title: 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 Arg90and Tyr102residues 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.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Xu
authors.affiliation: The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Wu
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Hongjin
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Orthopedic Surgery, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Zheer
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Oral Prophylaxis and Hygiene, School and Hospital of Stomatology, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Liqin
authors.initials: L
authors.lastname: Mei
authors.affiliation: The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Yuanrong
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.affiliation: The Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Xiaoou
authors.initials: X
authors.lastname: Shan
authors.affiliation: Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced* / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D000818:Animals; D002599:Chalcone / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D047188:Chalcones / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000473:pathology; D051218:Lymphocyte Antigen 96 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000067996:RAW 264.7 Cells; D012772:Shock, Septic / Q000139:chemically induced / Q000473:pathology
chemical_list: C000621699:(E)-2,3-dimethoxy-3',4'-dihydroxychalcone; D047188:Chalcones; D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D051218:Lymphocyte Antigen 96; D020011:Protective Agents; D002599:Chalcone
keywords: 
  LPS
  ; acute lung injury; chalcone; myeloid differentiation 2; sepsis