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Am J Physiol Lung Cell Mol Physiol 297: L920-L930, 2009. First published September 11, 2009; doi:10.1152/ajplung.00139.2009
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Therapeutic effects of hypercapnia on chronic lung injury and vascular remodeling in neonatal rats

Azhar Masood,1,2,7 Man Yi,1,2,7 Mandy Lau,1,2,7 Rosetta Belcastro,1,2 Samuel Shek,1,2 Jingyi Pan,1,2 Crystal Kantores,3 Patrick J. McNamara,2,6 Brian P. Kavanagh,1,2,4,5,7 Jaques Belik,1,2,6,7 Robert P. Jankov,3,6,7 and A. Keith Tanswell1,2,6,7

1Canadian Institutes of Health Research Group in Lung Development, and ; 2Lung Biology Programme, Physiology and Experimental Medicine, Hospital for Sick Children Research Institute; ; 3Clinical Integrative Biology, Sunnybrook Research Institute; and ; Departments of 4Anaesthesia, ; 5Critical Care Medicine, ; 6Paediatrics, and ; 7Physiology, University of Toronto, Toronto, Ontario, Canada

Submitted 24 April 2009 ; accepted in final form 9 September 2009

Permissive hypercapnia, achieved using low tidal volume ventilation, has been an effective protective strategy in patients with acute respiratory distress syndrome. To date, no such protective effect has been demonstrated for the chronic neonatal lung injury, bronchopulmonary dysplasia. The objective of our study was to determine whether evolving chronic neonatal lung injury, using a rat model, is resistant to the beneficial effects of hypercapnia or simply requires a less conservative approach to hypercapnia than that applied clinically to date. Neonatal rats inhaled air or 60% O2 for 14 days with or without 5.5% CO2. Lung parenchymal neutrophil and macrophage numbers were significantly increased by hyperoxia alone, which was associated with interstitial thickening and reduced secondary crest formation. The phagocyte influx, interstitial thickening, and impaired alveolar formation were significantly attenuated by concurrent hypercapnia. Hyperoxic pups that received 5.5% CO2 had a significant increase in alveolar number relative to air-exposed pups. Increased tyrosine nitration, a footprint for peroxynitrite-mediated reactions, arteriolar medial wall thickening, and both reduced small peripheral pulmonary vessel number and VEGF and angiopoietin-1 (Ang-1) expression, which were observed with hyperoxia, was attenuated by concurrent hypercapnia. We conclude that evolving chronic neonatal lung injury in a rat model is responsive to the beneficial effects of hypercapnia. Inhaled 5.5% CO2 provided a significant degree of protection against parenchymal and vascular injury in an animal model of chronic neonatal lung injury likely due, at least in part, to its inhibition of a phagocyte influx.

carbon dioxide; lung growth; inflammation


Address for reprint requests and other correspondence: A. K. Tanswell, Division of Neonatology, The Hospital for Sick Children, 555 Univ. Ave., Toronto, ON, Canada M5G 1X8 (e-mail: keith.tanswell{at}sickkids.ca).






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