Abstract
Wound healing generally induces an inflammatory response associated with tissue fibrosis in which activated macrophage and myofibroblast cells are primarily involved. Although this is known to be the underlying mechanism for scarring and various fibrotic pathologies, no effective intervention is currently available. We identified (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol (LCB 03-0110), a thienopyridine derivative, as a potent inhibitor of discoidin domain receptor family tyrosine kinases and discovered that this compound strongly inhibits several tyrosine kinases, including the c-Src family, spleen tyrosine kinase, Bruton's tyrosine kinase, and vascular endothelial growth factor receptor 2, which are important for immune cell signaling and inflammatory reactions. LCB 03-0110 suppressed the proliferation and migration of primary dermal fibroblasts induced by transforming growth factor β1 and type I collagen, and this result correlated with the inhibition ability of the compound against enhanced expression of α-smooth muscle actin and activation of Akt1 and focal adhesion kinase. In J774A.1 macrophage cells activated by lipopolysaccharide LCB 03-0110 inhibited cell migration and nitric oxide, inducible nitric-oxide synthase, cyclooxygenase 2, and tumor necrosis factor-α synthesis. LCB 03-0110 applied topically to full excisional wounds on rabbit ears suppressed the accumulation of myofibroblast and macrophage cells in the healing wound and reduced hypertrophic scar formation after wound closing, without delaying the wound closing process. Taken together, the pharmacological activities of LCB 03-0110 suggest that it could be an effective agent for suppressing fibroinflammation by simultaneously targeting activated fibroblasts and macrophages.
Footnotes
This study was supported by the Korea Institute of Science and Technology [Grant 2V01550] and LegoChem Biosciences Inc. [Grant 2I20750].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- NO
- nitric oxide
- iNOS
- inducible nitric-oxide synthase
- DDR
- discoidin domain receptor
- FAK
- focal adhesion kinase
- LPS
- lipopolysaccharide
- TNF
- tumor necrosis factor
- COX
- cyclooxygenase
- PDGF
- platelet-derived growth factor
- TGF
- transforming growth factor
- VEGF
- vascular endothelial growth factor
- Btk
- Bruton's tyrosine kinase
- Syk
- spleen tyrosine kinase
- FLT
- fms-like tyrosine kinase
- Hck
- hematopoietic cell kinase
- Lck
- lymphocyte-specific protein tyrosine kinase
- ECM
- extracellular matrix
- DMEM
- Dulbecco's modified Eagle's media
- HEK
- human embryonic kidney
- FBS
- fetal bovine serum
- TBS
- Tris-buffered saline
- HPF
- high-power field
- RTK
- receptor tyrosine kinase
- JNK
- c-Jun NH2-terminal kinase
- MAPK
- mitogen-activated protein kinase
- IκB
- inhibitor of nuclear factor-κB
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- Eph
- ephrin
- LCB 03-0110
- (3-(2-(3-(morpholinomethyl)phenyl)thieno[3,2-b]pyridin-7-ylamino)phenol.
- Received August 31, 2011.
- Accepted November 28, 2011.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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