COPD合并慢性缺氧患者肺血管对急性缺氧反应变化中肺动脉平滑肌细胞钾通道的作用

目的：以人离体肺动脉环缺氧张力变化为对象研究钾通道在缺氧性肺血管收缩（HPV）发生中的作用。 方法： 从手术室切取人肺动脉环，进行人肺动脉环张力试验，分正常对照组，单纯慢性阻塞性肺病（chronic obstructive pulmonary disease ，COPD）组和COPD合并慢性缺氧组，分别利用相应的特异性阻断剂观察电压门控性钾通道（KV），钙离子激活的钾通道（KCa）， ATP敏感的钾通道（KATP），在缺氧性肺血管收缩（HPV）的作用。 结果： （1）3组肺动脉环在急性缺氧时血管收缩张力均增加，同时COPD＋慢性缺氧组增加百分比显著低于对照组；COPD组与对照组无显著差异。（2）4-AP阻断Kv后较阻断前，3组肺血管环缺氧张力增加幅度均显著降低（P<0.05），同时正常对照组和COPD组降低幅度明显大于慢性缺氧组。TEA阻断KCa后以及格列苯脲（glybenclamide）阻断KATP后二者较阻断前，3组肺血管环缺氧张力均显著增加（P<0.05），同时COPD＋慢性缺氧组增加的幅度明显大于正常组（分别是P<0.01和P<0.05）。 结论： （1）慢性缺氧可降低肺血管的收缩性及肺血管对急性缺氧的收缩反应；（2）Kv在3组人离体肺动脉环HPV反应中均起介导作用，慢性缺氧可使此介导作用加强；KCa和KATP在3组人离体肺动脉环HPV反应中均起调节作用，慢性缺氧可使此调节作用加强。     

Effect of adenovirus-mediated gene transfer of nitric oxide synthase on vascular reactivity of rat isolated pulmonary arteries

Aerosol gene transfer of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) to rat lungs increased NOS expression and activity, and prevented hypoxic pulmonary vasoconstriction (HPV) in vivo. Hereby, we examined the effect of eNOS and iNOS aerosol gene transfer on the endothelium-dependent relaxation (EDR) and on acute HPV in isolated rat pulmonary arteries. Changes in isometric forces were recorded in organ baths for large conduit arteries (diameter 1.8±0.1 mm) and in a wire myograph for small resistance arteries (258±35 μm). Male Wistar rats were randomly aerosolized with adenovirus (Ad) encoding β-galactosidase (control), eNOS, or iNOS. Four days later, exhaled nitric oxide was measured, NOS expression within rat lungs was evaluated by quantitative real-time polymerase chain reaction and immunohistochemistry, vasoconstricting agonist and acetylcholine concentration response curves were generated, and the time course of HPV was recorded. Human eNOS and murine iNOS were expressed within rat lung tissue mostly in parenchyma and endothelial cells. Large arteries isolated from Ad-i, eNOS-aerosolized rats developed lower agonist-induced tension than those of control rats. The first and second contractions of the HPV were smaller in the Ad-i, eNOS-aerosolized rats. Contractions were modestly, but significantly and inversely, related to exhaled NO. Agonist- and hypoxia-induced contractions were even more reduced after eNOS aerosolization. There was no significant effect on EDR and no notable difference between small and large vessels. We conclude that adenovirus (Ad)-mediated NOS gene transfer can counteract both pharmacologically and hypoxia-induced increases in pulmonary vascular tone in isolated rat pulmonary arteries. eNOS seems as efficient as iNOS in regulating pulmonary vascular tone.     

Acute and chronic hypoxic pulmonary vasoconstriction: a central role for endothelin-1?

In the pulmonary circulation, a decrease in oxygen tension results in the development of hypoxic pulmonary vasoconstriction (HPV), although the exact mechanism by which HPV occurs remains unclear. Evidence gathered from many laboratories suggests that while pulmonary arterial smooth muscle cells (PASMCs) can sense and respond to changes in oxygen tension, full expression of HPV requires modulating influences from the endothelium. In this review, we propose a model of HPV, based on recent studies from our laboratory, in which endothelin-1 (ET-1), a vasoactive peptide released from the endothelium, plays a central role and discuss how this model may be involved in the long-term adaptation to hypoxia.     

The principal pathways involved in the in vivo modulation of hypoxic pulmonary vasoconstriction,pulmonary arterial remodelling and pulmonary hypertension

Hypoxic pulmonary vasoconstriction (HPV) serves to optimize ventilation–perfusion matching in focal hypoxia and thereby enhances pulmonary gas exchange. During global hypoxia, however, HPV induces general pulmonary vasoconstriction, which may lead to pulmonary hypertension (PH), impaired exercise capacity, right‐heart failure and pulmonary oedema at high altitude. In chronic hypoxia, generalized HPV together with hypoxic pulmonary arterial remodelling, contribute to the development of PH. The present article reviews the principal pathways in the in vivo modulation of HPV, hypoxic pulmonary arterial remodelling and PH with primary focus on the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways. In summary, endothelin‐1 and thromboxane A₂ may enhance, whereas nitric oxide and prostacyclin may moderate, HPV as well as hypoxic pulmonary arterial remodelling and PH. The production of prostacyclin seems to be coupled primarily to cyclooxygenase‐1 in acute hypoxia, but to cyclooxygenase‐2 in chronic hypoxia. The potential role of adenine nucleotides in modulating HPV is unclear, but warrants further study. Additional modulators of the pulmonary vascular responses to hypoxia may include angiotensin II, histamine, serotonin/5‐hydroxytryptamine, leukotrienes and epoxyeicosatrienoic acids. Drugs targeting these pathways may reduce acute and/or chronic hypoxic PH. Endothelin receptor antagonists and phosphodiesterase‐5 inhibitors may additionally improve exercise capacity in hypoxia. Importantly, the modulation of the pulmonary vascular responses to hypoxia varies between species and individuals, with hypoxic duration and age. The review also define how drugs targeting the endothelin‐1, nitric oxide, cyclooxygenase and adenine nucleotide pathways may improve pulmonary haemodynamics, but also impair pulmonary gas exchange by interference with HPV in chronic lung diseases.     

K~ 通道在正常与慢性低氧大鼠低氧性肺血管收缩反应中的作用

目的 :探讨K 通道在慢性低氧致低氧性肺血管收缩反应降低中的作用。方法 :采用离体肺灌流实验 ,研究 4-AP(4-aminopyridine ,电压依赖性K 通道 -Kv阻滞剂 )、TEA(tetraethylamonium ,Ca2 激活性K 通道 -KCa阻滞剂 )、GLIB(glibenclamide,ATP敏感性K 通道 -KATP阻滞剂 )对正常与慢性低氧大鼠肺血管低氧反应的影响。结果 :4-AP、TEA均可使正常大鼠肺动脉基础压上升 ,且使其肺血管低氧反应明显增强 ;对于慢性低氧大鼠 ,其肺血管对低氧反应明显低下 ,4-AP、TEA升肺动脉基础压的作用明显低于对照鼠肺 ,GLIB也呈现升高肺动脉基础压力作用 ,4-AP、TEA、GLIB均可使肺血管低氧反应大大增强 ,增强的比例明显大于正常对照组。结论 :在离体灌流鼠肺HPV中 ,Kv、KCa的开放起调节作用 ,大鼠经慢性低氧后 ,肺血管反应性明显降低 ,可能与Kv、KCa、KATP在HPV中的调节作用相对增强有关     

交感神经在肺泡缺氧性肺血管收缩反应中的作用

在大鼠毁髓模型上观察缺氧与不缺氧情况下电刺激肺血管的脊髓交感中枢时体、肺循环的变化。常氧时电刺激脊髓T_(1～3)节段时P_(pa)、PVR增高(P<0.05);毁髓去神经支配大鼠吸入12%O_2低氧气体后仍能引起肺血管收缩反应(HPV),但PVR上升幅度较正常大鼠降低。在缺氧基础上电刺激T_(1～3)节段引起P_(pa)、PVR大幅度增高(P<0.05),约为常氧时电刺激效应的二倍;酚妥拉明可抑制这一反应。提示交感神经兴奋对HPV的形成有一定的促进作用。缺氧时体循环对交感兴奋的反应减弱。     

钾离子通道在大鼠慢性低氧所致肺血管低反应中的作用

目的与方法：采用阻断剂及离体肺内动脉血管环方法,研究不同类型钾离子通道对慢性低压低氧的大鼠模型的低氧性肺血管收缩反应（HPV）的作用,旨在探讨钾离子通道在慢性低氧肺血管低反应机制中的作用。结果：①慢性低氧15 d、30 d可降低肺血管对急性低氧的收缩反应。②分别阻断正常对照组、慢性低氧组大鼠肺血管钙激活性钾通道（K_Ca）、ATP敏感的钾通道（K_ATP）,均使其HPV反应明显增强,其中慢性低氧组增强幅度显著高于正常对照组（P<0.01）。③阻断正常对照组、慢性低氧组大鼠肺血管延迟整流性钾通道（K_DR）对其HPV均无明显影响。结论：K_Ca、K_ATP在HPV反应起着重要的调节作用,慢性低氧可使此调节作用显著加强,这可能是导致肺血管低反应一个重要机制。     

连代低氧培养肺动脉平滑肌及内皮细胞的急性低氧反应中环核苷酸的作用

目的:探讨环核苷酸在慢性低氧动物的低氧性肺血管收缩反应(HPV)弱化机制中的作用。方法:用RIA法测定连代常氧与连代低氧培养猪肺动脉平滑肌细胞(PASMC)和内皮细胞(PAEC)的cAMP和cGMP及其在急性低氧时的变化;用图像分析系统检测常氧与低氧培养PASMC在急性低氧时的收缩程度。结果:低氧组PASMC的cAMP、cGMP和PAEC的cGMP基础值较常氧组低(P＜0.01)。急性低氧状态下,低氧组PASMC的cAMP、cGMP含量升高(P＜0.01);低氧组弱收缩反应PASMC的百分率明显高于常氧组。结论:慢性低氧PASMC和PAEC的cAMP、cGMP基础值下降可能与慢性低氧动物肺动脉基础张力增高有关;慢性低氧PASMC在急性低氧反应时cAMP、cGMP含量升高可能是慢性低氧机体HPV弱化的机制之一。     

K+通道在正常与慢性低氧大鼠低氧性肺血管收缩反应中的作用

目的:探讨K⁺通道在慢性低氧致低氧性肺血管收缩反应降低中的作用。方法:采用离体肺灌流实验,研究4-AP(4-aminopyridine,电压依赖性K⁺通道-Kv阻滞剂)、TEA(tetraethylamonium,Ca²⁺激活性K⁺通道-K_Ca阻滞剂)、GLIB(glibenclamide,ATP敏感性K⁺通道-K_ATP阻滞剂)对正常与慢性低氧大鼠肺血管低氧反应的影响。结果:4-AP、TEA均可使正常大鼠肺动脉基础压上升,且使其肺血管低氧反应明显增强;对于慢性低氧大鼠,其肺血管对低氧反应明显低下,4-AP、TEA升肺动脉基础压的作用明显低于对照鼠肺,GLIB也呈现升高肺动脉基础压力作用,4-AP、TEA、GLIB均可使肺血管低氧反应大大增强,增强的比例明显大于正常对照组。结论:在离体灌流鼠肺HPV中,Kv、K_Ca的开放起调节作用,大鼠经慢性低氧后,肺血管反应性明显降低,可能与Kv、K_Ca、K_ATP在HPV中的调节作用相对增强有关。     

Hypoxic pulmonary vasoconstriction is heterogeneously distributed in the prone dog

Hypoxic pulmonary vasoconstriction (HPV) is thought to protect gas exchange by decreasing perfusion to hypoxic regions. However, with global hypoxia, non-uniformity in HPV may cause over-perfusion to some regions, leading to high-altitude pulmonary edema. To quantify the spatial distribution of HPV and regional PO2 (PRO2) among small lung regions (approximately 2.0 cm3), five prone beagles (approximately 8.3 kg) were anesthetized and ventilated (PEEP approximately 2 cm H2O) with an F1O2 of 0.21, then 0.50, 0.18, 0.15, and 0.12 in random order. Regional blood perfusion (Q), ventilation (VA) and calculated PRO2 were obtained using iv infusion of 15 microm and inhalation of 1 microm fluorescent microspheres. Lung pieces were clustered by their relative blood flow response to each F1O2. Clusters were shown to be spatially grouped within animals and across animals. Lung piece resistance increased as PRO2 decreased to 60-70 mmHg but dropped at PRO2's < 60mmHg. Regional ventilation changed little with hypoxia. HPV varied more in strength of response, rather than PRO2 response threshold. In initially homogeneous VA/Q lungs, we conclude that HPV response is heterogeneous and spatially clustered.     

Chronic hypoxia inhibits tetrahydrobiopterin-induced NO production in rat lungs

Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS). Oxidative stress oxidises BH4 to dihydrobioptein (BH2), resulting in the uncoupling of the two enzymatic domains of NOS and the production of superoxide rather than NO (NOS uncoupling). Oxidative stress is known to be increased in the early stage of chronic hypoxia. This study investigated the participation of NOS uncoupling in the early phase of hypoxia-induced pulmonary hypertension in rats.Rats were exposed to 10% O₂ for 4 days. We investigated the effect of BH4 in vitro on isolated rat lungs and isolated rat peripheral pulmonary blood vessels and in vivo on exhaled NO concentration in exhaled air.BH4 attenuated hypoxic pulmonary vasoconstriction in isolated lungs and its effect was reversed by l-NAME (NOS inhibitor). The main finding of the study is that the effect of BH4 was smaller in rats exposed to 4 days of hypoxia than in normoxic controls. The finding was similar in isolated pulmonary blood vessels. BH4 increased exhaled NO in both normoxic and hypoxic rats. This increase was blunted by l-NIL (specific iNOS inhibitor) and therefore attributable to iNOS.We conclude that BH4 increased NO production in both normoxic and hypoxic rats. The increase was, however, smaller in hypoxic lungs than in controls. We assume that the smaller increase in NO production in hypoxic lungs is due to the decreased BH4/BH2 ratio in chronic hypoxia and NOS uncoupling resulting from this condition.     

High altitude pulmonary edema: a pressure-induced leak

High altitude pulmonary edema (HAPE) is a non-cardiogenic pulmonary edema that can occur in healthy individuals who ascend rapidly to altitudes above 3000-4000m. Excessive pulmonary artery pressure (PAP) is crucial for the development of HAPE, since lowering pulmonary artery pressure by nifedipine or tadalafil (phosphodiesterase-5-inhibitor) will in most cases prevent HAPE. Recent studies using microspheres in swine and magnetic resonance imaging in humans strongly support the concept and primacy of nonuniform hypoxic arteriolar vasoconstriction to explain how hypoxic pulmonary vasoconstriction occurring predominantly at the arteriolar level can cause leakage. Evidence is accumulating that the excessive PAP response in HAPE-susceptible individuals is due to a reduced NO bioavailability. HAPE-susceptible individuals show an endothelial dysfunction in the systemic circulation in hypoxia. Lower levels of exhaled NO in hypoxia before and during HAPE suggest that this abnormality also occurs in the lungs and polymorphisms of the eNOS gene are associated with susceptibility to HAPE in the Indian and Japanese population.     

环氧合酶及脂氧合酶抑制剂对猕猴急性肺泡缺氧性肺血管收缩反应的研究

猕猴吸入10%的氧时,肺动脉压明显升高,肺血管阻力显著增加。缺氧三分钟即出现最大反应,其肺血管阻力变化率达39.6%。缺氧持续十分钟,HPV未见明显减弱。脂氧合酶抑制剂——乙胺嗪明显抑制猕猴的HPV,但给药后六十分钟,HPV恢复到给药前的水平。环氧合酶抑制剂——消炎痛则明显增强猕猴的HPV,最大肺血管阻力变化率可达57%。这些结果提示:花生四烯酸脂氧合酶代谢产物——白三烯在猕猴的HPV中可能起介导作用,而前列腺素则可能调整HPV,这种调整作用与某些扩血管性前列腺素的作用有关。     

Hilltop大鼠和Wistar大鼠肺血管对急性缺氧反应的差异与PGs和LTs的关系

本工作对比观察了几种花生四烯酸代谢过程的酶抑制剂对Hilltop大鼠和Wistar大鼠急性缺氧性肺血管收缩反应(HPV)的影响。结果表明,Hilltop大鼠的HPV显著强于Wistar大鼠,股静脉注入U-60257B(5-脂加氧酶抑制剂,10mg/kg)抑制LTs合成,使Hilltop大鼠的HPV降低46.7%,使Wistar大鼠的HPV降低88.7%;TXA_2合成酶抑制剂U-63557A(5mg/kg)可显著减弱Hilltop大鼠的HPV,对Wistar大鼠无明显影响,从而消除了两种大鼠间的HPV差异;消炎痛(环加氧酶抑制剂)可升高Wistar大鼠的HPV,降低Hilltop大鼠的HPV。本工作提示前列腺素类物质在两种大鼠的HPV中作用不同,可能是Hilltop大鼠的HPV比Wistar大鼠强的重要原因。     

缺氧和空气栓塞对清醒山羊肺动脉增压反应及肺内液体交换的影响

作者采用山羊慢性肺淋巴瘘方法,观察缺氧、空气栓塞单独和复合作用,对清醒山羊肺动脉压、肺微血管壁通透性和肺内液体交换的影响。实验结果表明:①缺氧所致的成年山羊肺动脉压增高,可能是毛细血管前阻力血管收缩的结果。成年山羊在模拟4000m高原缺氧1小时,未致肺微血管壁通透性增高;②肺血管空气栓塞可致肺动脉压和微血管壁通透性增高;③缺氧和空气栓塞复合作用时,肺动脉增压反应的幅度并非两者单独作用的叠加;④空气栓塞引起的肺血管壁通透性增高未为缺氧所加重。     

Impact of mitochondria and NADPH oxidases on acute and sustained hypoxic pulmonary vasoconstriction

Hypoxic pulmonary vasoconstriction (HPV) matches lung perfusion with ventilation to optimize pulmonary gas exchange. However, it remains unclear whether acute HPV (occurring within seconds) and the vasoconstrictor response to sustained alveolar hypoxia (developing over several hours) are triggered by identical mechanisms. We investigated the effect of mitochondrial and NADPH oxidase inhibitors on both phases of HPV in intact rabbit lungs. These studies revealed that the sustained HPV is largely dependent on mitochondrial complex I and totally dependent on complex IV, whereas NADPH oxidase dependence was only observed for acute HPV. These findings were reinforced by an alternative approach employing lungs from mice deficient in the NADPH oxidase subunit p 47(phox). In these mice (which lack a subunit suggested to be important for the function of most NADPH oxidase isoforms), but not in gp 91(phox)-deficient mice (which represent only one isoform of NADPH oxidases), acute HPV was significantly reduced, while non-hypoxia-induced vasoconstrictions elicited by the thromboxane mimetic U46619 were not affected. We concluded that the acute phase and the sustained phase of HPV are differentially regulated, with NADPH oxidase activity predominating in the acute phase, while a strong dependence on mitochondrial participation was observed for the second phase.     

Branching properties of the pulmonary arterial tree during pre- and postnatal development

It was already documented that acute hypoxemia reduces the oxidative stress following static as well as dynamic handgrip bouts in humans. Then, we examined if chronic hypoxemia could produce the same effect in patients suffering from chronic respiratory insufficiency. In rats, we studied the respective consequence of a one-month exposure to normobaric hypoxia on two muscles (soleus, SOL, and extensor digitorum longus, EDL) which have high and low aerobic metabolism, respectively. Compared to healthy humans, the resting level of erythrocyte reduced glutathione (GSH) was significantly lower in chronic hypoxemic patients, and after a handgrip contraction sustained at 50% of maximal until exhaustion the GSH level and plasma thiobarbituric acid reactive substances (TBARS) did not vary. A 20-min period of oxygen supplementation partly restored the post-handgrip oxidative stress. Compared to control rats, SOL muscle of hypoxemic animals had lower intra-muscular resting level of GSH; after a 3-min muscle stimulation (MS) leading to fatigue, TBARS did not vary in SOL and EDL and the GSH decrease was absent in SOL whereas it persisted in EDL. We concluded that chronic hypoxemia depressed the fatigue-induced oxidative stress, the effects prevailing in muscles having a high oxygen demand.     

Hypoxia,energy state and pulmonary vasomotor tone

Vasomotor responses to hypoxia constitute a fundamental adaptation to a commonly encountered stress. It has long been suspected that changes in cellular energetics may modulate both hypoxic systemic artery vasodilatation (HSV) and hypoxic pulmonary artery vasoconstriction (HPV). Although limitation of energy has been shown to underlie hypoxic relaxation in some smooth muscles, the response to hypoxia in vascular smooth muscle does not appear to be a simple function of energy stores, but instead may involve perturbations of ATP or energy delivery to mechanisms controlling muscle force, and/or changes associated with anaerobic metabolism. Recent work in pulmonary vascular smooth muscle has demonstrated that energy stores are maintained during hypoxic pulmonary vasoconstriction, and that this is dependent on glucose availability and up-regulation of glycolysis. There is increasing evidence that glycolysis is preferentially coupled to a variety of membrane associated ATP dependent processes, including the Na(+) pump, Ca(2+)-ATPase, and possibly some protein kinases. These and other mechanisms may influence excitation-contraction coupling in both systemic and pulmonary arteries by effects on intracellular Ca(2+) and/or Ca(2+) sensitivity. Hypoxia has also been postulated to have major effects on other cytosolic second messenger systems including phosphatidylinositol pathways, cell redox state and mitochondrial reactive oxygen species production. This review examines the relationship between energy state, anaerobic respiration and hypoxic vasomotor tone, with a particular emphasis on hypoxic pulmonary vasoconstriction.     

Nitric oxide (NO)-dependent but not NO-independent guanylate cyclase activation attenuates hypoxic vasoconstriction in rabbit lungs

Hypoxic pulmonary vasoconstriction (HPV) is essential for matching lung perfusion with ventilation, thus optimizing pulmonary gas exchange. Preceding studies provided evidence for a role of both nitric oxide (NO) and superoxide/ H(2)O(2) formation in this vasoregulatory mechanism. Both agents might be operative via stimulation of guanylate cyclase with formation of the vasodilatory cyclic guanosine monophosphate (cGMP), the loss of which under conditions of hypoxia contributes to HPV. This view is challenged by the recent suggestion of increased rather than decreased superoxide/H(2)O(2) formation in hypoxia. We addressed the role of NO-dependent versus NO-independent guanylate cyclase activity in hypoxic and pharmacologically evoked vasoconstriction in perfused rabbit lungs. Two inhibitors of soluble guanylate cyclase, LY83583 (2 to 16 microM) and methylene blue (20 to 60 microM), increased baseline pulmonary artery pressure under normoxic conditions and markedly amplified the vasoconstrictor response to both hypoxia and the stable thromboxane analogue U46619. Under conditions of preblocked lung NO synthesis (N(G)-mono-methyl-L-arginine), however, additional guanylate cyclase inhibition further enhanced the vasoconstrictor response to U46619 but did not influence the strength of HPV. The selective phosphodiesterase V inhibitor Zaprinast (1 to 10 microM), used for prolongation of the cGMP half-life, reduced the hypoxia-induced pressor response to a larger extent than the pressor response to U46619. This difference was lost under conditions of preblocked NO synthesis. Equilibration of the lung perfusate with molecular NO suppressed the HPV more potently than the U46619-induced vasoconstrictor response. We conclude that NO-dependent guanylate cyclase activity has an important role in attenuating the vasoconstrictor response to alveolar hypoxia in rabbit lungs. In contrast, no evidence was obtained for a role of NO-independent cGMP formation in HPV. In this feature, HPV differs from that elicited by the thromboxane analogue U46619.     

Hypoxic pulmonary vasoconstriction

It has been known for more than 60 years, and suspected for over 100, that alveolar hypoxia causes pulmonary vasoconstriction by means of mechanisms local to the lung. For the last 20 years, it has been clear that the essential sensor, transduction, and effector mechanisms responsible for hypoxic pulmonary vasoconstriction (HPV) reside in the pulmonary arterial smooth muscle cell. The main focus of this review is the cellular and molecular work performed to clarify these intrinsic mechanisms and to determine how they are facilitated and inhibited by the extrinsic influences of other cells. Because the interaction of intrinsic and extrinsic mechanisms is likely to shape expression of HPV in vivo, we relate results obtained in cells to HPV in more intact preparations, such as intact and isolated lungs and isolated pulmonary vessels. Finally, we evaluate evidence regarding the contribution of HPV to the physiological and pathophysiological processes involved in the transition from fetal to neonatal life, pulmonary gas exchange, high-altitude pulmonary edema, and pulmonary hypertension. Although understanding of HPV has advanced significantly, major areas of ignorance and uncertainty await resolution.