory System / Q000166:cytology / Q000378:metabolism*; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D005353:Fibronectins; D006835:Hydrazones; C477872:IC 87114; D015850:Interleukin-6; D007527:Isoenzymes; D009025:Morpholines; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011744:Pyrimidinones; D011799:Quinazolines; D013449:Sulfonamides; C504718:TGX 221; D016212:Transforming Growth Factor beta; D042461:Vascular Endothelial Growth Factor A; D058539:Phosphatidylinositol 3-Kinase; D000225:Adenine