Beneficial effects of a bradykinin antagonist in a model of gram-negative sepsis.
Activation of the kallikrein-kinin system in sepsis has long been recognized, but its role, beneficial or pathologic, has not been determined. Recently, however, specific bradykinin (BK) antagonists have become available and we sought to determine the effects of a BK antagonist, NPC17731, in a model of sepsis-induced acute lung injury (ALI).


METHODS
Anesthetized swine were studied for 5 hours, receiving a 1-hour infusion of saline (Controls) or live Pseudomonas aeruginosa (Septic untreated). Treatment groups received a 5 mg/kg bolus of NPC17731 followed by a 1 mg/kg bolus hourly commencing either just before sepsis (Pretreatment) or 30 minutes following the onset of sepsis (Posttreatment).


RESULTS
Septic untreated animals showed a rapid, progressive decline in arterial PaO2 compared to controls, and this was significantly improved in both treatment groups. Bronchoalveolar lavage at 5 hours in both treatment groups also showed significant decreases in neutrophil (PMN) counts and protein content compared to untreated septic animals, indicating decreased PMN migration and alveolar-capillary membrane damage. Both treatment groups also showed reduced PMN sequestration in the lung compared to untreated animals, although PMNs did exhibit significant upregulation of PMN CD18 receptor expression and superoxide generation.


CONCLUSIONS
These data imply a significant role for BK in the pathogenesis of sepsis-induced ALI. Use of a competitive BK antagonist significantly attenuated the development of ALI without inhibiting PMN activation. BK antagonists may be a useful adjunct in the armamentarium against sepsis-induced ALI.
Ridings
P C
PC
Department of Surgery, Medical College of Virginia, Richmond 23298, USA.
Blocher
C R
CR
Fisher
B J
BJ
Fowler
A A
AA
Sugerman
H J
HJ
D000818:Animals; D001920:Bradykinin / Q000037:antagonists & inhibitors*; D001992:Bronchoalveolar Lavage Fluid; D004195:Disease Models, Animal; D006439:Hemodynamics / Q000187:drug effects; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology / Q000627:therapeutic use*; D011552:Pseudomonas Infections / Q000188:drug therapy* / Q000276:immunology; D011659:Pulmonary Gas Exchange; D018805:Sepsis / Q000188:drug therapy* / Q000276:immunology; D013552:Swine
D009842:Oligopeptides; C071327:NPC 17731; D001920:Bradykinin