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Ontogeny of Poly(ADP-Ribose) Polymerase-1 in Lung and Developmental Implications

Cardiovascular Research Institute, and Department of Pediatrics, University of California, San Francisco, California

Address correspondence to: Louis M. Scavo, M.D., Department of Neonatology, Children's National Medical Center, 111 Michigan Avenue, Washington, D.C. 20010. E-mail: lscavo{at}cnmc.org

Poly(ADP-ribose) polymerase 1 (PARP-1) is the predominant NAD-dependent modifying enzyme in DNA repair, transcription, and apoptosis; its involvement in development has not been defined. Here, we report expression and cellular localization of PARP-1 in developing rat and human fetal lung, in vivo and in explant culture, and effects of inhibiting PARP-1 activity on lung surfactant protein (SP) expression. PARP-1 was expressed as 113-kD (p113) and 85-kD (p85) fragment in both rat and human lung. In rat lung, p113 content by Western was maximal at Embryonic Days 16–18, decreased sharply by Embryonic Day 20, and continued to decrease postnatally. p85 level was constant in the fetus and decreased postnatally. In human fetal lung, both PARP-1 mRNA expression and protein content changed little between 15 and 24 wk. Immunohistochemistry for PARP-1 in Embryonic Day 18 rat lung showed predominantly nuclear staining in most cells. In later gestation and postnatally, PARP-1 staining was primarily cytoplasmic and progressively restricted to a subset of cells, mainly bronchial epithelial and smooth muscle cells. Cell subfractionation showed that p113 localized to nucleus and p85 to cytoplasm. Inhibition of PARP-1 activity by 5-iodo-6-amino-1,2-benzopyrone in fetal rat lung explant culture did not affect SP-A and -B mRNA, but significantly increased SP-C mRNA. These findings indicate that in lung (i) PARP-1 is abundantly expressed during fetal development; (ii) p113 and p85 levels are differentially regulated; (iii) PARP-1 undergoes complex developmental changes in cellular and subcellular expression, including extensive cytoplasmic localization; and (iv) inhibition of PARP-1 activity differentially affects expression of SPs.

Abbreviations: dithiothreitol, DTT • human fetal lung fibroblasts, HFL • poly(ADP-ribose) polymerase 1, PARP-1 • phosphate-buffered saline, PBS • rat fetal lung fibroblasts, RFL • reverse transcriptase–polymerase chain reaction, RT-PCR • surfactant protein, SP • Tris-buffered saline, TBS

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