EDITORIAL FOCUS
Nitric oxide and the developing airway

Robin Steinhorn1 and Richard J. Martin2

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


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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.


    FOOTNOTES

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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1.   Bancalari, EH. Neonatal chronic lung. In: Neonatal/Perinatal Medicine (7th ed.), edited by Fanaroff AA, and Martin RJ.. St. Louis, MO: Mosby, 2002.

2.   Bland, RD, Albertine KH, Carlton DP, Day RW, Stolworthy LD, Jones GP, and Lagerquist K. Continuous inhalation of nitric oxide from birth decreases airway resistance, and bronchiolar smooth muscle in chronically ventilated preterm lambs (Abstract). Pediatr Res 43: 275A, 1998.

3.   Iben, SC, Dreshaj IA, Farver CF, Haxhiu MA, and Martin RJ. Role of endogenous nitric oxide in hyperoxia induced airway hyperreactivity in maturing rats. J Appl Physiol 89: 1205-1212, 2000[Abstract/Free Full Text].

4.   Khassawneh, MY, Dreshaj IA, Liu S, Chang C-H, Haxhiu MA, and Martin RJ. Endogenous nitric oxide modulates responses of tissue, and airway resistance to vagal stimulation in piglets. J Appl Physiol 93: 450-456, 2002[Abstract/Free Full Text].

5.   McCurnin, DC, Yoder BT, Kerecman J, Grubb P, Coalson J, and Shaul PW. Effect of inhaled nitric oxide on cardiac, and pulmonary function in premature baboons (Abstract). Am J Respir Crit Care Med 165: A645, 2002.

6.   Nagase, T, Moretto A, Dallaire MJ, Eidelman DH, Martin JG, and Ludwig MS. Airway, and tissue response to antigen challenge in sensitized Brown Norway rats. Am J Respir Crit Care Med 150: 318-226, 1994[Abstract].

7.   Potter, CF, Dreshaj IA, Haxhiu MA, Stork EK, Chatburn RL, and Martin RJ. Effect of exogenous, and endogenous nitric oxide [NO] on the airway and tissue components of lung resistance in the newborn piglet. Pediatr Res 41: 886-891, 1997[Abstract].

8.   Rairigh, RL, Parker TA, Ivy DD, Kinsella JP, Fan ID, and Abman SH. Role of inducible nitric oxide synthase in the pulmonary vascular response to birth-related stimuli in the ovine fetus. Circ Res 88: 721-726, 2001[Abstract/Free Full Text].

9.   Shaul, PW, Afshar S, Gibson LL, Sherman TS, Kerecman JD, Grubb PH, Yoder BA, and McCurnin DC. 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.

10.   Sherman, TS, Chen Z, Yuhanna IS, Lau KS, Margraf LR, and Shaul PW. Nitric oxide synthase isoform expression in the developing lung epithelium. Am J Physiol Lung Cell Mol Physiol 276: L383-L390, 1999[Abstract/Free Full Text].

11.   Tomioka, S, Bates JHT, and Irvin CG. Airway, and tissue mechanics in a murine model of asthma: alveolar capsule vs. forced oscillations. J Appl Physiol 93: 263-270, 2002[Abstract/Free Full Text].


Am J Physiol Lung Cell Mol Physiol 283(6):L1190-L1191
1040-0605/02 $5.00 Copyright © 2002 the American Physiological Society