Targeting myeloid differentiation protein 2 by the new chalcone L2H21 protects LPS-induced acute lung injury.

Abstract

Acute inflammatory diseases are the leading causes of mortality in intensive care units. Myeloid differentiation 2 (MD-2) is required for recognizing lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and represents an attractive therapeutic target for LPS-induced inflammatory diseases. In this study, we report a chalcone derivative, L2H21, as a new MD2 inhibitor, which could inhibit LPS-induced inflammation both in vitro and in vivo. We identify that L2H21 as a direct inhibitor of MD-2 by binding to Arg90 and Tyr102 residues in MD-2 hydrophobic pocket using a series of biochemical experiments, including surface plasmon response, molecular docking and amino acid mutation. L2H21 dose dependently inhibited LPS-induced inflammatory cytokine expression in primary macrophages. In mice with LPS intratracheal instillation, L2H21 significantly decreased LPS-induced pulmonary oedema, pathological changes in lung tissue, protein concentration increase in bronchoalveolar lavage fluid, inflammatory cells infiltration and inflammatory gene expression, accompanied with the decrease in pulmonary TLR4/MD-2 complex. Meanwhile, administration with L2H21 protects mice from LPS-induced mortality at a degree of 100%. Taken together, this study identifies a new MD2 inhibitor L2H21 as a promising candidate for the treatment of acute lung injury (ALI) and sepsis, and validates that inhibition of MD-2 is a potential therapeutic strategy for ALI.

• Authors: Yali Zhang, Tingting Xu, Beibei Wu, Hongjin Chen, Zheer Pan, Yi Huang, Liqin Mei, Yuanrong Dai, Xing Liu, Xiaoou Shan, Guang Liang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 4 Pg. 746-757 (04 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 27860279 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• (E)-2,3-dimethoxy-3',4'-dihydroxychalcone
• Chalcones
• Cytokines
• Inflammation Mediators
• Lipopolysaccharides
• Lymphocyte Antigen 96
• Protective Agents
• Chalcone

Topics

• Acute Lung Injury (chemically induced, drug therapy, mortality, pathology)
• Animals
• Chalcone (chemistry, pharmacology, therapeutic use)
• Chalcones (chemistry, pharmacology, therapeutic use)
• Cytokines (metabolism)
• Humans
• Inflammation Mediators (metabolism)
• Lipopolysaccharides
• Lung (pathology)
• Lymphocyte Antigen 96 (antagonists & inhibitors, chemistry, metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Models, Molecular
• Molecular Targeted Therapy
• Protective Agents (chemistry, pharmacology, therapeutic use)
• RAW 264.7 Cells
• Shock, Septic (chemically induced, pathology)