Anesthesiology 2008; 108:1047–54 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc. Vascular Remodeling Protects against Ventilator-induced Lung Injury in the In Vivo Rat Alik Kornecki, M.D.,* Doreen Engelberts, A.H.T.,† Patrick McNamara, M.B.,‡ Robert P. Jankov, M.D.,§ Cona ´ n McCaul, M.B., Cameron Ackerley, Ph.D.,# Martin Post, Ph.D.,** Brian P. Kavanagh, M.B.†† Background: The role of the pulmonary vasculature in the pathogenesis of ventilator-induced lung injury is not well estab- lished. In this study, the authors investigated the effect of vas- cular remodeling due to chronic pulmonary hypertension on susceptibility to ventilator-induced lung injury. The authors hypothesized that the enhanced vascular tensile strength asso- ciated with pulmonary vascular remodeling would protect against ventilator-induced lung injury. Methods: Chronic pulmonary arterial hypertension was in- duced in rats by exposure to hypoxia for 28 days and was confirmed by demonstration of right ventricular hypertrophy. Normotensive and hypertensive groups of rats (as well as a group in which pulmonary hypertension was acutely reversed with a Rho-kinase inhibitor, Y-27632) were exposed to injurious ventilation (respiratory rate 30 min 1 , 30/0 cm H 2 O) for 90 min. Lung injury was assessed by change in lung mechanics, oxygen- ation, edema development, and cytokine levels. Electron mi- croscopy was used to examine vascular structure in additional animals. Results: Injurious ventilation caused significant lung injury (lung compliance, oxygenation, pulmonary edema) in the nor- motensive controls, but not in the presence of pulmonary hy- pertension; acute reversal of pulmonary hypertension did not alter the lessened susceptibility to ventilator-induced lung in- jury. Electron microscopy demonstrated capillary endothelial and epithelial breaks in injuriously ventilated normotensive controls that were not seen with pulmonary hypertension, whether or not the pulmonary hypertension was acutely reversed. Conclusions: Vascular remodeling induced by chronic pul- monary hypertension confers protection against the effects of injurious mechanical ventilation in vivo by a mechanism that may involve structural alterations rather than increased pulmo- nary artery pressure. CLINICAL data demonstrate that higher tidal volumes are in general associated with greater mortality than lower tidal volumes 1 ; this has been attributed to lung injury associated with injurious ventilation. Ventilator-induced lung injury (VILI) has been mainly studied in short-term animal models. 2 Previous examples include surfactant depletion, 3 oleic acid administration, 4 acid aspiration, 5 acute sepsis or lipopolysaccharide exposure, 6 and ischemia– reperfusion. 7 Most investigations of VILI have focused on the inflammatory 8 or alveolar elements of lung injury, 2 and the pulmonary vasculature—although obviously central to any considerations of pulmonary pathophys- iology— has received less attention. Nevertheless, in- formation that is available suggests that the vascula- ture might be important in the pathogenesis of VILI for the following reasons. First, exposure of the lungs to high stretch during mechanical ventilation is asso- ciated with structural failure that has been termed stress failure, 9,10 which corresponds to physical frac- tures in pulmonary endothelial as well as epithelial cell membranes. Second, during positive-pressure ven- tilation, interactions between intravascular pres- sure 11–13 or flow 14,15 affect the propensity to lung injury. Third, vasoactive prostanoids that are known to cause or exacerbate pulmonary hypertension are increased in experimental ventilator-induced lung in- jury, 16 and inhibition of prostanoid synthesis can re- duce the pulmonary vascular responses associated with such injury. 17 Fourth, structural elements of the pulmonary vasculature may play a role, e.g., the threshold for mechanical failure of the alveolar– cap- illary barrier is related to the thickness of the capillary basement membrane. 18 In the current study, we ex- plored the effect of a relatively common clinical con- dition, secondary chronic pulmonary arterial hyper- tension, on the development of VILI. We conclude that chronic pulmonary artery hypertension is protec- tive through vascular remodeling which enhances vas- cular mechanical strength. * Assistant Professor, Program in Physiology and Experimental Medicine and Departments of Critical Care Medicine and Anesthesia, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Paediatrics, Critical Care Unit, Chil- dren’s Hospital of Western Ontario, University of Western Ontario, London, Ontario, Canada. † Research Technologist, Program in Physiology and Experi- mental Medicine, ‡ Assistant Professor, Program in Physiology and Experimental Medicine and Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada. § Assistant Professor, Department of Pediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada; Clinical Integrative Biology, Sunnybrook Research Institute, Toronto, Ontario, Canada.  Consultant Anesthe- siologist, Program in Physiology and Experimental Medicine and Departments of Critical Care Medicine and Anesthesia, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada. # Assistant Professor, Department of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada. ** Professor, Program in Phys- iology and Experimental Medicine and Department of Pediatrics, Hospital for Sick Children, Toronto, Ontario, Canada; Departments of Laboratory Medicine, Physiology and Pediatrics, University of Toronto, Toronto, Ontario, Canada. †† Professor, Program in Physiology and Experimental Medicine and Depart- ments of Critical Care Medicine and Anesthesia, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Anesthesia, Department of Physiology and the Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, Ontario, Canada. Received from the Program in Physiology and Experimental Medicine, Hospi- tal for Sick Children, Toronto, Ontario, Canada. Submitted for publication July 9, 2007. Accepted for publication February 11, 2008. Supported by the Canadian Institutes of Health Research, Ottawa, Ontario, Canada. Dr. Kavanagh is the recipient of a New Investigator Award (Canadian Institutes of Health Research) and the Premier’s Research Excellence Award (Ontario Ministry of Science and Technology). Dr. Post is the holder of a Canadian Research Chair in Fetal, Neonatal and Maternal Health. Address correspondence to Dr. Kavanagh: Department of Critical Care Medi- cine, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, Can- ada M5G 1X8. brian.kavanagh@sickkids.ca. This article may be accessed for personal use at no charge through the Journal Web site, www.anesthesiology .org. Anesthesiology, V 108, No 6, Jun 2008 1047