Averbeck, N.

Mueller-Klieser, W.

Tschachojan, V.

GSI Repository

GSITemp late2007  Mucositis represents a potential risc for astronauts on extended space flights* V. Tschachojan1, N. Averbeck2,  W. Mueller-Klieser1 1 Institute of Physiology and Pathophysiology, University Medical Center Mainz, Germany;                                       2GSI Helmholtz Centre for Heavy Ion Research, Darmstadt, Germany.Radiation-induced mucositis is a severe complication of heavy ion radiotherapy [1] and may also represent a health risk during extended space flights [2]. To evaluate the risk of developing a radiation-induced mucositis through highly energetic heavy ions in space, a three-dimensional organotypic oral mucosa model of im-mortalized human keratinocytes and fibroblasts was irra-diated with 12C particles (150 MeV/u) at the SIS accelera-tor at GSI. The focus of this study was on immediate and early effects after irradiation, where NFκB activation and increased expression of the cytokines are precursors of oral mucositis. 3D cultures were irradiated with 2 or 4 Gy and NFκB activation as well as IL6/IL8 expression was analyzed 4, 8, 24 and 48 h after treatment. In order to study NFκB activation NFκB p50 was immunofluores-cence stained in cryosections of irradiated 3D cultures. This revealed a translocation of NFκB p50 from the cyto-plasm to the nucleus after irradiation. The nuclear NFκB p50 signal was quantified and normalized against the nu-clear DAPI signal. The relative change of the NFκB p50 amount in the nucleus upon irradiation is shown in Figure 1. In cultures exposed to 2 Gy 12C heavy ions we ob-served a translocation of the transcription factor to the nucleus 24 h and 48 h after treatment. 4 Gy of 12C irradia-tion caused a nuclear increase of NFκB p50 already after 4 h; this localization could still be seen after 8 h, 24 h and 48 h.   Figure 1: The percentage change of the NFκB p50 amount in cell nuclei upon 12C irradiation. Cryosections of 3D cultures were immunofluorescence stained against NFκB p50. Only nuclear NFκB p50 stained areas were related to whole DAPI stained areas (n=4, mean ± sd;  *p < 0,02 with reference to not irradiated cultures).  The pro-inflammatory cytokines IL6 and IL8 were ana-lyzed in the culture’s supernatants in four independent experiments (Figure 2). In general, a tendency of dose-dependent increase of IL6 and IL8 could be detected for up to 24 h after irradiation. 48 h after irradiation the IL6 and IL8 level was back to the initial value.     Figure 2: ELISA analyzes of cytokines IL6 and IL8 from supernatants of organotypic cultures. The relative increase compared to the control level (untreated) in IL6 or IL8 is shown. (n=4, mean ± sd)  Taken together, inflammatory responses as a sign of the initiation stage of oral mucositis could be detected in or-ganotypic mucosa models exposed to highly energetic carbon ions. This suggests that mucositis indeed poses a risk for astronauts on extended space flights. References [1] Schultz-Ertner, D et al., (2002). Radiotherapy and Oncology 64; 189–195. [2] Gonda, TA et al., (2009). Cell Cycle 8:13:2005-2013. -200204060801001201401601804h 8h 24h 48hNFκB p50 activation (%) Incubation time 2 Gy4 Gy0204060801001201401601804h 8h 24h 48hIncrease of IL6 (%) Inkubation time 2 Gy4 Gy-200204060801001201401601804h 8h 24h 48hIncrease of IL8 (%) Inkubation time 2 Gy4 Gy** Support: ESA, Deutsches Zentrum für Luft- und Raumfahrt e. V. (DLR), Bundesministerium für Wirt-schaft und Technologie (BMWi), #50 WB 0926.  * GSI SCIENTIFIC REPORT 2012 HEALTH-67491

Mucositis represents a potential risc for astronauts on extended space flights

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Mucositis represents a potential risc for astronauts on extended space flights

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