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.)

To understand ventilator-induced lung injury (VILI) during positive pressure ventilation, mechanisms of normal alveolar mechanics must first be established. Isotropic "balloonlike" alveolar volume (VA) change has been viewed as the prevailing mechanism of normal lung volume (VL) changes. We hypothesized that change in VL is predominantly caused by alveolar recruitment-derecruitment (R/D). Fifteen mongrel dogs were anesthetized and intubated with a tracheal divider. Through a thoracotomy incision, in vivo microscopy of subpleural alveoli was performed as the degassed lung was inflated to 80% TLC, and then deflated to residual volume (RV). Still photomicrographs were evaluated to determine if change in VL is due to change in VA or R/D of alveoli. We noted a steady, significant increase in alveolar recruitment as VL increased to 80% TLC (p < 0.05). However, VA increased significantly, but only to 20% TLC (p < 0.05). Once recruited, alveoli did not demonstrate any further volume change, whereas the lung as a whole maintained a normal pressure/volume relationship. In our model, changes in VL predominantly are caused by R/D.

Our results indicate that preoperative left ventricular systolic function continues to influence postoperative prognosis and suggest that the discordant conclusions of previous studies probably resulted from interpretive differences and differences in patient selection.

No abstract