Published ahead of print on January 30, 2004, doi:10.1165/rcmb.2003-0248OC Am. J. Respir. Cell Mol. Biol., Volume 30, Number 6, June 2004, 853-861 A more recent version of this article appeared on June 1, 2004
Submitted on June 27, 2003 Ontogeny of Poly(ADP-Ribose) Polymerase-1 in Lung and Developmental ImplicationsRobert Ertsey1,1 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA, 2 Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, USA; Pediatrics, University of California, San Francisco, San Francisco, CA, USA, 3 Pediatrics, University of California, San Francisco, San Francisco, CA, USA; Neonatology, Children's National Medical Center, Washington, D.C., USA * To whom correspondence should be addressed. 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 lung (HFL), 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 ed16-18, decreased sharply by ed20 and continued to decrease post-natally. p85 level was constant in the fetus and decreased post-natally. In HFL, both PARP-1 mRNA expression and protein content changed little between 15 and 24 wks. Immunohistochemistry for PARP-1 in ed18 rat lung showed predominantly nuclear staining in most cells. In later gestation and post-natally, 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 (a) PARP-1 is abundantly expressed during fetal development (b) p113 and p85 levels are differentially regulated (c) PARP-1 undergoes complex developmental changes in cellular and subcellular expression, including extensive cytoplasmic localization and (d) inhibition of PARP-1 activity differentially affects expression of SPs.
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