title: Blockade of the JNK signalling as a rational therapeutic approach to modulate the early and late steps of the inflammatory cascade in polymicrobial sepsis.
abstract: Cecal ligation and puncture (CLP) is an experimental polymicrobial sepsis induced systemic inflammation that leads to acute organ failure. Aim of our study was to evaluate the effects of SP600125, a specific c-Jun NH2-terminal kinase (JNK) inhibitor, to modulate the early and late steps of the inflammatory cascade in a murine model of CLP-induced sepsis. CB57BL/6J mice were subjected to CLP or sham operation. Animals were randomized to receive either SP600125 (15 mg/kg) or its vehicle intraperitoneally 1 hour after surgery and repeat treatment every 24 hours. To evaluate survival, a group of animals was monitored every 24 hours for 120 hours. Two other animals were sacrificed 4 or 18 hours after surgical procedures; lung and liver samples were collected for biomolecular and histopathologic analysis. The expression of p-JNK, p-ERK, TNF-α, HMGB-1, NF-κB, Ras, Rho, Caspase 3, Bcl-2, and Bax was evaluated in lung and liver samples; SP600125 improved survival, reduced CLP induced activation of JNK, NF-κB, TNF-α, and HMGB-1, inhibited proapoptotic pathway, preserved Bcl-2 expression, and reduced histologic damage in both lung and liver of septic mice. SP600125 protects against CLP induced sepsis by blocking JNK signalling; therefore, it can be considered a therapeutic approach in human sepsis.
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Gabriele
authors: 0000-0002-7806-435X
authors: G
authors: Pizzino
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Alessandra
authors: 0000-0001-9300-7532
authors: A
authors: Bitto
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Giovanni
authors: 0000-0002-4187-2265
authors: G
authors: Pallio
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Natasha
authors: 0000-0002-1134-7080
authors: N
authors: Irrera
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Federica
authors: 0000-0002-8786-8042
authors: F
authors: Galfo
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Monica
authors: M
authors: Interdonato
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Anna
authors: A
authors: Mecchio
authors: Department of Paediatric, Gynaecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy.
authors: Filippo
authors: F
authors: De Luca
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.
authors: Letteria
authors: L
authors: Minutoli
authors: Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy ; Section of Pharmacology, Department of Clinical and Experimental Medicine, Torre Biologica 5th Floor, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98125 Messina, Italy.
authors: Francesco
authors: F
authors: Squadrito
authors: Department of Paediatric, Gynaecological, Microbiological and Biomedical Sciences, University of Messina, Messina, Italy.
authors: Domenica
authors: 0000-0002-1033-0527
authors: D
authors: Altavilla
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000627:therapeutic use; D053148:Caspase 3 / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D018631:ras Proteins / Q000032:analysis
chemical_list: D000873:Anthracenes; D016328:NF-kappa B; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; C432165:pyrazolanthrone; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D018631:ras Proteins