Pulmonary vascular endothelial growth factor and nitric oxide interaction during total cardiopulmonary bypass in...

Lung injury after cardiopulmonary bypass includes pulmonary hypertension and lung edema. Both complications are related to endothelial pulmonary vascular dysfunction, leukocyte sequestration, and increased capillary permeability. This study was done in an attempt to better define the endothelial dysfunction and the cause of edema.

Twenty-five neonatal piglets were subjected to total cardiopulmonary bypass for 90 minutes without crossclamping of the aorta. After weaning from cardiopulmonary bypass, they were allowed to survive 2 hours, at which time they were killed. Preoperative and postoperative hemodynamic studies, lung (n = 16) and muscular (n = 5) vascular endothelial growth factor contents, and exhaled nitric oxide (n = 8) were recorded. Immediately after the animals were killed, pulmonary arterial rings were obtained from 12 piglets and mounted in organ chamber for assessment of endothelial function with receptor-dependent (acetylcholine) or non-receptor-dependent (calcium ionophore A23187) studies and compared with control pulmonary arterial rings. The left lungs of 13 piglets were mounted in isolated perfused lung chambers for filtration coefficient assessment and comparison with control preparations.

After cardiopulmonary bypass, pulmonary vascular resistance increased from 953.7 +/- 302.6 dyne x s x cm(-5) to 1973.6 +/- 925.4 dyne x s x cm(-5) (P =.03). This was associated with an increase in lung vascular endothelial growth factor content from 91.07 +/- 5.314 pg/100 mg tissue to 151.6 +/- 11.4 pg/100 mg tissue (P <.0001), an increase in muscle vascular endothelial growth factor from 76.02 +/- 11.53 pg/100 mg tissue to 81.58 +/- 7.7 pg/100 mg tissue (P not significant), and a decrease in exhaled nitric oxide from 6 +/- 1.7 ppb to 3.12 +/- 1.4 ppb (P =.003). The filtration coefficient was statistically significantly higher after cardiopulmonary bypass than in control preparations (0.259 +/- 0.02 vs 0.525 +/- 0.07, P <.0001). Variations in lung vascular endothelial growth factor accumulation were statistically significantly higher than in muscular vascular endothelial growth factor accumulation (60.5 +/- 9.1 vs 5.5 +/- 5.9, P =.0008). In addition, a statistically significant correlation was found between postbypass lung vascular endothelial growth factor and lung filtration coefficient (P =.0058), as well as between change in lung vascular endothelial growth factor and change in lung filtration coefficient (P =.03). Pulmonary vascular endothelial receptor-dependent (acetylcholine) function was statistically significantly blunted after bypass relative to control values (15.44% +/- 4.8% vs 55.5% +/- 5.96% of maximal relaxation, P =.0001), whereas non-receptor-dependent endothelial function was unaffected by cardiopulmonary bypass (110.77% +/- 8.9% vs 120.63% +/- 15.46% of maximal relaxation, P not significant).

These findings suggest that lung ischemia that occurs during cardiopulmonary bypass affects the signal transduction from membrane receptors to intracellular calcium mobilization and nitric oxide synthase activation. Lung edema after bypass is probably due in part to lung accumulation of vascular endothelial growth factor, a finding that was not found in systemic muscular nonischemic territories.