Red blood cells induce hypoxic lung inflammation.
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 (RBCs) 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 Ca(2+), leading to P-selectin-dependent leukocyte recruitment. However, in the presence of RBC-free perfusion, all hypoxia-induced responses were completely inhibited. Because hemoglobin (Hb) autoxidation causes RBC superoxide formation that readily dismutates to H(2)O(2), hypoxia-induced responses were lost when we inhibited Hb autoxidation with CO or nitrite, or when the H(2)O(2) inhibitor, catalase was added to the infusion to neutralize the RBC-derived ROS. By contrast, perfusion with RBCs 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 RBCs. Consequently, RBCs release H(2)O(2) that diffuses to the lung microvascular endothelium, thereby initiating Ca(2+)-dependent leukocyte recruitment. These findings are the first evidence that RBCs contribute to hypoxia-induced inflammation.
Kiefmann
Rainer
R
Lung Biology Laboratory, College of Physicians & Surgeons, Columbia University, St Luke's Roosevelt Hospital Center, New York, NY, USA.
Rifkind
Joseph M
JM
Nagababu
Enika
E
Bhattacharya
Jahar
J
D000818:Animals; D002634:Chemotaxis, Leukocyte; D042783:Endothelial Cells / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D004912:Erythrocytes / Q000378:metabolism / Q000502:physiology*; D006454:Hemoglobins / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D000860:Hypoxia / Q000150:complications*; D066298:In Vitro Techniques; D008168:Lung; D051379:Mice; D011014:Pneumonia / Q000209:etiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*
D006454:Hemoglobins; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide