Tyrphostin AG 556 improves survival and reduces multiorgan failure in canine Escherichia coli peritonitis.
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.
Sevransky
J E
JE
Department of Critical Care Medicine, National Institutes of Health, Bethesda, Maryland 20892, USA. jsevransky@nih.gov
Shaked
G
G
Novogrodsky
A
A
Levitzki
A
A
Gazit
A
A
Hoffman
A
A
Elin
R J
RJ
Quezado
Z M
ZM
Freeman
B D
BD
Eichacker
P Q
PQ
Danner
R L
RL
Banks
S M
SM
Bacher
J
J
Thomas
M L
ML
Natanson
C
C
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
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