Several experimental models have been studied to explore the pathogenesis and pathophysiology of PPHN (21, 54). Such models have included exposure to acute or chronic hypoxia after birth, chronic hypoxia in utero, placement of meconium into the airways ofneonatal animals, sepsis and others. Although each model demonstrates interesting physiologic changes that may be especially relevant to particular clinical settings, most studies examine only brief changes in the pulmonary circulation, and mechanisms underlying altered lung vascular structure and function ofPPHN remain poorly understood. Clinical observations that neonates with severe PPHN who die during the first days after birth already have pathologic signs of chronic pulmonary vascular disease suggest that intrauterine events may play an important role in this syndrome. Adverse intrauterine stimuli during late gestation, such as abnormal hemodynamics, changes in substrate or hormone delivery to the lung, hypoxia, inflammation or others, may potentially alter lung vascular function and structure, contributing to abnormalities of postnatal adaptation. Several investigators have examined the effects of chronic intrauterine stresses, such as hypoxia or hypertension, in animal models in order to attempt to mimic the clinical problem of PPHN. Whether chronic hypoxia alone can cause PPHN is controversial. A past report that maternal hypoxia in rats increases pulmonary vascular smooth muscle thickening in newborns, but this observation has not been reproduced in maternal rats or guinea pigs with more extensive studies (54).
Pulmonary hypertension induced by early closure of the DA in fetal lambs alters lung vascular reactivity and structure, causing the failure of postnatal adaptation at delivery, and providing an experimental model of PPHN (8, 45, 51). Over days, pulmonary artery pressure and PVR progressively increase, but flow remains low and Pa02 is unchanged (8). Marked right ventricular hypertrophy and structural remodeling ofsmall pulmonary arteries develops after 8 days of hypertension. After delivery, these lambs have persistent elevation of PVR despite mechanical ventilation with high 02 concentrations. Studies with this model show that chronic hypertension without high flow can alter fetal lung vascular structure and function. This model is characterized further by endothelial cell dysfunction and altered smooth muscle cell reactivity and growth, including findings of impaired NO production and activity due to downregulation of lung endothelial NOS mRNA and protein expression (69). Fetal pulmonary hypertension also impaired cGC and upregulated cGMP specific phosphodiesterase (type 5; PDE5) activities, suggesting further impairments in the NO-cGMP cascade (Fig. 2) (27, 50, 75, 78, 85). Thus, alterations in the NO-cGMP cascade appear to play an essential role in the pathogenesis and pathophysiology of experimental PPHN. Abnormalities of NO production and responsiveness contribute to altered structure and function of the developing lung circulation, leading to failure of postnatal cardiorespiratory adaptation. Recent evidence indicates that excessive production of reactive oxygen species such as superoxide in the pulmonary vasculature may further contribute to the disruption in NO-cGMP signaling in this model (13).
Upregulation of ET-1 may also contribute to the pathophysiology of PPHN. Circulating levels of ET-1, a potent vasoconstrictor and co-mitogen for vascular smooth muscle cell hyperplasia, are increased in human newborns with severe PPHN (69). In the experimental model of PPHN due to compression of the DA in fetal sheep, lung ET-1 mRNA and protein content is markedly increased, and the balance of ET receptors are altered, favoring vasoconstriction (33, 34). Chronic inhibition of the ET A receptor attenuates the severity of pulmonary hypertension, decreases pulmonary artery wall thickening, and improves the fall in PVR at birth in this model. Thus, experimental studies have shown the important role of the NO-cGMP cascade and the ET-1 system in the regulation of vascular tone and reactivity of the fetal and transitional pulmonary circulation. Finally, in addition to vasoactive mediators, such as NO and ET-1, it has become clear that alterations of growth factors, such as VEGF and platelet-derived growth factor (PDGF), are likely to play key roles in the modulation of vascular maturation, growth and structure. For example, inhibition ofPDGF-B attenuates smooth muscle hyperplasia in experimental pulmonary hypertension in fetal lambs, suggesting a potential role in the pathogenesis of PpHN (12).
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