| First Author | Sharma AK | Year | 2014 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 306 |
| Issue | 1 | Pages | L69-79 |
| PubMed ID | 24186876 | Mgi Jnum | J:210907 |
| Mgi Id | MGI:5572866 | Doi | 10.1152/ajplung.00205.2013 |
| Citation | Sharma AK, et al. (2014) NADPH oxidase mediates synergistic effects of IL-17 and TNF-alpha on CXCL1 expression by epithelial cells after lung ischemia-reperfusion. Am J Physiol Lung Cell Mol Physiol 306(1):L69-79 |
| abstractText | Ischemia-reperfusion (I/R) injury leads to increased mortality and morbidity in lung transplant patients. Lung I/R injury involves inflammation contributed by innate immune responses. IL-17 and TNF-alpha, from iNKT cells and alveolar macrophages, respectively, contribute importantly to lung I/R injury. This study tests the hypothesis that IL-17 and TNF-alpha synergistically mediate CXCL1 (a potent neutrophil chemokine) production by alveolar type II epithelial (ATII) cells via an NADPH oxidase-dependent mechanism during lung I/R. Using a hilar clamp model, wild-type and p47(phox-/-) (NADPH oxidase-deficient) mice underwent left lung I/R, with or without recombinant IL-17 and/or TNF-alpha treatment. Wild-type mice undergoing I/R treated with combined IL-17 and TNF-alpha had significantly enhanced lung dysfunction, edema, CXCL1 production, and neutrophil infiltration compared with treatment with IL-17 or TNF-alpha alone. However, p47(phox-/-) mice had significantly less pulmonary dysfunction, CXCL1 production, and lung injury after I/R that was not enhanced by combined IL-17-TNF-alpha treatment. Moreover, in an acute in vitro hypoxia-reoxygenation model, murine ATII cells showed a multifold synergistic increase in CXCL1 expression after combined IL-17-TNF-alpha treatment compared with treatment with either cytokine alone, which was significantly attenuated by an NADPH oxidase inhibitor. Conditioned media transfer from hypoxia-reoxygenation-exposed iNKT cells and macrophages, major sources of IL-17 and TNF-alpha, respectively, to ATII cells significantly enhanced CXCL1 production, which was blocked by NADPH oxidase inhibitor. These results demonstrate that IL-17 and TNF-alpha synergistically mediate CXCL1 production by ATII cells after I/R, via an NADPH oxidase-dependent mechanism, to induce neutrophil infiltration and lung I/R injury. |
