bay-11-7082 and Sepsis

Acute inflammatory diseases, such as sepsis, are life-threatening illnesses. Regulating the α7 nicotinic acetylcholine receptor (α7 nAchR)-mediated signaling may be a promising strategy to treat sepsis. Diarylheptanoids have long been found to exhibit anti-inflammatory properties. However, the possible mechanism of diarylheptanoids has rarely been investigated. In this study, we isolated and synthesized 49 diarylheptanoids and analogues and evaluated their anti-inflammatory activities. Among them, compounds 28 and 40 markedly blocked lipopolysaccharide (LPS)-induced production of nitric oxide (NO), interleukin-1β (IL-1β) and interleukin-6 in murine RAW264.7 cells. Furthermore, compounds 28 and 40 also effectively attenuated LPS-induced sepsis, acute lung injury, and cytokines release in vivo. Mechanistically, compounds 28 and 40 significantly induced phosphorylation of janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling and suppression of nuclear factor-κB (NF-κB) pathway. Furthermore, blocking α7 nAchR could effectively abolish compounds 28 and 40-mediated activation of JAK2-STAT3 signaling as well as inhibition of NF-κB activation and NO production in LPS-exposed RAW264.7 cells. Collectively, our findings have identified a new diarylheptanoid, compound 28, as an agonist of α7 nAchR-JAK2-STAT3 signaling, which can be potentially developed as a valuable candidate for the treatment of sepsis, and provide a new lead structure for the development of anti-inflammatory agents targeting α7 nAchR-JAK2-STAT3 signaling.

Topics: Animals; Anti-Inflammatory Agents; Diarylheptanoids; Janus Kinase 2; Lipopolysaccharides; Macrophages; Mice; NF-kappa B; Sepsis; STAT3 Transcription Factor

Experiments on random-bred albino mice showed that NF-κB inhibitor (BAY 11-7082) and β2-adrenoreceptor agonist (dexmedetomidine hydrochloride) significantly reduced mouse mortality in 4 and 24 h after sepsis modeling (intraperitoneal administration of E. coli) by reducing blood levels of proinflammatory cytokines TNFα, IL-1β, and IL-6. The combined administration of NF-κB inhibitor and β2-adrenoreceptors agonist have an additive effect.

Topics: Adrenergic beta-Agonists; Animals; Cytokines; Dexmedetomidine; Female; Male; Mice; NF-kappa B; Nitriles; Sepsis; Signal Transduction; Sulfones

Toll-like receptors and complement are two components of the innate immunity. Complement factor B is essential for the alternative pathway of complement activation. We have recently reported that complement factor B is significantly up-regulated in the kidney and may contribute to acute tubular injury in an animal model of sepsis. This study investigates the mechanisms responsible for the complement factor B up-regulation and its role in sodium transporter expression in tubular cells during sepsis.. Animal study.. Laboratory investigation.. C57BL/6 J wild-type, complement factor B(-/-), and Nfkb1(tm1Bal) p50(-/-) mice.. Human proximal tubular cells and mouse tubular epithelial cells were stimulated with Toll-like receptor agonists. Bay 11-7082 was used to block nuclear factor-κB pathway. Alternative pathway activation was detected by C3 zymosan deposition. Polymicrobial sepsis was created by cecal ligation and puncture. Sodium transporter gene expression was determined by quantitative reverse transcriptase-polymerase chain reaction.. The agonists for Toll-like receptor 4 (lipopolysaccharide) or Toll-like receptor 3 (polyinosinic-polycytidylic acid) induced a marked increase in complement factor B expression in human proximal tubular cells and mouse tubular epithelial cells both at gene and protein levels. The Toll-like receptor 1/2 agonist, Pam3cys, induced complement factor B production only in human proximal tubular cells, not in mouse tubular epithelial cells. The Toll-like receptor 9 ligand, CpG oligodeoxynucleotides failed to induce complement factor B production either in human proximal tubular cells or in mouse tubular epithelial cells. Lipopolysaccharide/polyinosinic-polycytidylic acid-induced complement factor B up-regulation was blocked by Bay 11-7082, a potent inhibitor of nuclear factor-κB signaling, and in mouse tubular epithelial cells deficient in p50 subunit of nuclear factor-κB. Media from the lipopolysaccharide-treated mouse tubular epithelial cell cultures contained de novo synthesized complement factor B and led to functional alternative pathway activation. In a cecal ligation and puncture model, wild-type septic mice had down-regulated expression of sodium transporters in the kidney compared with the sham. In comparison, complement factor B mice or mice treated with anti-complement factor B displayed preserved levels of Na⁺/K⁺ ATPase-α1 following sepsis.. 1) Toll-like receptor 3/4 activation is sufficient to induce complement factor B production via nuclear factor-κB pathway and to enhance alternative pathway activation in the kidney tubular epithelial cells. 2) Complement factor B may contribute to the down-regulation of certain sodium transporter expression during sepsis.

Topics: Animals; Biological Transport, Active; Complement Factor B; Disease Models, Animal; Down-Regulation; Epithelial Sodium Channels; Female; Gene Expression; Humans; Kidney; Kidney Tubules, Proximal; Male; Mice; Mice, Inbred C57BL; NF-kappa B; Nitriles; Potassium Channels; Reverse Transcriptase Polymerase Chain Reaction; Sepsis; Signal Transduction; Sulfones; Toll-Like Receptors; Up-Regulation

Hydrogen sulfide (H(2)S) is recognized increasingly as a proinflammatory mediator in various inflammatory conditions. Here, we have investigated the role of H(2)S in regulating expression of some endothelial adhesion molecules and recruitment of leukocytes to inflamed sites in sepsis. Male Swiss mice were subjected to cecal ligation and puncture (CLP)-induced sepsis and treated with saline (i.p.), DL-propargylglycine (PAG; 50 mg/kg, i.p.), an inhibitor of H(2)S formation or NaHS (10 mg/kg, i.p.), an H(2)S donor. PAG was administered 1 h before or after the induction of sepsis, and NaHS was given at the same time of CLP. Using intravital microcopy, we found that in sepsis, prophylactic and therapeutic administration of PAG reduced leukocyte rolling and adherence significantly in mesenteric venules coupled with decreased mRNA and protein levels of adhesion molecules (ICAM-1, P-selectin, and E-selectin) in lung and liver. In contrast, injection of NaHS up-regulated leukocyte rolling and attachment significantly, as well as tissue levels of adhesion molecules in sepsis. Conversely, normal mice were given NaHS (10 mg/kg, i.p.) to induce lung inflammation, with or without NF-kappaB inhibitor BAY 11-7082 pretreatment. NaHS treatment enhanced the level of adhesion molecules and neutrophil infiltration in lung. These alterations were reversed by pretreatment with BAY 11-7082. Moreover, expression of CXCR2 in neutrophils obtained from H(2)S-treated mice was up-regulated significantly, leading to an obvious elevation in MIP-2-directed migration of neutrophils. Therefore, H(2)S acts as an important endogenous regulator of leukocyte activation and trafficking during an inflammatory response.

Topics: Alkynes; Animals; Cell Adhesion; Cell Adhesion Molecules; Chemokine CXCL2; Enzyme Inhibitors; Glycine; Hydrogen Sulfide; Inflammation Mediators; Leukocyte Rolling; Liver; Lung; Male; Mesenteric Veins; Mice; Neutrophil Infiltration; Neutrophils; NF-kappa B; Nitriles; Pneumonia; Receptors, Interleukin-8B; Sepsis; Sulfides; Sulfones; Up-Regulation