title: Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.
abstract: Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial products and TNF. Using a canine model of gram-negative septic shock, we investigated the effect of tyrosine kinase inhibitors (tyrphostins) on survival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated immediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 10), or with control (n = 50), and followed for 28 d or until death. All animals received supplemental oxygen, fluids, and antibiotics. Tyrphostin AG 556 improved survival times when compared to controls (P = 0.05). During the first 48 h after infection, AG 556 also improved mean arterial pressure, left ventricular ejection fraction, cardiac output, oxygen delivery, and alveolar-arterial oxygen gradient compared to controls (all P < or = 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 556 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF levels (P = 0.03). These data are consistent with the conclusion that AG 556 prevented cytokine-induced multiorgan failure and death during septic shock by inhibiting cell-signaling pathways without impairing host defenses as determined by clearance of bacteria and endotoxin.
authors.affiliation: Department of Critical Care Medicine, National Institutes of Health, Bethesda, Maryland 20892, USA. jsevransky@nih.gov
authors.forename: J E
authors.initials: JE
authors.lastname: Sevransky
authors.forename: G
authors.initials: G
authors.lastname: Shaked
authors.forename: A
authors.initials: A
authors.lastname: Novogrodsky
authors.forename: A
authors.initials: A
authors.lastname: Levitzki
authors.forename: A
authors.initials: A
authors.lastname: Gazit
authors.forename: A
authors.initials: A
authors.lastname: Hoffman
authors.forename: R J
authors.initials: RJ
authors.lastname: Elin
authors.forename: Z M
authors.initials: ZM
authors.lastname: Quezado
authors.forename: B D
authors.initials: BD
authors.lastname: Freeman
authors.forename: P Q
authors.initials: PQ
authors.lastname: Eichacker
authors.forename: R L
authors.initials: RL
authors.lastname: Danner
authors.forename: S M
authors.initials: SM
authors.lastname: Banks
authors.forename: J
authors.initials: J
authors.lastname: Bacher
authors.forename: M L
authors.initials: ML
authors.lastname: Thomas
authors.forename: C
authors.initials: C
authors.lastname: Natanson
mesh_terms: D000818:Animals; D001597:Benzylidene Compounds / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D009102:Multiple Organ Failure / Q000209:etiology / Q000517:prevention & control*; D009570:Nitriles / Q000494:pharmacology*; D010538:Peritonitis / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D010636:Phenols / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D012772:Shock, Septic / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D020032:Tyrphostins; D005723:gamma-Glutamyltransferase / Q000097:blood
chemical_list: D001597:Benzylidene Compounds; D004791:Enzyme Inhibitors; D009570:Nitriles; D010636:Phenols; D014409:Tumor Necrosis Factor-alpha; D020032:Tyrphostins; C069028:AG 127; C098981:AG 556; D005723:gamma-Glutamyltransferase; D011505:Protein-Tyrosine Kinases