morphinans and Acute-Lung-Injury

Sepsis is a systemic inflammatory response syndrome caused by a host's immune response to infection. Acute lung injury (ALI) is one of the most common complications of sepsis with high mortality and morbidity. Recent evidence demonstrated that the 'gut-lung axis' was related to the progression of septic acute lung injury, which regarded gut microbiota and intestinal barrier as two critical factors correlated with acute lung injury. Sinomenine is an isoquinoline alkaloid component extracted from Sinomenium acutum Rehd，et Wils, which has been already reported to have significant anti-inflammatory, immunosuppressive, and anti-arthritis properties. In this research, we observed that sinomenine could repair the lung injury and alleviate inflammatory response induced by cecum ligation and puncture (CLP). Illumine sequencing of 16S rDNA revealed that sinomenine could improve the richness of gut microbiota and modulate the composition of intestinal flora in cecum ligation and puncture mice. Meanwhile, sinomenine could reduce the colon pathological damage and improve the intestine barrier integrity in cecum ligation and puncture mice. We also found that the molecular mechanism of sinomenine's protective effect on intestinal tract was related to the activation of aryl hydrocarbon receptor/nuclear factor erythroid-2 related factor 2（Nrf2）pathway both in vivo and vitro experiments. Collectively, the prevention of septic acute lung injury by sinomenine might be mediated by modulating gut microbiota and restoring intestinal barrier via aryl hydrocarbon receptor/Nrf2-dependent pathway.

Topics: Acute Lung Injury; Animals; Anti-Inflammatory Agents; Basic Helix-Loop-Helix Transcription Factors; Cecum; Cell Line, Tumor; Cytokines; Disease Models, Animal; Gastrointestinal Microbiome; Gastrointestinal Tract; Homeostasis; Humans; Inflammation; Ligation; Male; Mice, Inbred ICR; Morphinans; NF-E2-Related Factor 2; Permeability; Protective Agents; Punctures; Receptors, Aryl Hydrocarbon

Stephania yunnanensis H. S. Lo is widely used as an antipyretic, analgesic and anti-inflammatory herbal medicine in SouthWest China. In this study, we investigated the anti-inflammatory activity and mechanism of sinoacutine (sino), one of the primary components extracted from this plant.. A RAW264.7 cell model was established using lipopolysaccharide (LPS) induced for estimation of cytokines in vitro, qPCR was used to estimate gene expression, western blot analysis was used to estimate protein level and investigate the regulation of NF- κB, JNK and MAPK signal pathway. In addition, an acute lung injury model was established to determine lung index and levels of influencing factors.. Taken together, our results demonstrate that sino is a promising drug to alleviate LPS-induced inflammatory reactions.

Topics: Acute Lung Injury; Animals; Animals, Outbred Strains; Anti-Inflammatory Agents; China; Male; MAP Kinase Kinase 4; MAP Kinase Signaling System; Mice; Molecular Structure; Morphinans; NF-kappa B; Plant Extracts; RAW 264.7 Cells

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

Acute lung injury (ALI) is a common disease characterized by pulmonary inflammation and oxidative stress. Sinomenine (SIN) is an alkaloid originally extracted from the Chinese medicinal plant Sinomenium acutum. It has been shown to have anti-inflammatory and anti-oxidative effect. However, it's unclear whether SIN can alleviate ALI. In this study, we assessed the effect of SIN on Escherichia coli (E.coli)-induced ALI mouse model. Mice were conditioned with SIN or placebo 1 h before intratracheally instilled with E.coli. Lung water content, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity, Myeloperoxidase (MPO) levels and inflammatory cytokines production were measured. Immunohistochemistry and western blot were performed to measure target protein expression. E.coli induced histological changes indicating tissues damage and increased W/D ratio, MPO activity, MDA content, and inflammatory cytokines production in the Lung. Whereas in mice pretreated with SIN, these changes were absent. E.coli-induced NF-κB activation was also inhibited by SIN. In addition, SIN increased the expression of HO-1, NQO1 and Nrf2 in lung tissues. Our results suggest that SIN attenuates ALI through the inhibition of inflammation and oxidative stress.

Topics: Acute Lung Injury; Animals; Bronchoalveolar Lavage Fluid; Cytokines; Escherichia coli; Female; Inflammation; Lung; Malondialdehyde; Mice, Inbred ICR; Morphinans; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Protective Agents; Protein Kinase C; Signal Transduction; Superoxide Dismutase

Zhengqing Fengtongning (ZQFTN), the pharmaceutical preparation of sinomenine (SIN) derived from the medicinal plant Sinmenium acutum, is well-known in China as an effective treatment for rheumatoid arthritis (RA). However, its histamine-release anaphylactoid reactions (HRARs) occur often in some patients. Therefore, it is desirable to establish effective clinical protocols to manage such HRARs. In the study, rat models with systemic HRARs and local HRARs of the skin were established. The level of vascular permeability and mast cell numbers was determined by quantitative analysis using Evans blue dye and histological assays. The levels of histamine, leukotriene B4 (LTB4) and IL-33 in plasma were detected by UHPLC-SPE-MS, ELISA and immunohistochemistry assays, respectively. The results demonstrated that SIN significantly induced both systemic and local HRARs in rats, showing significant decrease of body temperature, increases in vascular permeability in skin, injury of lung tissues and mast cell infiltration and IL-33 expression in skin and lung tissues. Mechanistic study showed that tranilast could prevent SIN-triggered HRARs via inhibition of H1 receptor gene expression and NF-κB signaling. Our findings provide evidence that mast cell membrane stabilizers and H1 receptor blockers effectively prevent SIN-induced HRARs, and cromolyn, cetirizine and tranilast can be used in the clinic for the management of HRARs induced by ZQFTN.

Topics: Acute Lung Injury; Anaphylaxis; Animals; Anti-Allergic Agents; Cetirizine; Cromolyn Sodium; Female; Histamine; Histamine H1 Antagonists; Histamine Release; Interleukin-33; Leukotriene B4; Lung; Mast Cells; Morphinans; NF-kappa B; ortho-Aminobenzoates; Rats, Sprague-Dawley; Receptors, Histamine H1; Signal Transduction; Skin

Sinomenine (SIN) is a bioactive alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, which is widely used in the clinical treatment of rheumatoid arthritis (RA). However, its role in acute lung injury (ALI) is unclear. In this study, we investigate the role of SIN in lipopolysaccharide (LPS)-induced ALI in mice. After ALI, lung water content and histological signs of pulmonary injury were attenuated, whereas the PaO2/FIO2 (P/F) ratios were elevated significantly in the mice pretreated with SIN. Additionally, SIN markedly inhibited inflammatory cytokine TNF-α and IL-1β expression levels as well as neutrophil infiltration in the lung tissues of the mice. Microarray analysis and real-time PCR showed that SIN treatment upregulated adenosine A(2A) receptor (A(2A)R) expression, and the protective effect of SIN was abolished in A(2A)R knockout mice. Further investigation in isolated mouse neutrophils confirmed the upregulation of A(2A)R by SIN and showed that A(2A)R-cAMP-PKA signaling was involved in the anti-inflammatory effect of SIN. Taken together, these findings demonstrate an A(2A)R-associated anti-inflammatory effect and the protective role of SIN in ALI, which suggests a potential novel approach to treat ALI.

Topics: Acute Lung Injury; Animals; Cells, Cultured; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Gene Expression Profiling; Gene Expression Regulation; Interleukin-1beta; Lipopolysaccharides; Mice; Mice, Knockout; Morphinans; Neutrophils; Receptor, Adenosine A2A; Signal Transduction; Sinomenium; Tumor Necrosis Factor-alpha