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1 Pediatric Pulmonary Medicine, Pediatric Heart Lung Center, Department of Pediatrics, 3 Department of Pathology, and 4 Pulmonary Hypertension Center, University of Colorado School of Medicine, Denver, Colorado 80218; and 2 Sugen Incorporated, South San Francisco, California 94080
To determine whether angiogenesis is necessary for normal alveolarization, we studied the effects of two antiangiogenic agents, thalidomide and fumagillin, on alveolarization during a critical period of lung growth in infant rats. Newborn rats were treated with daily injections of fumagillin, thalidomide, or vehicle during the first 2 wk of life. Compared with control treatment, fumagillin and thalidomide treatment reduced lung weight-to-body weight ratio and pulmonary arterial density by 20 and 36%, respectively, and reduced alveolarization by 22%. Because these drugs potentially have nonspecific effects on lung growth, we also studied the effects of Su-5416, an inhibitor of the vascular endothelial growth factor receptor known as kinase insert domain-containing receptor/fetal liver kinase (KDR/flk)-1. As observed with the other antiangiogenic agents, Su-5416 treatment decreased alveolarization and arterial density. We conclude that treatment with three different antiangiogenic agents attenuated lung vascular growth and reduced alveolarization in the infant rat. We speculate that angiogenesis is necessary for alveolarization during normal lung development and that injury to the developing pulmonary circulation during a critical period of lung growth can contribute to lung hypoplasia.
bronchopulmonary dysplasia; congenital diaphragmatic hernia; fumagillin; lung growth; lung hypoplasia; pulmonary circulation; pulmonary hypertension; thalidomide; vascular endothelial growth factor
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S. K. Banerjee, H. W. J. Young, A. Barczak, D. J. Erle, and M. R. Blackburn Abnormal Alveolar Development Associated with Elevated Adenine Nucleosides Am. J. Respir. Cell Mol. Biol., January 1, 2004; 30(1): 38 - 50. [Abstract] [Full Text] [PDF]
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V. Balasubramaniam, J.-R. Tang, A. Maxey, C. G. Plopper, and S. H. Abman Mild hypoxia impairs alveolarization in the endothelial nitric oxide synthase-deficient mouse Am J Physiol Lung Cell Mol Physiol, June 1, 2003; 284(6): L964 - L971. [Abstract] [Full Text] [PDF]
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S. G. Kallapur, A. H. Jobe, M. Ikegami, and C. J. Bachurski Increased IP-10 and MIG Expression after Intra-amniotic Endotoxin in Preterm Lamb Lung Am. J. Respir. Crit. Care Med., March 1, 2003; 167(5): 779 - 786. [Abstract] [Full Text] [PDF]
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T. D. Le Cras, N. E. Markham, R. M. Tuder, N. F. Voelkel, and S. H. Abman Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure Am J Physiol Lung Cell Mol Physiol, September 1, 2002; 283(3): L555 - L562. [Abstract] [Full Text] [PDF]
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M. R. Chinoy, M. M. Graybill, S. A. Miller, C. M. Lang, and G. L. Kauffman Angiopoietin-1 and VEGF in vascular development and angiogenesis in hypoplastic lungs Am J Physiol Lung Cell Mol Physiol, July 1, 2002; 283(1): L60 - L66. [Abstract] [Full Text] [PDF]
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S. H. Abman Bronchopulmonary Dysplasia . ""A Vascular Hypothesis"" Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1755 - 1756. [Full Text] [PDF]
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W. M. Maniscalco, R. H. Watkins, G. S. Pryhuber, A. Bhatt, C. Shea, and H. Huyck Angiogenic factors and alveolar vasculature: development and alterations by injury in very premature baboons Am J Physiol Lung Cell Mol Physiol, April 1, 2002; 282(4): L811 - L823. [Abstract] [Full Text] [PDF]
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