Session Information
Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud's - Pathogenesis, Animal Models and Genetics
Session Type: Abstract Submissions (ACR)
Background/Purpose: The hallmark of pulmonary fibrosis is thickening and scarring of the tissue caused by increased deposition of extracellular matrix (ECM) proteins like collagen and fibronectin. Pulmonary fibrosis is a feature of several diseases including systemic sclerosis (SSc). MMS-350, a highly soluble small organic bis-oxetanyl sulfoxide, was recently shown to protect against radiation induced fibrosis. The low toxicity, high solubility and oral bioavailability of MMS-350 make it a promising therapeutic agent. Our goal was to determine the efficacy of this novel drug, MMS-350 and its analogs, in both in vitro and in vivo models of pulmonary fibrosis.
Methods: Primary human lung fibroblasts from normal donors were treated with TGFβ and MMS-350 for 72 h. Levels of ECM and pro-fibrotic proteins were assessed using immunoblotting. To study the effects of MMS-350 in vivo, 8-week old C57BL/6J mice were given bleomycin intratracheally to induce pulmonary fibrosis and PBS or MMS-350 orally on a daily basis for either 5 or 14 days. RNA was isolated from lung tissues and collagen 1A2 mRNA levels were measured by qRT-PCR. Paraffin embedded lung tissues were examined histologically following H&E staining and imaging. Collagen content was measured using the hydroxyproline assay.
Results: Fibroblasts treated with TGFβ and MMS-350 versus TGFβ alone showed a significant reduction in ECM (collagen and fibronectin), secreted (CTGF and IGFBP-3), and intracellular (α-SMA) pro-fibrotic markers. MMS-350 decreased these markers when added at the same time and when added up to 6 hours after TGFβ. One analog that differed from MMS-350 by the replacement of an oxetanyl methylene side chain with a phenyl ring, KRL507-031, showed a decrease in ECM and pro-fibrotic factors at concentrations 10-fold lower than the parent compound. Both the survival and mouse weight improved in the MMS-350 treated mice. Collagen 1A2 mRNA levels were significantly reduced in MMS-350 treated mice. H&E staining of lung tissue from mice treated with bleomycin and MMS-350 exhibited a reduction of scarring, and a significant reduction of collagen content in comparison to bleomycin.
Conclusion: These studies demonstrate that MMS-350 is an anti-fibrotic agent and are consistent with recent data demonstrating the ability of MMS-350 to reduce fibrosis in thoracic irradiated C57BL/6NTac mice. MMS-350 significantly reduced pro-fibrotic factors and ECM proteins both in vitro and in vivo. A lipophilic analog of MMS-350, KRL507-031, exhibited similar anti-fibrotic effect albeit at lower concentrations. The fact that MMS-350 was effective at reducing pulmonary fibrosis induced by different triggers and that it is orally available make it an attractive lead candidate for the development of a therapy for organ fibrosis.
Disclosure:
L. Mlakar,
None;
T. Takihara,
None;
M. Sprachman,
None;
P. Wipf,
None;
C. Feghali-Bostwick,
None.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/anti-fibrotic-effects-of-an-investigational-drug-bis-oxetanyl-sulfoxide/