Red blood cells induce hypoxic lung inflammation

Rainer Kiefmann, Joseph M. Rifkind, Enika Nagababu, Jahar Bhattacharya

Research output: Contribution to journalArticlepeer-review

Abstract

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 per- fusion, 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 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 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 H2O2 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.

Original languageEnglish (US)
Pages (from-to)5205-5214
Number of pages10
JournalBlood
Volume111
Issue number10
DOIs
StatePublished - May 15 2008
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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