The large surface area covered by the intestinal epithelium is particularly prone to inflammation-associated hypoxia as may occur during inflammatory bowel disease. Here, extracellular adenosine signaling events play a major role in attenuating acute inflammation, particularly during conditions of limited oxygen availability. However, extracellular adenosine has an extremely short half-life on the epithelial surface of the intestine. This is due to rapid transport by nucleoside transporters and enzymatic metabolism. Therefore, we hypothesized the existence of endogenous non-adenosine-like compounds with biological activity on adenosine receptors (ARs). To pursue this hypothesis, we screened fractions derived from supernatants of hypoxic epithelia for AR activity. These studies found a single fraction with biological activity. Using mass spectrometry, we found that this fraction contained a dominant peak consistent with the mass of the neuronal guidance molecule netrin-1. Such studies revealed a surprising role for neuronal guidance molecule netrin-1 in alternative adenosine receptor activation and attenuation of mucosal inflammation during hypoxia. Based on these preliminary studies, it is our hypothesis that endogenous netrin-1 is released from hypoxic epithelia, and attenuates inflammatory hypoxia through AR-dependent signaling pathways. In the present proposal, we will further characterize the role of netrin-1 in alternative AR activation and its biological role in endogenous attenuation of mucosal inflammation as occurs during experimental colitis.
The present studies are designed to identify endogenous anti-inflammatory signaling pathways and to test these pathways in a therapeutic setting. This work will lay the groundwork for novel and specific therapeutic approaches in the treatment of mucosal inflammation, which are urgently needed - for example in the treatment of patients suffering from inflammatory bowel disease.
| Baudiß, Kristin; de Paula Vieira, Rodolfo; Cicko, Sanja et al. (2016) C1P Attenuates Lipopolysaccharide-Induced Acute Lung Injury by Preventing NF-?B Activation in Neutrophils. J Immunol 196:2319-26 |
| Hoegl, Sandra; Zwissler, Bernhard; Eltzschig, Holger K et al. (2016) Acute respiratory distress syndrome following cardiovascular surgery: current concepts and novel therapeutic approaches. Curr Opin Anaesthesiol 29:94-100 |
| Neudecker, Viola; Brodsky, Kelley S; Kreth, Simone et al. (2016) Emerging Roles for MicroRNAs in Perioperative Medicine. Anesthesiology 124:489-506 |
| Seo, Seong-wook; Koeppen, Michael; Bonney, Stephanie et al. (2015) Differential Tissue-Specific Function of Adora2b in Cardioprotection. J Immunol 195:1732-43 |
| Hoegl, Sandra; Brodsky, Kelley S; Blackburn, Michael R et al. (2015) Alveolar Epithelial A2B Adenosine Receptors in Pulmonary Protection during Acute Lung Injury. J Immunol 195:1815-24 |
| Masterson, Joanne C; McNamee, Eóin N; Fillon, Sophie A et al. (2015) Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis. Gut 64:1236-47 |
| Vohwinkel, Christine U; Hoegl, Sandra; Eltzschig, Holger K (2015) Hypoxia signaling during acute lung injury. J Appl Physiol (1985) 119:1157-63 |
| Kork, Felix; Balzer, Felix; Spies, Claudia D et al. (2015) Minor Postoperative Increases of Creatinine Are Associated with Higher Mortality and Longer Hospital Length of Stay in Surgical Patients. Anesthesiology 123:1301-11 |
| Tak, Eunyoung; Ridyard, Douglas; Kim, Jae-Hwan et al. (2014) CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy. J Am Soc Nephrol 25:547-63 |
| Eltzschig, Holger K; Bratton, Donna L; Colgan, Sean P (2014) Targeting hypoxia signalling for the treatment of ischaemic and inflammatory diseases. Nat Rev Drug Discov 13:852-69 |
Showing the most recent 10 out of 62 publications
