Loss of Vascular Control in Pediatric Lung Injury: Disruption of NO Biotransport by Oxidative Stress

Principal Investigator(s):

Allan Doctor, M.D. - Pediatrics

Status: Completed

Center(s): Center for Pediatric Pulmonary Disease

Award Mechanism: Interdisciplinary Research Initiative

Project Period: 2/1/2007 - 8/31/2009

Total Amount: $200,000

Collaborators: R. Reid Townsend, Nathan A. Baker, Julia Gloeckner

Project Summary:
Disordered control of the pulmonary microcirculation is an early pathophysiologic signature of lung injury that evolves as a complication of severe systemic inflammatory states in children. Investigation into this problem has focused upon circulating cytokines and/or leukocytes as propagants of injury to the lung. Dr. Doctor’s team will examine red blood cells (RBCs) as biochemical links between dysregulated pulmonary blood flow and remote inflammation. Recent strong evidence suggests a previously unrecognized pivotal role for RBCs in transducing regional O2 gradients into signals that govern vessel tone. Red cells apportion vascular resistance to match regional flow requirements by exerting dynamic control over the bioavailability of vasoactive effectors in plasma. The team believes that oxidative stress disrupts normal pulmonary vascular nitrosative signaling3 and may explain the dysregulated blood flow that underlies pulmonary perfusion mismatching and maladaptive physiologic and cellular responses in the lung microcirculation that characterize many forms of critical illness, and so, inform novel therapies for these conditions.