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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.

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3−/− mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β: IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.

Ibuprofen-induced patent ductus arteriosus closure improved pulmonary mechanics, decreased total lung water, increased epithelial sodium channel expression, and decreased the detrimental effects of preterm birth on alveolarization.

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.

Objective To determine if low platelet counts are related to the incidence of patent ductus arteriosus (PDA) after indomethacin treatment in preterm human infants. Study design Multivariable logistic regression modeling was used for a cohort of 497 infants, who received indomethacin (within 15 hours of birth). Results Platelet counts were not related to the incidence of permanent closure following indomethacin constriction. There was a relationship between platelet counts and the initial degree of constriction; however, this relationship appeared to be primarily influenced by the high end of the platelet distribution curve. PDA incidence was similar in infants with platelet counts <50 × 109/L and those with platelet counts above this range. Only when platelet counts were consistently >230 × 109/L was there a decrease in PDA incidence. Conclusion In contrast to the evidence in mice, low circulating platelet counts do not affect permanent ductus closure (or ductus reopening) in human preterm infants.

. 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). ...

Premature newborn baboons [125 d (67%) gestation], exposed to a moderate-size patent ductus arteriosus (PDA) [pulmonary-to-systemic blood-flow-ratio (Qp/Qs) ϭ 1.8] for 14 d, have impaired pulmonary function and arrested alveolar development and surface area when compared with age matched fetuses (140 d gestation). Pharmacologic closure of the PDA reduces the detrimental effects of preterm delivery on pulmonary function and surface area. We used preterm baboons (delivered at 125 d gestation and ventilated for 14 d) to study the effects of surgical PDA ligation on pulmonary function and alveolar surface area. After ligation (on day of life 6), ligated animals had lower Qp/Qs ratios [Qp/Qs (ligated, n ϭ 10) ϭ 1.00 Ϯ 0.04; (nonligated, n ϭ 12) ϭ 2.05 Ϯ 0.17; mean Ϯ SD] and higher systemic blood pressures than nonligated control animals. Ventilation and oxygenation indices did not differ between the groups, during either the pre-or postoperative periods. Alveolar surface area measurements were made by digital image analysis and compared with measurements made from fetal lungs at 125 d (n ϭ 6) and 140 d (n ϭ 7) gestation. PDA ligation failed to improve the postnatal arrest in alveolar surface area. In contrast with pharmacologic closure of the PDA, surgical closure failed to improve either pulmonary function or alveolar surface area in baboons with a moderate PDA shunt. (Pediatr Res 63: 299-302, 2008) L ung injury, superimposed on an immature lung, leads to bronchopulmonary dysplasia (BPD). BPD is now characterized primarily by impaired alveolar and vascular growth, rather than by extensive fibrosis, smooth muscle proliferation, and regional heterogeneity (1). A persistent patent ductus arteriosus (PDA) has been shown to impair pulmonary mechanics (2-4) and prolong the need for mechanical ventilation (5). Although numerous studies have found an association between the presence of a PDA and the development of BPD, there is little available information to indicate whether this is a cause-and-effect relationship (6,7). Most of the controlled clinical trials examining PDA treatments were not specifically designed to address this issue; nor has there been an appropriate animal model to test the hypothesis (8 -10).The premature baboon, delivered at 125 d gestation (67% of gestation, term ϭ 185 d) has recently been used to explore the causes of BPD. The premature baboon has a similar neonatal course as the premature human delivered between 26 and 27 wk of gestation (11): they both develop respiratory distress and fail to close their PDA after birth. Despite antenatal glucocorticoids, surfactant treatment, total parenteral nutrition, low tidal volume ventilation, and low supplemental oxygen administration during the first 2 wk after delivery, premature baboons develop pulmonary histopathologic changes that are similar to those described in premature human infants with BPD (1,12).Using this model, we have examined the effects of pharmacologic closure of a PDA (with ibuprofen) on the development of BPD (13). Ibuprofe...