Blunted hypoxic pulmonary vasoconstriction in experimental neonatal chronic lung disease.
Blunted hypoxic pulmonary vasoconstriction in experimental neonatal chronic lung disease.
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DOI：
10.1164/rccm.200711-1631oc
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发表时间：
2008-08
影响因子：
24.7
通讯作者：
G. Rey-Parra;S. Archer;R. Bland;K. Albertine;D. Carlton;S. Cho;Beth Kirby;A. Haromy;F. Eaton;Xichen Wu;B. Thébaud
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文献类型：
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作者：
G. Rey-Parra;S. Archer;R. Bland;K. Albertine;D. Carlton;S. Cho;Beth Kirby;A. Haromy;F. Eaton;Xichen Wu;B. Thébaud
原理新生儿慢性肺病(CLD)是极早产儿长期住院和反复呼吸道疾病的最常见原因，它是由富含O(2)气体的长时间机械通气(MV)引起的。反复发作的低氧血症和相关的呼吸机调整往往会导致CLD的恶化。导致这些低氧血症发作的机制尚不清楚。缺氧性肺血管收缩反应(HPV)部分由O(2)敏感的电压门控钾(K(V))通道控制，是对局部低氧的一种重要的适应性反应，有助于匹配肺的灌流和换气。目的验证慢性肺损伤(CLI)损害人乳头瘤病毒(HPV)的假设。方法研究对象为早产羔羊和新生大鼠，其中早产羔羊在富氧的机械通气下持续3周，新生大鼠呼吸95%-O(2)持续2周，均可导致肺内动脉扩张和肺血管改变，符合慢性阻塞性肺疾病。测量和主要结果：早产羔羊在机械通气2周后接受CLI，新生大鼠在高氧2周后HPV减弱。高氧大鼠离体肺远端动脉(DPA)表现为K(V)1.5、K(V)2.1mRNA和K(+)电流降低，HPV和对K(V)1.x特异性抑制剂Correolide的收缩作用优先减弱。肺内基因转移K(V)1.5，编码被认为触发HPV的离子通道，增加培养的大鼠DPA平滑肌细胞的O(2)敏感性K(+)电流，并恢复高氧大鼠的HPV。结论DPA中O(2)敏感性K(V)通道的表达/活性降低是新生儿CLD中HPV钝化的原因之一。
RATIONALE Neonatal chronic lung disease (CLD), caused by prolonged mechanical ventilation (MV) with O(2)-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 O(2)-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 O(2)-rich gas for 3 weeks and newborn rats that breathed 95%-O(2) 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(v)1.x-specific inhibitor, correolide, were preferentially blunted in excised distal pulmonary arteries (dPAs) from hyperoxic rats, whose dPAs exhibited decreased K(v)1.5 and K(v)2.1 mRNA and K(+) current. Intrapulmonary gene transfer of K(v)1.5, encoding the ion channel that is thought to trigger HPV, increased O(2)-sensitive K(+) current in cultured smooth muscle cells from rat dPAs, and restored HPV in hyperoxic rats. CONCLUSIONS Reduced expression/activity of O(2)-sensitive K(v) channels in dPAs contributes to blunted HPV observed in neonatal CLD.