1 Department of Pediatrics, Northwestern University, The Feinburg School of Medicine, Chicago, Illinois 60611; and 2 Department of Pediatrics, Division of Neonatology, Rainbow Babies and Childrens Hospital, Case Western Reserve University, Cleveland, Ohio 44106
SHAUL AND COLLEAGUES, in one of the
current articles in focus (Ref. 9, see p.
L1192 in this issue), investigate an intriguing subject, the
role of endogenously released nitric oxide (NO) on airway function in
the developing respiratory system. Their prior studies in the
developing sheep have demonstrated that the three isoforms of nitric
oxide synthase (NOS) are expressed to varying degrees in proximal and
distal airway epithelium (10). The interspecies consistency of these data is now confirmed in a maturing primate model,
and more insights are provided as to the specific developmental time
courses of expression for the three NOS isoforms in the developing lung
(9).
So what is the functional significance of epithelial NOS? It would
appear unlikely that the only role for NO generated from airway
epithelium is to modulate the contractility of nearby pulmonary vascular smooth muscle cells. An alternative role for NOS is the production and subsequent release of NO from proximal airway
epithelium, which, in turn, may contribute to late fetal and early
postnatal improvement in pulmonary mechanics, especially bronchodilatation.
In healthy and diseased lungs, it appears that both proximal and distal
airway structures may contribute to airway resistance. Unfortunately,
assessing the mechanical properties of lung parenchyma independently of
other respiratory structures such as larger airways and vessels is not
straightforward (11). Nonetheless, increased peripheral or
tissue responsiveness to cholinergic challenge does contribute to
airway reactivity in mature animal models of asthma (6).
Employing the alveolar capsule technique, Khassawneh et al.
(4) have recently demonstrated in piglets that NOS
blockade increases the airway and tissue contributions to total
resistance in response to vagal stimulation. In the study by Shaul et
al. (9), immunohistochemical studies focused on the
proximal one-third of lung parenchyma. If correlated with functional
changes, future studies of NOS immunolocalization at proximal and
distal sites will contribute to our understanding of the relative
contributions of NO released at various locations to airway relaxant
responses mediated by NO in the developing respiratory system.
The assumed correlation between maturation of NOS isoforms and
enhancement in respiratory function around the time of birth clearly
raises as many questions as it answers (9). For example, what is the significance of the very different maturational change observed between the various NOS isoforms in later fetal life? What are
the possible relative contributions of NO-mediated bronchodilatation and NO-mediated changes in fluid balance to developmental changes in
lung function? Perhaps most important, how might pathophysiological states impair this normal developmental progression in NOS maturation, and what might the functional consequences be?
Bronchopulmonary dysplasia (BPD) is a troublesome clinical problem in
the preterm survivors of neonatal intensive care. It is widely accepted
that elevated lung resistance and heightened airway reactivity are,
respectively, early and late features of this disorder
(1). Although the etiology of BPD is multifactorial, in
hyperoxia-exposed rat pups, Iben et al. (3) have shown
that loss of NO-mediated airway relaxation contributes to increased airway contractility under in vivo conditions. Further study is needed
to characterize whether NO plays a role in airway function in other
pathophysiological states. Meanwhile, several large multicenter clinical trials are underway to test whether inhaled NO will decrease the incidence and/or severity of BPD in preterm infants. Sequential measurements of pulmonary function will determine whether inhaled NO
acutely lowers airway resistance as reported in healthy piglets (7) or whether it might benefit respiratory function via a longer-term antiproliferative effect on airway smooth muscle (2, 5).
Although Shaul and colleagues (9) focus on epithelial NO
production, we are provided with important clues and avenues for new
investigation on the regulation of pulmonary vascular response to NO. A
particularly interesting finding is that expression of neuronal NOS and
endothelial (eNOS) rises between 125 and 140 days and falls by the end
of gestation. In contrast, inducible (iNOS) expression remains low
during this early period and dramatically rises at the very end of
gestation. Although most studies have focused on the role of eNOS in
the vascular function of the term lung, the results of Shaul et al.
(9) suggest a pivotal role for the iNOS isoform. Their
findings support the functional studies using iNOS antagonists recently
reported by Rairigh et al. (8) and suggest that further
investigation of the role of iNOS in disorders affecting the term
infant, such as persistent pulmonary hypertension, is warranted.
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ARTICLE
REFERENCES
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FOOTNOTES |
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Address for reprint requests and other correspondence: R. J. Martin, Div. of Neonatology, Rainbow Babies and Childrens Hospital, Case Western Reserve Univ., 11100 Euclid Ave., Ste. 3100, Cleveland, OH 44106-6010 (E-mail: rxm6{at}po.cwru.edu).
10.1152/ajplung.00251.2002
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REFERENCES |
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