title: Recombinant human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia.
abstract: Recent studies suggest that VEGF may worsen pulmonary edema during acute lung injury (ALI), but, paradoxically, impaired VEGF signaling contributes to decreased lung growth during recovery from ALI due to neonatal hyperoxia. To examine the diverse roles of VEGF in the pathogenesis of and recovery from hyperoxia-induced ALI, we hypothesized that exogenous recombinant human VEGF (rhVEGF) treatment during early neonatal hyperoxic lung injury may increase pulmonary edema but would improve late lung structure during recovery. Sprague-Dawley rat pups were placed in a hyperoxia chamber (inspired O(2) fraction 0.9) for postnatal days 2-14. Pups were randomized to daily intramuscular injections of rhVEGF(165) (20 microg/kg) or saline (controls). On postnatal day 14, rats were placed in room air for a 7-day recovery period. At postnatal days 3, 14, and 21, rats were killed for studies, which included body weight and wet-to-dry lung weight ratio, morphometric analysis [including radial alveolar counts (RAC), mean linear intercepts (MLI), and vessel density], and lung endothelial NO synthase (eNOS) protein content by Western blot analysis. Compared with room air controls, hyperoxia increased pulmonary edema by histology and wet-to-dry lung weight ratios at postnatal day 3, which resolved by day 14. Although treatment with rhVEGF did not increase edema in control rats, rhVEGF increased wet-to-dry weight ratios in hyperoxia-exposed rats at postnatal days 3 and 14 (P < 0.01). Compared with room air controls, hyperoxia decreased RAC and increased MLI at postnatal days 14 and 21. Treatment with VEGF resulted in increased RAC by 181% and decreased MLI by 55% on postnatal day 14 in the hyperoxia group (P < 0.01). On postnatal day 21, RAC was increased by 176% and MLI was decreased by 58% in the hyperoxia group treated with VEGF. rhVEGF treatment during hyperoxia increased eNOS protein on postnatal day 3 by threefold (P < 0.05). We conclude that rhVEGF treatment during hyperoxia-induced ALI transiently increases pulmonary edema but improves lung structure during late recovery. We speculate that VEGF has diverse roles in hyperoxia-induced neonatal lung injury, contributing to lung edema during the acute stage of ALI but promoting repair of the lung during recovery.
authors.affiliation: Pediatric Heart Lung Center, University of Colorado School of Medicine and The Children's Hospital, Pediatrics, Mail Stop 8317, PO Box 6511, Aurora, 80045, USA. anette.kunig@uchsc.edu
authors.forename: Anette M
authors.initials: AM
authors.lastname: Kunig
authors.forename: Vivek
authors.initials: V
authors.lastname: Balasubramaniam
authors.forename: Neil E
authors.initials: NE
authors.lastname: Markham
authors.forename: Gregory
authors.initials: G
authors.lastname: Seedorf
authors.forename: Jason
authors.initials: J
authors.lastname: Gien
authors.forename: Steven H
authors.initials: SH
authors.lastname: Abman
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D005260:Female; D006801:Humans; D018496:Hyperoxia / Q000188:drug therapy* / Q000473:pathology; D018919:Neovascularization, Physiologic / Q000187:drug effects; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009929:Organ Size; D011014:Pneumonia / Q000188:drug therapy / Q000473:pathology; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D011652:Pulmonary Circulation / Q000187:drug effects; D011654:Pulmonary Edema / Q000139:chemically induced* / Q000473:pathology; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology*
chemical_list: D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D052250:Nitric Oxide Synthase Type III