morphinans and Sepsis

Our present study focused on assessing whether Sinomenine (SIN) could attenuate sepsis-induced acute lung injury (ALI).. The mice were conditioned with SIN 1 h before intraperitoneal injection of lipopolysaccharide (LPS). Lung wet/dry (W/D) ratio, inflammatory level in bronchoalveolar lavage fluid (BALF), malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity and inflammatory cytokines production were detected. The expression of nuclear factor erythroid 2-like 2 (Nrf2) and autophagy-related proteins were detected by Western blot and immunohistochemical analyses. In addition, the RAW264.7 cells were treated with SIN 1 h before treatment with LPS. Inflammatory cytokines, iNOS and COX2 were detected. The expression of Nrf2 and autophagy-related proteins were explored by Western blot analysis.. Experiments in vivo and in vitro discovered that LPS significantly increased the degree of injury, inflammatory cytokines production and oxidative stress. However, the increase was significantly inhibited by treatment of SIN. In addition, SIN was found to upregulate the expression of Nrf2 and autophagy-related proteins both in vivo and in vitro.. Our data suggested that SIN could attenuate septic-associated ALI effectively, probably due to the inhibition of inflammation and oxidative stress through Nrf2 and autophagy pathways.

Topics: Acute Lung Injury; Animals; Autophagy; Cytokines; Female; Inflammation; Kelch-Like ECH-Associated Protein 1; Lipopolysaccharides; Mice; Mice, Inbred ICR; Morphinans; NF-E2-Related Factor 2; Oxidative Stress; RAW 264.7 Cells; Sepsis

Sepsis, a systemic inflammatory response to infection, is the major cause of death in intensive care units (ICUs). The mortality rate of sepsis remains high even though the treatment and understanding of sepsis both continue to improve. Sinomenine (SIN) is a natural alkaloid extracted from Chinese medicinal plant Sinomenium acutum, and its hydrochloride salt (Sinomenine hydrochloride, SIN-HCl) is widely used to treat rheumatoid arthritis (RA). However, its role in sepsis remains unclear. In the present study, we investigated the role of SIN-HCl in sepsis induced by cecal ligation and puncture (CLP) in BALB/c mice and the corresponding mechanism. SIN-HCl treatment improved the survival of BALB/c mice that were subjected to CLP and reduced multiple organ dysfunction and the release of systemic inflammatory mediators. Autophagy activities were examined using Western blotting. The results showed that CLP-induced autophagy was elevated, and SIN-HCl treatment further strengthened the autophagy activity. Autophagy blocker 3-methyladenine (3-MA) was used to investigate the mechanism of SIN-HCl in vitro. Autophagy activities were determined by examining the autophagosome formation, which was shown as microtubule-associated protein light chain 3 (LC3) puncta with green immunofluorescence. SIN-HCl reduced lipopolysaccharide (LPS)-induced inflammatory cytokine release and increased autophagy in peritoneal macrophages (PM). 3-MA significantly decreased autophagosome formation induced by LPS and SIN-HCl. The decrease of inflammatory cytokines caused by SIN-HCl was partially aggravated by 3-MA treatment. Taken together, our results indicated that SIN-HCl could improve survival, reduce organ damage, and attenuate the release of inflammatory cytokines induced by CLP, at least in part through regulating autophagy activities.

Topics: Adenine; Animals; Autophagy; Cecum; Cell Line; Cytokines; Disease Models, Animal; Kidney; Lipopolysaccharides; Liver; Lung; Macrophages; Male; Mice; Mice, Inbred BALB C; Microtubule-Associated Proteins; Morphinans; Sepsis; Survival Rate

Topics: Adult; Age Factors; Amenorrhea; Endocarditis; Female; France; Gangrene; Hepatitis; Heroin; Humans; Injections; Male; Middle Aged; Morphinans; Pharmaceutic Aids; Sepsis; Sexually Transmitted Diseases; Skin Manifestations; Social Behavior Disorders; Social Conditions; Substance-Related Disorders