Nitric oxide (NO) serves multiple functions in the developing lung, and pulmonary NO production is decreased in a baboon model of chronic lung disease (CLD) after premature birth at 125 days (d) gestation (term = 185d). To determine whether postnatal NO administration alters the genesis of CLD, the effects of inhaled NO (iNO, 5 ppm) were assessed in the baboon model over 14d. iNO caused a decrease in pulmonary artery pressure in the first 2d and a greater rate of spontaneous closure of the ductus arteriosus, and lung compliance was greater and expiratory resistance was improved during the first week. With iNO, postmortem pressure-volume curves were shifted upward, lung DNA content and cell proliferation were increased, and lung growth was preserved to equal that which occurs during the same period in utero. In addition, the excessive elastin deposition characteristic of CLD was normalized by iNO, and there was evidence of stimulation of secondary crest development. Thus, in the baboon model of CLD, iNO improves early pulmonary function and alters lung growth and extracellular matrix deposition. As such, NO biosynthetic pathway dysfunction may contribute to the pathogenesis of CLD.

Nitric oxide (NO), produced by NO synthase (NOS), serves multiple functions in the perinatal lung. In fetal baboons, neuronal (nNOS), endothelial (eNOS), and inducible NOS (iNOS) are all primarily expressed in proximal respiratory epithelium. In the present study, NOS expression and activity in proximal lung and minute ventilation of NO standard temperature and pressure (VeNO(STP)) were evaluated in a model of chronic lung disease (CLD) in baboons delivered at 125 days (d) of gestation (term = 185 d) and ventilated for 14 d, obtaining control lung samples from fetuses at 125 or 140 d of gestation. In contrast to the normal 73% increase in total NOS activity from 125 to 140 d of gestation, there was an 83% decline with CLD. This was related to marked diminutions in both nNOS and eNOS expression and enzymatic activity. nNOS accounted for the vast majority of enzymatic activity in all groups. The normal 3.3-fold maturational rise in iNOS protein expression was blunted in CLD, yet iNOS activity was elevated in CLD compared with at birth. The contribution of iNOS to total NOS activity was minimal in all groups. VeNO(STP) remained stable in the range of 0.5-1.0 nl x kg(-1) x min(-1) from birth to day 7 of life, and it then rose by 2.5-fold. Thus the baboon model of CLD is characterized by deficiency of the principal pulmonary isoforms, nNOS and eNOS, and enhanced iNOS activity over the first 2 wk of postnatal life. It is postulated that these alterations in NOS expression and activity may contribute to the pathogenesis of CLD.

. Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung. Am J Physiol Lung Cell Mol Physiol 283: L1192-L1199, 2002. First published July 3, 2002 10.1152/ajplung.00112.2002, produced by NO synthase (NOS), plays a critical role in multiple processes in the lung during the perinatal period. To better understand the regulation of pulmonary NO production in the developing primate, we determined the cell specificity and developmental changes in NOS isoform expression and action in the lungs of third-trimester fetal baboons. Immunohistochemistry in lungs obtained at 175 days (d) of gestation (term ϭ 185 d) revealed that all three NOS isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), are primarily expressed in proximal airway epithelium. In proximal lung, there was a marked increase in total NOS enzymatic activity from 125 to 140 d gestation due to elevations in nNOS and eNOS, whereas iNOS expression and activity were minimal. Total NOS activity was constant from 140 to 175 d gestation, and during the latter stage (160-175 d gestation), a dramatic fall in nNOS and eNOS was replaced by a rise in iNOS. Studies done within 1 h of delivery at 125 or 140 d gestation revealed that the principal increase in NOS during the third trimester is associated with an elevation in exhaled NO levels, a decline in expiratory resistance, and greater pulmonary compliance. Thus, there are developmental increases in pulmonary NOS expression and NO production during the early third trimester in the primate that may enhance airway and parenchymal function in the immediate postnatal period. airway epithelium; compliance; expiratory resistance; primate THE SIGNALING MOLECULE nitric oxide (NO), produced by nitric oxide synthase (NOS), plays a critical role in physiological processes in the pulmonary epithelium (1,10,17). NO is detectable in expired gas (9), and studies in both animals and humans suggest that the principle source of expired NO is the lung epithelium rather than the pulmonary vasculature (7, 12). The functions of NO in the mature airway include neurotransmission, smooth muscle relaxation, and bacteriostasis, and also the modulation of mucin secretion, ciliary motility, and plasma exudation (1, 10).There is mounting evidence that NO is of great importance to lung epithelial function in the perinatal period. The stimulation of NO synthesis by acetylcholine or bradykinin causes marked decreases in lung liquid production in late-gestation fetal lambs (5), and the instillation of NO or cGMP, the second messenger for NO, into the fetal lung liquid has the same effect (4, 6). The decrease in lung liquid production by the respiratory epithelium at the time of birth is an essential component of the transition of the fetus from a liquidbreathing to an air-breathing status. Epithelium-derived NO is also critical to the regulation of bronchomotor tone in the early newborn period, playing an important role in the opposition of airway contraction (14). ...

Although a patent ductus arteriosus (PDA) increases fluid and protein efflux from the pulmonary vasculature in preterm infants (1, 2), a compensatory increase in pulmonary lymph flow appears to prevent pulmonary edema during the first 72 h after delivery in both premature animals (3, 4) and humans (5). However, a symptomatic left-to-right ductus shunt that persists beyond the first week of life increases the likelihood of edema formation and respiratory compromise. Several studies (performed in the presurfactant era) found that, by 7 d after birth, a PDA can alter pulmonary mechanics (6-8). In addition, preterm infants with a PDA have increased ventilatory needs compared with infants whose PDA has been closed (6, 7, 9-12). Whether these alterations are due to increasing pulmonary edema or to more permanent histopathologic changes is currently unknown. Chronic pulmonary histopathologic changes consisting of alveolar simplification, fibrosis, and chronic inflammation frequently follow preterm birth (13). These changes, known as bronchopulmonary dysplasia (BPD), appear to be due to inflammatory and repair processes that interfere with normal lung development (14-17). Airway aspirates from infants that develop BPD contain proinflammatory cytokines (e.g., interleukin [IL] 6 and IL-8) during the first days after delivery (18), and ventilation of preterm animals initiates a similar inflammatory response (13,18). Although numerous studies have found an association between the presence of a PDA and development of BPD, there is little information suggesting a cause-and-effect relationship (19,20). Infants with a persistent PDA frequently require prolonged ventilatory support similar to infants with a more severe form of BPD; however, previous studies have failed to demonstrate consistent worsening in the radiographic features of BPD among infants with a persistent PDA (11,12,21). Studies to unravel the mechanisms responsible for the late pulmonary deterioration associated with a persistent PDA have been hampered by both the absence of randomized controlled clinical trials that address this question and by the absence of an appropriate animal model.The premature baboon (delivered at 125 d gestation; term ϭ 185 d) has a similar postnatal course as humans delivered between 25 and 27 wk of gestation. As in very-low-birthweight human infants, the ductus arteriosus of the premature baboon has only a 20 to 30% chance of closing spontaneously after birth (22). Despite surfactant treatment, low tidal volume breathing, and low supplemental oxygen administration, premature baboons develop pulmonary histopathologic changes during the first 2 wk after delivery that are similar to those described in premature human infants (13,23). The purpose of the present study was to examine the effectiveness of surgical ligation as a means of treating infants with a PDA by assessing its effects on cardiopulmonary function and the development of lung injury in mechanically ventilated premature baboons during the first 2 wk after delivery. We hypot...