Inhibition of tyrosine kinase signaling after trauma-hemorrhage: a novel approach for improving organ function and decreasing susceptibility to subsequent sepsis.
OBJECTIVE
To determine whether administration of a tyrosine kinase inhibitor after trauma-hemorrhage has any beneficial effects on cardiovascular parameters and hepatocellular function and on survival rate after subsequent sepsis.


BACKGROUND
Increased inflammatory cytokine release and concomitant activation of intracellular signaling pathways contributes to multiple organ dysfunction and increased susceptibility to subsequent sepsis after severe hemorrhagic shock.


METHODS
Male Sprague-Dawley rats underwent a midline laparotomy (i.e., soft-tissue trauma induced) and were then bled to and maintained at a mean arterial pressure of 40 mmHg until 40% of the maximal shed blood volume was returned in the form of Ringer's lactate. The rats were then resuscitated with four times the shed blood volume in the form of Ringer's lactate during a 60-minute period. A tyrosine kinase inhibitor, AG 556 (7.5 mg/kg), or vehicle was administered intraperitoneally at the middle of resuscitation. At 24 hours after resuscitation, various in vivo parameters such as heart performance, cardiac index, and hepatocellular function (i.e., the maximum velocity and the overall efficiency of indocyanine green clearance) were determined. Phosphorylation state of the mitogen-activated protein kinases p44/42 and p38 in the liver was assessed by Western blot analysis. In additional groups of rats, sepsis was induced by cecal ligation and puncture at 20 hours after hemorrhage. The necrotic cecum was excised 10 hours thereafter, and the survival rate was monitored for a period of 10 days.


RESULTS
AG 556 treatment restored the depressed cardiovascular and hepatocellular functions after trauma-hemorrhage and resuscitation, which was associated with reduced phosphorylation of mitogen-activated protein kinases p44/42 and p38. Moreover, treatment with AG 556 significantly increased the survival rate of rats after trauma-hemorrhage and induction of subsequent sepsis compared with vehicle-treated rats.


CONCLUSIONS
Inhibition of tyrosine kinase signaling after trauma-hemorrhage may represent a novel therapeutic approach for improving organ functions and decreasing the death rate from subsequent sepsis under such conditions.
Jarrar
D
D
Center for Surgical Research and Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence 02903, USA.
Wang
P
P
Song
G Y
GY
Cioffi
W G
WG
Bland
K I
KI
Chaudry
I H
IH
D000818:Animals; D002302:Cardiac Output / Q000187:drug effects; D004198:Disease Susceptibility; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D006470:Hemorrhage / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D015151:Immunoblotting / Q000379:methods; D008099:Liver / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018805:Sepsis / Q000209:etiology* / Q000503:physiopathology / Q000517:prevention & control; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors; D020032:Tyrphostins / Q000494:pharmacology* / Q000627:therapeutic use; D014947:Wounds and Injuries / Q000097:blood / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*
D004791:Enzyme Inhibitors; D020032:Tyrphostins; C098981:AG 556; D011505:Protein-Tyrosine Kinases