A CRTH2 antagonist, CT-133, suppresses NF-κB signalling to relieve lipopolysaccharide-induced acute lung injury.

Abstract

Acute lung injury (ALI) and acute respiratory distress syndrome are life-threatening conditions that still have no definite pharmacotherapy. Hence, we investigate the potential effectiveness and underlying mechanism of CT-133, a newly developed selective antagonist of prostaglandin D2 receptor 2 (DP2) or of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2), against lipopolysaccharide (LPS)-induced ALI. CT-133 (10 or 30 mg/kg) or dexamethasone (1 mg/kg, positive control) were intragastrically administered 1 h before and 12 h after intratracheal LPS instillation, and primary neutrophils and macrophages and RAW264.7 macrophages were used to investigate the role of CT-133 in regulation of their functions. LPS induced a significant secretion of PGD2 from primary macrophages, however, CT-133 dose-dependently and markedly decreased the infiltration of neutrophils and macrophages into lungs, reduced the IL-1β, TNF-α, IL-6, and KC levels in broncho-alveolar lavage (BAL) fluids, decreased the wet weight and myeloperoxidase activity of lungs, reduced Evans blue and albumin exudation into lungs, and improved the lung histopathological changes and hypoxemia. Moreover, CT-133 significantly suppressed the primary neutrophil migration toward the PGD2 and robustly inhibited the mRNA and protein expression of IL-1β, TNF-α, IL-6, and KC in primary and RAW264.7 macrophages in response to either LPS- or PGD2 stimulation. Finally, CT-133 significantly blocked the LPS-induced P65 activation in both RAW264.7 macrophages and mouse lungs. Thus, This is the first report that a CRTH2 antagonist, CT-133, is capable of significantly alleviating LPS-induced lung injury by probably down-regulating the NF-κB signalling.

• Authors: Musaddique Hussain, Chengyun Xu, Xiling Wu, Meiping Lu, Lanfang Tang, Fugen Wu, Ximei Wu, Junsong Wu
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 854 Pg. 79-91 (Jul 05 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 30951719 (Publication Type: Journal Article)
• Copyright: Copyright © 2019. Published by Elsevier B.V.

Chemical References

• Boronic Acids
• CRTH2 antagonist CT-133
• Chemokines
• Lipopolysaccharides
• NF-kappa B
• Receptors, Immunologic
• Receptors, Prostaglandin
• Prostaglandin D2
• prostaglandin D2 receptor

Topics

• Acute Lung Injury (drug therapy, pathology)
• Animals
• Boronic Acids (pharmacology, therapeutic use)
• Bronchoalveolar Lavage Fluid (chemistry)
• Cell Movement (drug effects)
• Chemokines (metabolism)
• Lipopolysaccharides
• Lung (drug effects, immunology, metabolism, pathology)
• Macrophages, Peritoneal (drug effects, metabolism)
• Mice
• Mice, Inbred BALB C
• NF-kappa B (metabolism)
• Neutrophils (cytology, drug effects)
• Permeability (drug effects)
• Prostaglandin D2 (metabolism)
• RAW 264.7 Cells
• Receptors, Immunologic (antagonists & inhibitors)
• Receptors, Prostaglandin (antagonists & inhibitors)
• Signal Transduction (drug effects)