title: Nuclear factor κB is a key transcription factor in the duodenal contractility alterations induced by lipopolysaccharide.
abstract: Alterations in intestinal motility are one of the features of sepsis induced by lipopolysaccharide (LPS). This study investigated the role of the nuclear transcription factor κB (NF-κB) in the LPS-induced duodenal contractility alterations, generation of reactive oxygen species (ROS) and production of cytokines in rabbit duodenum. Rabbits were treated with saline, LPS, sulfasalazine + LPS, pyrrolidinedithiocarbamate (PDTC) + LPS or RO 106-9920 + LPS. Contractility studies were performed in an organ bath. The formation of products of oxidative damage to proteins (carbonyls) and lipids (malondialdehyde and 4-hydroxyalkenals) was quantified in intestinal tissue and plasma. The protein expression of NF-κB was measured by Western blot. The DNA binding activity of NF-κB was evaluated by transcription factor activity assay. The expression of interleukin-1β, tumour necrosis factor α (TNF-α), interleukin-6, interleukin-10 and interleukin-8 mRNA was determined by RT-PCR. Sulfasalazine, PDTC and RO 106-9920 blocked the inhibitory effect of LPS on contractions induced by ACh in the longitudinal smooth muscle of rabbit duodenum. Sulfasalazine, PDTC and RO 106-9920 reduced the increased levels of malondialdehyde and 4-hydroxyalkenals and the carbonyls induced by LPS in plasma. Lipopolysaccharide induced the activation, translocation to the nucleus and DNA binding of NF-κB. Lipopolysaccharide increased the mRNA expression of interleukin-6 and TNF-α in duodenal tissue, and this effect was partly reversed by PDTC, sulfasalazine and RO 106-9920. In conclusion, NF-κB mediates duodenal contractility disturbances, the generation of ROS and the increase in the expression of interleukin-6 and TNF-α induced by LPS. Sulfasalazine, PDTC and RO 106-9920 may be therapeutic drugs to reduce these effects.
authors: Department of Pharmacology and Physiology, Faculty of Veterinary Medicine, University of Zaragoza, 50013 Zaragoza, Spain. lgralo@unizar.es
authors: Ligia Verónica
authors: LV
authors: Hernández
authors: Sergio
authors: S
authors: Gonzalo
authors: Marta
authors: M
authors: Castro
authors: María Pilar
authors: MP
authors: Arruebo
authors: Miguel Angel
authors: MA
authors: Plaza
authors: María Divina
authors: MD
authors: Murillo
authors: Laura
authors: L
authors: Grasa
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis; D004386:Duodenum / Q000187:drug effects* / Q000502:physiology; D005769:Gastrointestinal Motility / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D011817:Rabbits; D012460:Sulfasalazine / Q000494:pharmacology; D013454:Sulfoxides / Q000494:pharmacology; D013777:Tetrazoles / Q000494:pharmacology; D013859:Thiocarbamates / Q000494:pharmacology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D011759:Pyrrolidines; C461648:Ro 106-9920; D013454:Sulfoxides; D013777:Tetrazoles; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D012460:Sulfasalazine