by Rekha Badiger, Jane A. Mitchell, Hime Gashaw, Neil A. Galloway-Phillipps, Stefan Foser, Fernando Tatsch, Thomas Singer, Trevor T. Hansel, Tobias Manigold
Alfa-interferons (IFNa2a, IFNa2b, 40KDa-PEGIFNa2a and 12KDa-PEGIFNa2b) are effective treatments for chronic hepatitis C infection. However, their usage has been associated with a variety of adverse events, including interstitial pneumonitis and pulmonary arterial hypertension. Although rare, these adverse events can be severe and potentially life-threatening, emphasizing the need for simple biomarkers of IFN-induced lung toxicity. Methods
Human lung microvascular endothelial cells (HLMVEC), human pulmonary artery smooth muscle (HPASM) cells and A549 cells were grown under standard conditions and plated into 96- or 6-well plates. Cells were stimulated with various concentrations of different IFNs in hydrocortisone-free medium. After 24 and 48 hours, IP10 and ET-1 were measured by ELISA in conditioned medium. In a second set of experiments, cells were pre-treated with tumour necrosis factor-a (TNF-a) (10 ng/mL). Results
IFNa2a, IFNa2b, 40KDa-PEGIFNa2a and 12KDa-PEGIFNa2b, but not IFN?, induced IP10 (CXCL10) release and increased IP10 gene induction in HLMVEC. In addition, all four IFNa preparations induced IP10 release from HPASM cells and A549 cells pre-treated with TNFa. In each of these cell types, 40KDa-PEGIFNa2a was significantly less active than the native forms of IFNa2a, IFNa2b or 12KDa-PEGIFNa2b. Similarly, IFNa2a, IFNa2b and 12KDa-PEGIFNa2b, but not 40KDa-PEGIFNa2a, induced endothelin (ET)-1 release from HPASM cells. Conclusions
Consistent with other interstitial pulmonary diseases, both IP10 and ET1 may serve as markers to monitor IFN-induced lung toxicity in patients. In addition, both markers may also serve to help characterize the risk associated with IFNa preparations to induce lung toxicity.