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Pulmonary vascular dysfunction in preterm lambs with chronic lung disease
Richard D Bland1, Con Yee Ling, Kurt H Albertine
1Department of Pediatrics, Stanford University School of Medicine, CCSR Bldg., Rm. 1225, 269 Campus Dr., Stanford, CA 94305-5162, USA. rbland@stanford.edu
Summary
In preterm lambs with chronic lung disease, inhaled nitric oxide (iNO) initially reduced pulmonary vascular resistance (PVR). However, this effect was lost over time due to impaired signaling, likely involving soluble guanylate cyclase (sGC).
Area of Science:
- Neonatology
- Pulmonary Medicine
- Cardiovascular Research
Background:
- Chronic lung injury from mechanical ventilation in premature lambs increases pulmonary vascular resistance (PVR) and alters lung vasculature.
- These changes include increased smooth muscle and elastin, fewer microvessels, and reduced endothelial nitric oxide synthase, contributing to impaired gas exchange in chronic lung disease (CLD).
- Inhaled nitric oxide (iNO) is known to reduce PVR in persistent pulmonary hypertension.
Purpose of the Study:
- To investigate the effect of iNO on PVR in preterm lambs with experimentally induced CLD.
- To determine if the pulmonary vascular response to iNO changes over time during mechanical ventilation.
- To explore the underlying mechanisms of altered iNO responsiveness, focusing on smooth muscle signaling pathways.
Main Methods:
- Preterm lambs (gestation ~125 days) were mechanically ventilated for 3 weeks, developing CLD.
- Pulmonary vascular pressures and blood flow were monitored using chronically implanted catheters.
- iNO (15 ppm) was administered for 1 hour during weeks 2 and 3 of ventilation. 8-bromo-cGMP was infused to assess smooth muscle responsiveness. Immunohistochemistry and immunoblotting analyzed soluble guanylate cyclase (sGC) expression.
Main Results:
- In week 2 of ventilation, iNO significantly decreased PVR by ~20% in lambs with evolving CLD.
- By week 3, iNO had no significant effect on PVR.
- Infusion of 8-bromo-cGMP caused a 30-35% decrease in PVR, indicating preserved smooth muscle function.
- Analysis revealed decreased sGC in pulmonary arteries of lambs with CLD compared to controls.
Conclusions:
- Pulmonary vascular responsiveness to iNO is transiently lost in preterm lambs with CLD.
- This loss of responsiveness is likely due to impaired nitric oxide signaling, specifically deficient or defective activation of sGC.
- These findings highlight a potential mechanism for persistent pulmonary hypertension in infants with CLD and suggest therapeutic targets beyond iNO.