Pulmonary vascular dysfunction in preterm lambs with chronic lung disease

Abstract

Chronic lung injury from prolonged mechanical ventilation after premature birth inhibits the normal postnatal decrease in pulmonary vascular resistance (PVR) and leads to structural abnormalities of the lung circulation in newborn sheep. Compared with normal lambs born at term, chronically ventilated preterm lambs have increased pulmonary arterial smooth muscle and elastin, fewer lung microvessels, and reduced abundance of endothelial nitric oxide synthase. These abnormalities may contribute to impaired respiratory gas exchange that often exists in infants with chronic lung disease (CLD). Nitric oxide inhalation (iNO) reduces PVR in human infants and lambs with persistent pulmonary hypertension. We wondered whether iNO might have a similar effect in lambs with CLD. We therefore studied the effect of iNO on PVR in lambs that were delivered prematurely at approximately 125 days of gestation (term = 147 days) and mechanically ventilated for 3 wk. All of the lambs had chronically implanted catheters for measurement of pulmonary vascular pressures and blood flow. During week 2 of mechanical ventilation, iNO at 15 parts/million for 1 h decreased PVR by approximately 20% in 12 lambs with evolving CLD. When the same study was repeated in eight lambs at the end of week 3, iNO had no significant effect on PVR. To see whether this loss of iNO effect on PVR might reflect dysfunction of lung vascular smooth muscle, we infused 8-bromo-guanosine 3',5'-cyclic monophosphate (cGMP; 150 microg. kg(-1). min(-1) iv) for 15-30 min in four of these lambs at the end of week 3. PVR consistently decreased by 30-35%. Lung immunohistochemistry and immunoblot analysis of excised pulmonary arteries from lambs with CLD, compared with control term lambs, showed decreased soluble guanylate cyclase (sGC). These results suggest that loss of pulmonary vascular responsiveness to iNO in preterm lambs with CLD results from impaired signaling, possibly related to deficient or defective activation of sGC, the intermediary enzyme through which iNO induces increased vascular smooth muscle cell cGMP and resultant vasodilation.

Characteristics of pulmonary hypertension in preterm neonates

“…Prolonged MV reduces soluble guanylate cyclase in pulmonary arteries in preterm lambs and a similar phenomenon may occur in preterm infants. 23 It is probable that the physiologic immaturity of the NO signaling pathway and the anatomic immaturity of the vascular smooth muscle are responsible for the lack of response to iNO. The response of preterm infants to iNO parallels the vasodilatory response of pulmonary circulation of fetal lambs to a rise in oxygen tension.…”

Maturational changes in the regulation of pulmonary vascular tone by nitric oxide in neonatal rats

“…Alterations in NO sensitivity due to relatively low sGC protein levels may underlie the poor responsiveness seen to inhaled NO in some patients. Indeed, Bland et al (10) found that lambs born prematurely who developed pulmonary hypertension had lower levels of sGC protein and activity than did age-matched controls. In addition, these lambs with pulmonary hypertension demonstrated attenuated responses to inhaled NO compared with age-matched controls.…”

Utility of large-animal models of BPD: chronically ventilated preterm lambs

“…Both models also recapitulate the pathophysiology and pathology of evolving neonatal CLD in preterm baboons (46,49,50,58,63,124,199) and preterm lambs (5,6,20,24,25,111,139,150). We use the term "evolving neonatal CLD" for the preterm baboon and preterm lamb models and reserve the term "BPD" for preterm human infants, to avoid confusion between large-animal models vs. the human disease.…”