Bronchopulmonary Dysplasia

Pulmonary hypertension contributes significantly to morbidity and mortality in BPD, but little is known about the relative contribution of arterial tone, structural remodeling, and vessel density to pulmonary hypertension, especially in older patients. To determine the role of high pulmonary vascular tone in pulmonary hypertension, Mourani and coworkers studied the acute effects of oxygen tension, inhaled nitric oxide, and calcium channel blockers in 10 patients with BPD who underwent cardiac catheterization for evaluation of pulmonary hypertension. During normoxic conditions, mean pulmonary arterial pressure and pulmonary to systemic vascular resistance ratio were 34 ± 3 mm Hg and 0.42 ± 0.07 mm Hg, respectively. In response to hypoxia, pulmonary arterial pressure and pulmonary to systemic vascular resistance ratio increased by 50 ± 8% and 82 ± 14%, respectively (p < 0.01). Hyperoxia decreased pulmonary to systemic vascular resistance ratio by 28 ± 9% (p = 0.05). The addition of inhaled nitric oxide treatment (20–40 ppm) to hyperoxia decreased pulmonary arterial pressure and pulmonary to systemic vascular resistance ratio by 29 ± 5% (p < 0.01) and 45 ± 6% (p < 0.05) from baseline values, respectively, achieving near normal values. The authors concluded that hyperoxia plus inhaled nitric oxide causes marked pulmonary vasodilatation in older patients with BPD, suggesting that heightened pulmonary vascular tone contributes to pulmonary vascular disease in BPD.

Superoxide anion and other oxygen-free radicals have been implicated in the pathogenesis of bronchopulmonary dysplasia. To determine whether a catalytic antioxidant metalloporphyrin (AEOL 10113) can protect against oxygen toxicity, Chang and coworkers studied baboons delivered 45 days prematurely. Compared with baboons given oxygen when needed, baboons receiving 100% oxygen had increased parenchymal mast cells and eosinophils, increased alveolar tissue volume, increased septal thickness, and decreased alveolar surface area. A continuous intravenous infusion of the antioxidant, AEOL 10113, partially reversed the oxygen-induced changes. Hyperoxia increased the number of neuroendocrine cells in the peripheral lung, which was preceded by increased levels of urine bombesin-like peptide at 48 hours of age. The increases in neuroendocrine cells and urine bombesin-like peptide were inhibited by the antioxidant. The authors conclude that a catalytic antioxidant metalloporphyrin (AEOL 10113) decreases the risk of oxygen toxicity in premature baboons. An editorial commentary by Tanswell and Jankov accompanies this article.

In newborn mice exposed to hyperoxia, Ahmed and coworkers determined whether targeted overexpression of human extracellular superoxide dismutase would promote normal lung development. Newborn transgenic mice and wild-type mice were exposed to 95% oxygen or air for 7 days. Activity of extracellular superoxide dismutase was 2.5 times greater in the transgenic mice than in the control mice. At 7 days, the transgenic mice had less pulmonary neutrophil influx and oxidized glutathione than did the control mice. After 14 days of exposure to 60% oxygen, transgenic mice had greater preservation of alveolar surface and volume density than did the control mice. The authors conclude that overexpression of human extracellular superoxide dismutase protects newborn mice against hyperoxia-induced inflammation at 7 days and impairment of lung development at 21 days.

To determine the role of fibroblast growth factor receptor-1 in compensatory lung growth after hyperoxic exposure, Jankov and coworkers exposed neonatal rats to 95% oxygen for 7 days after birth. The rats showed inhibited lung growth, DNA synthesis, and secondary septation, all of which recovered during a period of air breathing. Expression of basic fibroblast growth factor was reduced at the end of 7 days of 95% oxygen; it increased after 3 days of recovery in air. Expression of fibroblast growth factor receptor-1 was not affected by hyperoxia or recovery in air. The role of fibroblast growth factor in the compensatory lung growth after discontinuation of hyperoxia was further evaluated by injecting (intraperitoneally) soluble truncated fibroblast growth factor receptor-1 at the onset of the recovery phase. (The truncated receptor acts as a decoy for the natural receptor ligands, which are then no longer available to bind to the endogenous receptor.) The truncated receptor arrested compensatory lung DNA synthesis and secondary septation. The authors conclude that the compensatory lung growth and septation in neonatal rats experiencing growth arrest secondary to hyperoxia is in part mediated by fibroblast growth factor receptor-1.

Bombesin-like peptides are elevated in newborns that go on to develop bronchopulmonary dysplasia, and blocking these peptides abrogates bronchopulmonary dysplasia in baboons. Subramaniam and coworkers determined whether bombesin-like peptides function postnatally as proinflammatory cytokines. In mice, intratracheal administration of bombesin induced increased numbers of mast cells after 48 hours. The mast cells revealed messenger RNAs encoding bombesin receptor subtype 3 and neuromedin-B receptor, but not gastrin-releasing peptide receptor. Only neuromedin-B receptor null mice accumulated fewer mast cells in the lungs after treatment with bombesin. In vitro studies revealed that bombesin, gastrin-releasing peptide, neuromedin-B receptor, and a bombesin receptor subtype 3–specific ligand induced proliferation of mast cells and chemotaxis. The authors conclude that multiple bombesin-like peptides promote mast cell responses and contribute to the development of bronchopulmonary dysplasia.

The American Thoracic Society presents a statement on care of the child with chronic lung disease of infancy and childhood.

In a state of the art review article, Kinnula and Crapo discuss superoxide dismutase in lung disease.

Citations 1-7 of 7 total displayed.

Pulmonary Vascular Effects of Inhaled Nitric Oxide and Oxygen Tension in Bronchopulmonary Dysplasia

Peter M. Mourani, D. Dunbar Ivy, Dexiang Gao, and Steven H. Abman
Am. J. Respir. Crit. Care Med. 170: 1006 -1013. First published online as doi:10.1164/rccm.200310-1483OC [Abstract] [Full text]

Bombesin-like Peptides and Mast Cell Responses: Relevance to Bronchopulmonary Dysplasia?

Meera Subramaniam, Kumiya Sugiyama, David H. Coy, Yanping Kong, York E. Miller, Peter F. Weller, Keiji Wada, Etsuko Wada, and Mary E. Sunday
Am. J. Respir. Crit. Care Med. 168: 601 -611. First published online as doi:10.1164/rccm.200212-1434OC [Abstract] [Full text]

Superoxide Dismutases in the Lung and Human Lung Diseases

Vuokko L. Kinnula and James D. Crapo
Am. J. Respir. Crit. Care Med. 167: 1600-1619. [Abstract] [Full text]

Fibroblast Growth Factor Receptor-1 and Neonatal Compensatory Lung Growth after Exposure to 95% Oxygen

Robert P. Jankov, Xiaoping Luo, Ann Campbell, Rosetta Belcastro, Judy Cabacungan, Leslie Johnstone, Helena Frndova, Stephen J. Lye, and A. Keith Tanswell
Am. J. Respir. Crit. Care Med. 167: 1554 -1561. First published online as doi:10.1164/rccm.200207-662OC [Abstract] [Full text]

Extracellular Superoxide Dismutase Protects Lung Development in Hyperoxia-exposed Newborn Mice

Mohamed N. Ahmed, Hagir B. Suliman, Rodney J. Folz, Eva Nozik-Grayck, Maria L. Golson, S. Nicholas Mason, and Richard L. Auten
Am. J. Respir. Crit. Care Med. 167: 400 -405. First published online as doi:10.1164/rccm.200202-108OC [Abstract] [Full text]

Bronchopulmonary Dysplasia: One Disease or Two?

A. Keith Tanswell and Robert P. Jankov
Am. J. Respir. Crit. Care Med. 167: 1-2. [Full text]

A Catalytic Antioxidant Attenuates Alveolar Structural Remodeling in Bronchopulmonary Dysplasia

Ling-Yi L. Chang, Meera Subramaniam, Bradley A. Yoder, Brian J. Day, Misoo C. Ellison, Mary E. Sunday, and James D. Crapo
Am. J. Respir. Crit. Care Med. 167: 57-64. [Abstract] [Full text]

Year in Review Home