Antifibrotic effect of lysophosphatidic acid receptors LPA1 and LPA3 antagonist on experimental murine scleroderma induced by bleomycin.

Abstract

The study of lysophosphatidic acid (LPA) receptor has recently focused on its involvement in the pathogenesis of systemic sclerosis (SSc). We examined the inhibitory effects of the antagonist for the LPA receptor, a selective LPA1 and LPA3 antagonist (Ki16425), on dermal and lung fibrosis in a mouse model of SSc. Ki16425 was administered intra-dermally after 6 h on the same sites as bleomycin injection. Histopathological examination showed that skin lesions were markedly attenuated by treatment with Ki16425 at doses of 1 and 10 mg/kg, along with reduced dermal thickness. Hydroxyproline contents in the Ki16425-treated skin showed a decrease of 35% (1 mg/kg) and 45% (10 mg/kg) compared with those in the oil-injected skin of the controls. The number of mast cells and phospho-Smad2/3-positive spindle cells of the Ki16425-treated skin was significantly decreased compared with that in the controls. Additionally, RT-PCR analysis showed that the mRNA levels of TGF-β1, CTGF, MIP-1α, IFN-γ and collagen α1(I) were significantly decreased in both the 1-mg/kg and 10-mg/kg groups of the Ki16425-treated mice compared with those in the controls. Furthermore, treatment with bleomycin and Ki16425 showed reduction in lung fibrosis, and the hydroxyproline contents in the lungs of the Ki16425-treated mice showed a decrease of 25% (1 mg/kg) and 32% (10 mg/kg) compared with those in the lungs of the controls. Taken together, Ki16425 was found to improve dermal and lung fibrosis in a mouse model of bleomycin-induced murine scleroderma. These results suggest that Ki16425 has the potential to be an effective new treatment for scleroderma.

• Authors: Takenobu Ohashi, Toshiyuki Yamamoto
• Journal: Experimental dermatology (Exp Dermatol) Vol. 24 Issue 9 Pg. 698-702 (Sep 2015) ISSN: 1600-0625 [Electronic] Denmark
• PMID: 25959255 (Publication Type: Journal Article)
• Copyright: © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Chemical References

• 3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid
• CCN2 protein, mouse
• Ccl3 protein, mouse
• Chemokine CCL3
• Collagen Type I
• Isoxazoles
• Propionates
• RNA, Messenger
• Receptors, Lysophosphatidic Acid
• Smad2 Protein
• Smad2 protein, mouse
• Smad3 Protein
• Smad3 protein, mouse
• Transforming Growth Factor beta1
• Bleomycin
• Connective Tissue Growth Factor
• Interferon-gamma
• Hydroxyproline

Topics

• Animals
• Bleomycin
• Cell Count
• Chemokine CCL3 (genetics)
• Collagen Type I (genetics)
• Connective Tissue Growth Factor (genetics)
• Disease Models, Animal
• Female
• Fibrosis
• Hydroxyproline (metabolism)
• Interferon-gamma (genetics)
• Isoxazoles (administration & dosage, therapeutic use)
• Lung (drug effects, metabolism, pathology)
• Mast Cells
• Mice
• Propionates (administration & dosage, therapeutic use)
• RNA, Messenger (metabolism)
• Receptors, Lysophosphatidic Acid (antagonists & inhibitors)
• Scleroderma, Systemic (chemically induced, drug therapy, metabolism, pathology)
• Skin (drug effects, metabolism, pathology)
• Smad2 Protein (metabolism)
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta1 (genetics)