Adenosine deaminase inhibition attenuates microvascular dysfunction and improves survival in sepsis.
The ability of increased endogenous adenosine to mitigate microvascular derangements in sepsis was studied. Pentostatin (2'-deoxycoformycin), an inhibitor of adenosine deaminase, was administered to mice immediately after induction of sepsis by cecal ligation and puncture. Intravital video microscopy of cremasteric postcapillary venules was performed. Leukocyte rolling and adhesion were significantly increased in septic mice compared with control mice. Treatment of septic mice with pentostatin significantly decreased leukocyte rolling and adhesion (6.02 +/- 0.09 versus 1.72 +/- 0.12 rolling cells/min, 2.07 +/- 0.04 versus 0.62 +/- 0.05 adherent cells/100 microm per minute; p < 0.001). Albumin leakage (ratio) was significantly attenuated in septic animals treated with pentostatin (0.42 +/- 0.05 versus 0.21 +/- 0.04; p < 0.01). Circulating levels of interleukin-6, tumor necrosis factor-alpha, and soluble tumor necrosis factor type II receptor were decreased in septic mice treated with pentostatin. Survival was significantly improved at 48 hours in mice treated with pentostatin. These results suggest an important role for adenosine in modulating both leukocyte-dependent and -independent mechanisms of endothelial injury in sepsis. Exploiting the advantageous action of endogenous adenosine represents a potentially useful and novel therapeutic approach for the treatment of sepsis.
Cohen
Elliott S
ES
Section of Pulmonary and Critical Care Medicine, Rush-Presbyterian-St. Lukes Medical Center, Chicago, Illinois 60612, USA. ecohenus@yahoo.com
Law
William R
WR
Easington
Cordus R
CR
Cruz
Kenneth Q
KQ
Nardulli
Beth A
BA
Balk
Robert A
RA
Parrillo
Joseph E
JE
Hollenberg
Steven M
SM
D000243:Adenosine Deaminase / Q000187:drug effects; D058892:Adenosine Deaminase Inhibitors; D000704:Analysis of Variance; D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects*; D004730:Endothelium, Vascular / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015649:Pentostatin / Q000494:pharmacology / Q000627:therapeutic use*; D018805:Sepsis / Q000188:drug therapy* / Q000503:physiopathology; D016019:Survival Analysis
D058892:Adenosine Deaminase Inhibitors; D004791:Enzyme Inhibitors; D015649:Pentostatin; D000243:Adenosine Deaminase