Background Single nucleotide polymorphisms in the human gene for the receptor for advanced glycation end-products (RAGE) are associated with an increased incidence of asthma. RAGE is highly expressed ...in the lung and has been reported to play a vital role in the pathogenesis of murine models of asthma/allergic airway inflammation (AAI) by promoting expression of the type 2 cytokines IL-5 and IL-13. IL-5 and IL-13 are prominently secreted by group 2 innate lymphoid cells (ILC2s), which are stimulated by the proallergic cytokine IL-33. Objective We sought to test the hypothesis that pulmonary RAGE is necessary for allergen-induced ILC2 accumulation in the lung. Methods AAI was induced in wild-type and RAGE knockout mice by using IL-33, house dust mite extract, or Alternaria alternata extract. RAGE's lung-specific role in type 2 responses was explored with bone marrow chimeras and induction of gastrointestinal type 2 immune responses. Results RAGE was found to drive AAI by promoting IL-33 expression in response to allergen and by coordinating the inflammatory response downstream of IL-33. Absence of RAGE impedes pulmonary accumulation of ILC2s in models of AAI. Bone marrow chimera studies suggest that pulmonary parenchymal, but not hematopoietic, RAGE has a central role in promoting AAI. In contrast to the lung, the absence of RAGE does not affect IL-33–induced ILC2 influx in the spleen, type 2 cytokine production in the peritoneum, or mucus hypersecretion in the gastrointestinal tract. Conclusions For the first time, this study demonstrates that a parenchymal factor, RAGE, mediates lung-specific accumulation of ILC2s.
Background The antioxidant properties of blood vessels contribute to their performance and patency of that vessel when used as a bypass conduit. Despite increased use of the radial artery (RA) in ...recent years, very little is known about its antioxidant properties. We compared the ability of the RA to generate superoxide and assessed its antioxidant protective capacity with that of the internal thoracic artery (ITA). Methods Vascular segments of the ITA and the RA were obtained from patients undergoing coronary artery bypass grafting (CABG) incubated in culture media for 2, 24, 48 and 72 hours. The amount of superoxide generated by each artery, and the deterioration of the endothelial function were assessed by using chemiluminescence (CL) and organ bath techniques. We also assessed the expression, localisation and the activity of superoxide dismutase ( SOD ) in both arteries; using reverse transcription-polymerase chain reaction (RT-PCR), immunolocalisation techniques and standard biochemical assessment of SOD activity. Results Under stress, the RA generated more superoxide (133.6 ± 54.7 at 72 h vs. 16.8 ± 6.4 at 2 h; P < 0.01) and its endothelial function deteriorated faster (56.3 ± 7.3 at 72 h vs. 20.2 ± 1.5 at 2 h; P < 0.0001) than that of ITA. Cu/Zn-SOD was found to be prevalent in the endothelium, while Ec-SOD was distributed evenly in the endothelium and media of both arteries. The activity of SOD was less in the RA compared with that of the ITA (510.2 ± 219.8 vs. 808.6 ± 343.7, respectively; P = 0.03). Conclusions Our study shows that the RA is less equipped with an antioxidant protective mechanism compared with the ITA. These findings could partially explain the differential clinical performance of these conduits in CABG.
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