Submitted September 20, 2007
Accepted January 30, 2008
RBC induce hypoxic lung inflammation
Rainer Kiefmann, Joseph M Rifkind, Enika Nagababu, and Jahar Bhattacharya*
Lung Biology Laboratory, College of Physicians & Surgeons, Columbia University, St. Luke's Roosevelt Hospital Center, New York, NY, United States
Molecular Dynamics Section, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States
* Corresponding author; email: jb39{at}columbia.edu.
Hypoxia, which commonly associates with respiratory and cardiovascular diseases, provokes an acute inflammatory response. However, underlying mechanisms are not well understood. Here we report that red blood cells (RBC) induce hypoxic inflammation by producing reactive oxygen species (ROS) that diffuse to endothelial cells of adjoining blood vessels. Real-time fluorescence imaging of rat and mouse lungs revealed that in the presence of RBC-containing vascular perfusion, hypoxia increased microvascular ROS and cytosolic Ca2+, leading to P-selectin-dependent leukocyte recruitment. However, in the presence of RBC-free perfusion all hypoxia-induced responses were completely inhibited. Since hemoglobin (Hb) autoxidation causes RBC superoxide formation that readily dismutates to H2O2, hypoxia-induced responses were lost when we inhibited Hb autoxidation with CO or nitrite, or when the H2O2 inhibitor, catalase was added to the infusion to neutralize the RBC-derived ROS. By contrast, perfusion with RBC from BERK-trait mice that are more susceptible to Hb autoxidation and to hypoxia-induced superoxide production, enhanced the hypoxia-induced responses. We conclude that in hypoxia, increased Hb autoxidation augments superoxide production in RBC. Consequently, RBC release H2O2 that diffuses to the lung microvascular endothelium, thereby initiating Ca2+-dependent leukocyte recruitment. These findings are the first evidence that RBC contribute to hypoxia-induced inflammation.
