Published online May 1, 2008
PEDIATRICS Vol. 121 No. 5 May 2008, pp. 945-956 (doi:10.1542/10.1542/peds.2007-2051)

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ARTICLE

Ibuprofen-Induced Patent Ductus Arteriosus Closure: Physiologic, Histologic, and Biochemical Effects on the Premature Lung

Donald McCurnin, MD^a, Steven Seidner, MD^a, Ling-Yi Chang, PhD^b, Nahid Waleh, PhD^c, Machiko Ikegami, MD, PhD^d, Jean Petershack, MD^a, Brad Yoder, MD^e, Luis Giavedoni, PhD^f, Kurt H. Albertine, PhD^e, Mar Janna Dahl, BS^e, Zheng-ming Wang, BS^e and Ronald I. Clyman, MD^g,h

^a Department of Pediatrics, University of Texas Health Science Center, San Antonio, Texas
^b Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado
^c Pharmaceutical Discovery Division, SRI International, Menlo Park, California
^d Pulmonary Biology, Cincinnati Children's Hospital, University of Cincinnati, Cincinnati, Ohio
^e Department of Pediatrics, University of Utah, Salt Lake City, Utah
^f Department of Virology and Immunology, Southwest Foundation for Biomedical Research, San Antonio, Texas
^g Cardiovascular Research Institute
^h Department of Pediatrics, University of California, San Francisco, California

OBJECTIVE. The goal was to study the pulmonary, biochemical, and morphologic effects of a persistent patent ductus arteriosus in a preterm baboon model of bronchopulmonary dysplasia.

METHODS. Preterm baboons (treated prenatally with glucocorticoids) were delivered at 125 days of gestation (term: 185 days), given surfactant, and ventilated for 14 days. Twenty-four hours after birth, newborns were randomly assigned to receive either ibuprofen (to close the patent ductus arteriosus; n = 8) or no drug (control; n = 13).

RESULTS. After treatment was started, the ibuprofen group had significantly lower pulmonary/systemic flow ratio, higher systemic blood pressure, and lower left ventricular end diastolic diameter, compared with the control group. There were no differences in cardiac performance indices between the groups. Ventilation index and dynamic compliance were significantly improved with ibuprofen. The improved pulmonary mechanics in ibuprofen-treated newborns were not attributable to changes in levels of surfactant protein B, C, or D, saturated phoshatidylcholine, or surfactant inhibitory proteins. There were no differences in tracheal concentrations of cytokines commonly associated with the development of bronchopulmonary dysplasia. The groups had similar messenger RNA expression of genes that regulate inflammation and remodeling in the lung. Lungs from ibuprofen-treated newborns were significantly drier (lower wet/dry ratio) and expressed 2.5 times more epithelial sodium channel protein than did control lungs. By 14 days after delivery, control newborns had morphologic features of arrested alveolar development (decreased alveolar surface area and complexity), compared with age-matched fetuses. In contrast, there was no evidence of alveolar arrest in the ibuprofen-treated newborns.

CONCLUSIONS. 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.

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Key Words: patent ductus arteriosus • cytokines • lung remodeling • bronchopulmonary dysplasia • pulmonary edema • wet/dry ratio • compliance • indomethacin • surfactant • epithelial sodium channel

Abbreviations: BPD—bronchopulmonary dysplasia • PDA—patent ductus arteriosus • ENaC—epithelial sodium channel • BALF—bronchoalveolar lavage fluid • MCP—monocyte chemoattractant protein • MIP—macrophage inflammatory protein • IL—interleukin • TNF—tumor necrosis factor • IFN—interferon

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Accepted Sep 17, 2007.

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