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Drug Repositioning to Alleviate Systemic Inflammatory Response Syndrome Caused by Gram‐Negative Bacterial Outer Membrane Vesicles
Author(s) -
Kim Ji Hyun,
Lee Jaewook,
Park KyongSu,
Hong SungWook,
Gho Yong Song
Publication year - 2018
Publication title -
advanced healthcare materials
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.288
H-Index - 90
eISSN - 2192-2659
pISSN - 2192-2640
DOI - 10.1002/adhm.201701476
Subject(s) - sepsis , systemic inflammatory response syndrome , bacterial outer membrane , gram negative bacteria , lipopolysaccharide , immune system , in vivo , microbiology and biotechnology , antibiotics , virulence , bacteria , tumor necrosis factor alpha , biology , pharmacology , immunology , escherichia coli , biochemistry , genetics , gene
Abstract Sepsis is characterized by systemic inflammatory response syndrome (SIRS) accompanied with infection. Gram‐negative bacteria can evoke sepsis by activating the host immune system, such as the release of IL‐6 and TNF‐α, through their virulence factors. Outer membrane vesicles (OMVs), nanosized bilayered proteolipids derived from Gram‐negative bacteria, harbor various virulence factors and are shown to induce SIRS. Here, drugs are repositioned to alleviate SIRS caused by Gram‐negative bacterial OMVs. Using novel OMV‐based drug screening systems, a total of 178 commercially available drugs are primarily screened, and a total of 18 repositioned drug candidates are found to effectively block IL‐6 and TNF‐α production from OMV‐stimulated macrophages. After excluding the compounds which are previously known to intervene sepsis or which show cytotoxicity to macrophages, the compounds which show dose‐dependency in inhibiting the release of IL‐6 and TNF‐α by the OMV‐stimulated macrophages in vitro and which reduce OMV‐induced SIRS in vivo are selected. Salbutamol, a β2 adrenergic receptor agonist, is selected as a novel candidate to alleviate OMV‐induced SIRS. This study sheds light on using Gram‐negative bacterial OMVs in exploring novel candidate compounds to alleviate inflammatory diseases including sepsis.