TYRPHOSTIN AG-556 IMPROVES SURVIVAL AND REDUCES MULTIORGAN FAILURE INCANINE ESCHERICHIA-COLI PERITONITIS

Tyrosine kinase-dependent cell signaling is postulated to be a pivotal control point in inflammatory responses initiated by bacterial produc ts and TNF. Using a canine model of gram-negative septic shock, we inv estigated the effect of tyrosine kinase inhibitors (tyrphostins) on su rvival. Animals were infected intraperitoneally with Escherichia coli 0111: B4, and then, in a randomized, blinded fashion, were treated imm ediately with one of two tyrphostins, AG 556 (n = 40) or AG 126 (n = 1 0), or with control (n = 50), and followed for 28 d or until death. Al l animals received supplemental oxygen, fluids, and antibiotics. Tyrph ostin 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 co ntrols (all P less than or equal to 0.05). These improvements in organ injury were significantly predictive of survival. Treatment with AG 5 56 had no effect on clearance of endotoxin or bacteria from the blood (both P = NS); however, AG 556 did significantly lower serum TNF level s (P = 0.03). These data are consistent with the conclusion that AG 55 6 prevented cytokine-induced multiorgan failure and death during septi c shock by inhibiting cell-signaling pathways without impairing host d efenses as determined by clearance of bacteria and endotoxin.