Background-Ischemia-reperfusion injury with the resulting inflammatory response is a devastating complication of lung transplantation; much of the tissue damage could be diminished by control of the inflammatory response. Recent studies have show that antithrombin III (AT III) has an anti-inflammatory effect in addition to its established role in the regulation of blood coagulation. Thus, we hypothesized that the administration of AT III might help to prevent ischemia-reperfusion injury after lung transplantation. Methods and Results-The study was performed in a dog model of orthotopic lung transplantation. Dogs were randomly assigned to receive either vehicle (controls) or AT III. We observed that in control dogs, during the 180-minute period after lung transplantation, the arterial O 2 partial pressure decreased and both the alveolar-arterial O 2 difference and the pulmonary vascular resistance increased. By contrast, these parameters remained unchanged in the group of dogs receiving AT III. Dogs with transplants receiving AT III did not show an increase in cell adhesion molecules, and histological examination revealed almost an absence of inflammatory response. The administration of AT III produced a marked increase in serum prostacyclin (PGI 2 ) levels, whereas in control dogs, the PGI 2 levels did not change. The beneficial effect of AT III was not observed when dogs received indomethacin to prevent the stimulation of PGI 2 release by AT III. Conclusions-Our results demonstrate that AT III prevents ischemia-reperfusion injury in a dog model of lung transplantation and that this effect is conditioned by an increase in PGI 2 production.

In septic shock, hypotension, disseminated intravascular coagulation, and neutrophil activation are related to the activation of the blood coagulation contact system. This study evaluates in dogs the effect of the Cl-esterase inhibitor (C1-INH), a main inhibitor of the blood coagulation contact system, on the cardiovascular and respiratory dysfunction associated with endotoxic shock. Two groups were included: controls, which received Escherichia coli endotoxin, and a C1-INH group in which Cl-INH was infused before E. coli endotoxin administration.In both groups, endotoxin produced hypodynamic shock; however, the decrease in the systolic index and the ventricular systolic work indexes were greater in controls than the C1-INH group. In controls, the arterial 02 partial pressure decreased by 30% and the alveolo-arterial 02 difference increased by 625%, these parameters remained unchanged in the C1-INH group. Hypoxemia was associated with increased intrapulmonary shunt, decreased blood coagulation contact factors, and decreased C3c. In contrast, C1-INH administration prevented endotoxin-induced hypoxemia, the increase in intrapulmonary shunt, and the decrease in blood coagulation contact factors.This study shows that, in dogs with endotoxic shock, pulmonary dysfunction is associated with an activation of the blood coagulation contact phase system. An inhibition of this system by C1-INH prevented the hypoxemia induced by endotoxic shock. (J. Clin. Invest. 1993.91:2754-2760

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SummaryIn order to assess the role of the kallikrein-kinin (K-K) system in the pathogenesis of the adult respiratory distress syndrome (ARDS) we have prospectively determined coagulation contact phase, blood gas and hemodynamic parameters in patients with ARDS at 0, 36 and 72 h from diagnosis.Compared to normal values, significantly lower mean levels of factor XII (71.4 ± 9.8%, p <0.0005), prekallikrein (PPK) (52 ± 5.7%, p <0.0005), high molecular weight kininogen (HMWK) (73 ± 2%, p <0.0005) and α2-macroglobulin (α2-M) (51 ± 7.1%, p <0.0005) were found in ARDS patients.The functional kallikrein inhibitory activity (KKI) and Cr esterase inhibitor antigenic (CIINH) were significantly higher in these patients (113.2 ± 5, p <0.005 and 124.7 ± 7.6, p <0.0005 respectively) compared with normal values during the entire study period.The KKI/CIINH ratio decreased significantly in our ARDS patients at 0, 36 and 72 h (p <0.025; p <0.05 and p <0.005 respectively).We found a significant correlation between PPK levels and oxigenation index (r = 0.69, p <0.001), PPK and the static thoracic compliance values (r = 0.64, p <0.001). There was also a significant correlation between PPK levels and Qs/Qt (r = -0.89, p <0.001). ARDS patients that survived presented a stability in the PPK values in successive tests. Nevertheless non-survivors showed a progressive decrease in PPK levels during the follow-up period.Our results suggest that the plasma kallikrein system becomes activated during ARDS and that this activation might increase the lung vessels’ permeability. In addition, PPK levels are in our opinion a useful prognostic parameter in predicting the outcome of ARDS patients.