Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis

Jonathan E. Sevransky, Gade Shaked, Abraham Novogrodsky, Alexander Levitzki, Aviv Gazit, Amnon Hoffman, Ronald J. Elin, Zenaide M.N. Quezado, Bradley D. Freeman, Peter Q. Eichacker, Robert L. Danner, Steven M. Banks, John Bacher, Marvin L. Thomas, Charles Natanson

Research output: Contribution to journalArticlepeer-review

53 Scopus citations


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 ≤ 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.

Original languageEnglish
Pages (from-to)1966-1973
Number of pages8
JournalJournal of Clinical Investigation
Issue number8
StatePublished - Apr 15 1997


  • cell signaling pathways
  • multiorgan failure
  • septic shock
  • tyrosine kinase inhibitor


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