Lipopolysaccharide (LPS)-induced production of Reactive Oxygen Species (ROS) leads to lung inflammation and damage associated with several respiratory diseases, including Acute Respiratory Distress Syndrome (ARDS). The link between oxidative stress and inflammation in ARDS led us to hypothesize that the non-selective, redox-sensitive TRPM2 cation channel contributes to the pathogenesis of this syndrome. Following intranasal LPS challenge, Trpm2-/- mice had attenuated alveolar hemorrhage compared to wild-type mice. Flow cytometric analyses showed a modest increase in PMNs and alveolar macrophages (AMs) in the lung tissue and airways of Trpm2-/- mice at the early phase (3-12 hours) of inflammation but significant reductions in PMNs, monocytes, monocyte-derived cells and lymphocytes at the mid (1-2 days) and late (3-7 days) phases. Furthermore, Trpm2-/- mice had decreased expression of proinflammatory/chemoattractant factors and matrix metalloproteases in the lung. Irradiated bone marrow chimeric mice revealed that the protective, TRPM2-deficient phenotype is mainly due to defects in irradiation-resistant lung cells, suggesting that TRPM2 may play an important role in non-hematopoietic cells (e.g. pulmonary endothelial and epithelial cells), as well as AMs. Our data support a harmful role for TRPM2 in ARDS and highlight its pharmacological inhibition as a potential therapeutic approach in treating acute pulmonary inflammation and injury in patients with bacterial infections.
- Copyright © 2013 by The American Association of Immunologists, Inc.