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Blunted Hypoxic Pulmonary Vasoconstriction in Experimental Neonatal Chronic Lung Disease

¹ Department of Pediatrics, and ⁷ Vascular Biology Group, University of Alberta, Edmonton, Alberta, Canada; ² Section of Cardiology, University of Chicago, Chicago, Illinois; ³ Department of Pediatrics, Stanford University School of Medicine, Stanford, California; ⁴ Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, Utah; ⁵ Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia; and ⁶ Department of Pediatrics, Chonbuk National University Medical School, Keum-am Dong, Chonju, Korea

Correspondence and requests for reprints should be addressed to Bernard Thébaud, M.D., Ph.D., Canada Research Chair in Translational Lung and Vascular Developmental Biology. University of Alberta, HMRC 407, Edmonton, AB, T6G 2S2 Canada. E-mail: bthebaud{at}ualberta.ca

Rationale: Neonatal chronic lung disease (CLD), caused by prolonged mechanical ventilation (MV) with O₂-rich gas, is the most common cause of long-term hospitalization and recurrent respiratory illness in extremely premature infants. Recurrent episodes of hypoxemia and associated ventilator adjustments often lead to worsening CLD. The mechanism that causes these hypoxemic episodes is unknown. Hypoxic pulmonary vasoconstriction (HPV), which is partially controlled by O₂-sensitive voltage-gated potassium (K_v) channels, is an important adaptive response to local hypoxia that helps to match perfusion and ventilation in the lung.

Objectives: To test the hypothesis that chronic lung injury (CLI) impairs HPV.

Methods: We studied preterm lambs that had MV with O₂-rich gas for 3 weeks and newborn rats that breathed 95%-O₂ for 2 weeks, both of which resulted in airspace enlargement and pulmonary vascular changes consistent with CLD.

Measurements and Main Results: HPV was attenuated in preterm lambs with CLI after 2 weeks of MV and in newborn rats with CLI after 2 weeks of hyperoxia. HPV and constriction to the K_v1.x-specific inhibitor, correolide, were preferentially blunted in excised distal pulmonary arteries (dPAs) from hyperoxic rats, whose dPAs exhibited decreased K_v1.5 and K_v2.1 mRNA and K⁺ current. Intrapulmonary gene transfer of K_v1.5, encoding the ion channel that is thought to trigger HPV, increased O₂-sensitive K⁺ current in cultured smooth muscle cells from rat dPAs, and restored HPV in hyperoxic rats.

Conclusions: Reduced expression/activity of O₂-sensitive K_v channels in dPAs contributes to blunted HPV observed in neonatal CLD.

Key Words: hyperoxia • lung injury • gene therapy • potassium channels • bronchopulmonary dysplasia

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Recurrent episodes of hypoxemia and associated ventilator adjustments often lead to worsening of neonatal chronic lung disease (CLD). The mechanism that causes these hypoxemic episodes is unknown. What This Study Adds to the Field Blunted hypoxic pulmonary vasoconstriction (HPV) due to reduced expression/activity of O2-sensitive Kv channels may explain hypoxemic episodes. Restoring Kv channel activity restores HPV. Modulation of Kv channels may improve management of neonatal CLD.