title: Profibrotic TGFβ responses require the cooperative action of PDGF and ErbB receptor tyrosine kinases.
abstract: Transforming growth factor β (TGFβ) has significant profibrotic activity both in vitro and in vivo. This reflects its capacity to stimulate fibrogenic mediators and induce the expression of other profibrotic cytokines such as platelet-derived growth factor (PDGF) and epidermal growth factor (EGF/ErbB) ligands. Here we address both the mechanisms by which TGFβ induced ErbB ligands and the physiological significance of inhibiting multiple TGFβ-regulated processes. The data document that ErbB ligand induction requires PDGF receptor (PDGFR) mediation and engages a positive autocrine/paracrine feedback loop via ErbB receptors. Whereas PDGFRs are essential for TGFβ-stimulated ErbB ligand up-regulation, TGFβ-specific signals are also required for ErbB receptor activation. Subsequent profibrotic responses are shown to involve the cooperative action of PDGF and ErbB signaling. Moreover, using a murine treatment model of bleomycin-induced pulmonary fibrosis we found that inhibition of TGFβ/PDGF and ErbB pathways with imatinib plus lapatinib, respectively, not only prevented myofibroblast gene expression to a greater extent than either drug alone, but also essentially stabilized gas exchange (oxygen saturation) as an overall measure of lung function. These observations provide important mechanistic insights into profibrotic TGFβ signaling and indicate that targeting multiple cytokines represents a possible strategy to ameliorate organ fibrosis dependent on TGFβ.
authors.affiliation: 1Stabile 858, Mayo Clinic, 200 First St., SW, Rochester, MN 55905, USA. leof.edward@mayo.edu.
authors.forename: Mahefatiana
authors.initials: M
authors.lastname: Andrianifahanana
authors.forename: Mark C
authors.initials: MC
authors.lastname: Wilkes
authors.forename: Shiv K
authors.initials: SK
authors.lastname: Gupta
authors.forename: Rod A
authors.initials: RA
authors.lastname: Rahimi
authors.forename: Claire E
authors.initials: CE
authors.lastname: Repellin
authors.forename: Maryanne
authors.initials: M
authors.lastname: Edens
authors.forename: Joshua
authors.initials: J
authors.lastname: Wittenberger
authors.forename: Xueqian
authors.initials: X
authors.lastname: Yin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Maidl
authors.forename: Jackson
authors.initials: J
authors.lastname: Becker
authors.forename: Edward B
authors.initials: EB
authors.lastname: Leof
mesh_terms: D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000627:therapeutic use; D001761:Bleomycin / Q000633:toxicity; D002460:Cell Line; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D025461:Feedback, Physiological; D000068877:Imatinib Mesylate; D000077341:Lapatinib; D008168:Lung / Q000503:physiopathology; D051379:Mice; D058628:Myofibroblasts / Q000378:metabolism; D019899:Paracrine Communication; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D011659:Pulmonary Gas Exchange; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation
chemical_list: D001549:Benzamides; D001761:Bleomycin; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D000068877:Imatinib Mesylate; D000077341:Lapatinib; D010879:Piperazines; D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta
keywords: EGF; pulmonary fibrosis
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