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: J E Sevransky, G Shaked, A Novogrodsky, A Levitzki, A Gazit, A Hoffman, R J Elin, Z M Quezado, B D Freeman, P Q Eichacker, R L Danner, S M Banks, J Bacher, M L Thomas 3rd, C Natanson
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 99 Issue 8 Pg. 1966-73 (Apr 15 1997) ISSN: 0021-9738 [Print] United States
• PMID: 9109441 (Publication Type: Journal Article)

Chemical References

• Benzylidene Compounds
• Enzyme Inhibitors
• Nitriles
• Phenols
• Tumor Necrosis Factor-alpha
• Tyrphostins
• AG 127
• AG 556
• gamma-Glutamyltransferase
• Protein-Tyrosine Kinases

Topics

• Animals
• Benzylidene Compounds (pharmacology)
• Disease Models, Animal
• Dogs
• Enzyme Inhibitors (pharmacology)
• Escherichia coli Infections (complications, drug therapy, physiopathology)
• Heart (drug effects, physiopathology)
• In Vitro Techniques
• Lung (drug effects, physiopathology)
• Multiple Organ Failure (etiology, prevention & control)
• Nitriles (pharmacology)
• Peritonitis (complications, drug therapy, physiopathology)
• Phenols (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Shock, Septic (complications, drug therapy, physiopathology)
• Signal Transduction (drug effects)
• Tumor Necrosis Factor-alpha (metabolism)
• Tyrphostins
• gamma-Glutamyltransferase (blood)