Background-Acute lung injury (ALI) after cardiopulmonary bypass (CPB) results from sequential priming and activation of neutrophils. Activated neutrophils release neutral serine, elastase, and matrix metalloproteinases (MMPs) and oxygen radical species, which damage alveolar-capillary basement membranes and the extracellular matrix, resulting in an ALI clinically defined as adult respiratory distress syndrome (ARDS). We hypothesized that treatment with a potent MMP and elastase inhibitor, a chemically modified tetracycline (CMT-3), would prevent ALI in our sequential insult model of ALI after CPB. Methods and Results-Anesthetized Yorkshire pigs were randomized to 1 of 5 groups: control (nϭ3); CPB (nϭ5), femoral-femoral hypothermic bypass for 1 hour; LPS (nϭ7), sham bypass followed by infusion of low-dose Escherichia coli lipopolysaccharide (LPS; 1 g/kg); CPBϩLPS (nϭ6), both insults; and CPBϩLPSϩCMT-3 (nϭ5), both insults plus intravenous CMT-3 dosed to obtain a 25-mol/L blood concentration. CPBϩLPS caused severe lung injury, as demonstrated by a significant fall in PaO 2 and an increase in intrapulmonary shunt compared with all groups (PϽ0.05). These changes were associated with significant pulmonary infiltration of neutrophils and an increase in elastase and MMP-9 activity. Conclusions-All pathological changes typical of ALI after CPB were prevented by CMT-3. Prevention of lung dysfunction followed an attenuation of both elastase and MMP-2 activity. This study suggests that strategies to combat ARDS should target terminal neutrophil effectors. (Circulation. 1999;100:400-406.)

This study explores graft geometry and hemodynamics in a reproducible canine arteriovenous loop graft model of intimal-medial hyperplasia. Untapered 6 mm diameter polytetrafluoroethylene grafts (n = 10) were paired with 4 to 7 mm taper (n = 5) or 7 to 4 mm taper (n = 5) grafts for a 12-week period. Several hemodynamic variables were assessed at multiple locations, and venous intimal-medial thickness was measured at locations corresponding to the hemodynamic measurements. Color Doppler imaging demonstrated energy transfer out of the vessel in the form of perivascular tissue vibration. This was quantitated by the distance required for Doppler signal attenuation or volume of the detected vibration signal. Differences among graft types were noted for pressure, flow velocity, tissue vibration, and venous intimal-medial thickness. Hyperplasia was significantly decreased in 4 to 7 mm taper grafts. Stepwise deletion regression indicated volume of the vibration signal had a better correlation with venous intimal-medial thickness than any other variable (r 0.9, p less than 0.001). We conclude that graft geometry can have a significant impact on hemodynamic factors and venous intimal-medial hyperplasia in arteriovenous loop grafts. Flow disturbances appear to cause energy transfer through the vessel wall and into perivascular tissue. Kinetic energy transfer in the form of perivascular tissue vibration was quantitated in vivo and correlates strongly with venous intimal-medial thickness.

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