RRC ID 57321
Author Chen H, Zhang Y, Zhang W, Liu H, Sun C, Zhang B, Bai B, Wu D, Xiao Z, Lum H, Zhou J, Chen R, Liang G.
Title Inhibition of myeloid differentiation factor 2 by baicalein protects against acute lung injury.
Journal Phytomedicine
Abstract BACKGROUND:ALI/ARDS is characterized by severe hypoxemic respiratory failure attributed to inflammatory tissue injury. There are no treatment modalities able to prevent/reverse the dire pathological sequelae in these patients. Evidence links the inflammatory lung injury to uncontrolled activation of the immune signaling complex, TLR4-MD2 (Toll-like receptor-myeloid differentiation factor 2). Baicalein, a natural flavonoid, is reported to have robust anti-inflammatory properties, but its inhibition mechanism remains unclear.
HYPOTHESIS/PURPOSE:This study investigated the protective mechanisms of baicalein on ALI/ARDS.
METHODS:We used two experimental mouse models of LPS-induced ALI, pulmonary infection model (intratracheal LPS), and systemic infection model (intravenous LPS). Blood, BALF, lung and liver tissues were analyzed using routine methods. In vitro studies using peritoneal mouse macrophages or recombinant proteins were designed to elucidate inhibition mechanisms of baicalein.
RESULTS:Our critical new findings revealed that Baicalein was an MD2 inhibitor, directly bound to MD2, effectively suppressing TLR4-MD2 activation and the subsequent MAPK and NF-κB signaling. The inhibited MD2 prevented development of inflammatory tissue injury and improved survival. The importance of MD2 in the inflammatory injury in ALI was corroborated by data obtained from MD2-/- mice, which did not develop the characteristic LPS-induced lung tissue damage. Thus, the findings indicated that MD2 was critical for development of ALI, functioning as an early upstream signal driving the progression of inflammatory injury.
CONCLUSION:Baicalein, as a direct and selective MD2 inhibitor, inhibited the early upstream TLR4-MD2 signaling and is a promising therapeutic agent for the treatment of ALI/ARDS.
Volume 63
Pages 152997
Published 2019-10-1
DOI 10.1016/j.phymed.2019.152997
PII S0944-7113(19)30164-3
PMID 31254764
MeSH Acute Lung Injury / chemically induced Acute Lung Injury / metabolism Acute Lung Injury / prevention & control* Animals Cells, Cultured Cytokines / metabolism Flavanones / chemistry Flavanones / metabolism Flavanones / pharmacology* Humans Lipopolysaccharides / toxicity Lymphocyte Antigen 96 / antagonists & inhibitors* Lymphocyte Antigen 96 / genetics Lymphocyte Antigen 96 / metabolism Macrophages / drug effects Macrophages / metabolism Macrophages / pathology Male Mice, Inbred C57BL Mice, Knockout NF-kappa B / metabolism Protective Agents / pharmacology* Toll-Like Receptor 4 / metabolism
IF 4.18
Times Cited 5
Resource
Mice B6.129P2-Ly96(RBRC02388)