Rescue effects: irradiated cells helped by unirradiated bystander cells.

The rescue effect describes the phenomenon where irradiated cells or organisms derive benefits from the feedback signals sent from the bystander unirradiated cells or organisms. An example of the benefit is the mitigation of radiation-induced DNA damages in the irradiated cells. The rescue effect can compromise the efficacy of radioimmunotherapy (RIT) (and actually all radiotherapy). In this paper, the discovery and subsequent confirmation studies on the rescue effect were reviewed. The mechanisms and the chemical messengers responsible for the rescue effect studied to date were summarized. The rescue effect between irradiated and bystander unirradiated zebrafish embryos in vivo sharing the same medium was also described. In the discussion section, the mechanism proposed for the rescue effect involving activation of the nuclear factor κB (NF-κB) pathway was scrutinized. This mechanism could explain the promotion of cellular survival and correct repair of DNA damage, dependence on cyclic adenosine monophosphate (cAMP) and modulation of intracellular reactive oxygen species (ROS) level in irradiated cells. Exploitation of the NF-κB pathway to improve the effectiveness of RIT was proposed. Finally, the possibility of using zebrafish embryos as the model to study the efficacy of RIT in treating solid tumors was also discussed.

Radiation-induced non-targeted response in vivo: role of the TGFß-TGFBR1-COX-2 signalling pathway.

BACKGROUND: Previous studies from our group and others have shown that cyclooxygenase-2 (COX-2) has an essential role in radiation-induced non-targeted responses and genomic instability in vivo. However, the signalling pathways involved in such effects remain unclear. METHODS: A 1 cm(2) area (1 cm × 1 cm) in the lower abdominal region of gpt delta transgenic mice was irradiated with 5 Gy of 300 keV X-rays. Nimesulide, a selective COX-2 inhibitor, was given to mice for five consecutive days before irradiation. Changes in transforming growth factor-beta (TGF-ß) and TGF-ß receptor type-1 (TGFBR1) mediated signalling pathways, in the out of radiation field lung and liver tissues were examined. RESULTS: While the plasma level of cytokines remained unchanged, the expression of TGF-ß and its receptors was elevated in non-targeted lung tissues after partial body irradiation. In contrast to the predominant expression of TGF-ß in stromal and alveolar cells, but not in bronchial epithelial cells, TGF-ß receptors, especially TGFBR1 were significantly elevated in non-targeted bronchial epithelial cells, which is consistent with the induction of COX-2. The different expression levels of TGFBR1 between liver and lung resulted in a tissue specific induction of COX-2 in these two non-targeted tissues. Multiple TGF-ß induced signalling pathways were activated in the non-targeted lung tissues. CONCLUSION: The TGFß-TGFBR1-COX-2 Signalling Pathway has a critical role in radiation-induced non-targeted response in vivo.

Unirradiated cells rescue cells exposed to ionizing radiation: Activation of NF-κB pathway in irradiated cells.

We studied the involvement of NF-κB pathway activation in the rescue effect in HeLa and NIH/3T3 cells irradiated by α particles. Firstly, upon irradiation by 5 cGy of α particles, for both cell lines, the numbers of 53BP1 foci/cell at 12 h post-irradiation were significantly smaller when only 2.5% of the cell population was irradiated as compared to 100% irradiation, which demonstrated the rescue effect. Secondly, we studied the effect of NF-κB on the rescue effect through the use of the NF-κB activation inhibitor BAY-11-7082. Novel experimental setup and procedures were designed to prepare the medium (CM) which had conditioned the bystander cells previously partnered with irradiated cells, to ensure physical separation between rescue and bystander signals. BAY-11-7082 itself did not inflict DNA damages in the cells or have effects on activation of the NF-κB response pathway in the irradiated cells through direct irradiation. The rescue effect was induced in both cell lines by the CM, which was abrogated if BAY-11-7082 was added to the CM. Thirdly, we studied the effect of NF-κB on the rescue effect through staining for phosphorylated NF-κB (p-NF-κB) expression using the anti-NF-κB p65 (phospho S536) antibody. When the fraction of irradiated cells dropped from 100% to 2.5%, the p-NF-κB expression in the cell nuclei of irradiated NIH/3T3 cells increased significantly, while that in the cell nuclei of irradiated HeLa cells also increased although not significantly. Moreover, the p-NF-κB expression in the cell nuclei of irradiated HeLa cells and NIH/3T3 cells treated with CM also increased significantly.

Modulation of NF-κB in rescued irradiated cells.

Studies by different groups on the rescue effect, where unirradiated bystander cells mitigated the damages in the irradiated cells, since its discovery by the authors' group in 2011 were first reviewed. The properties of the rescue effect were then examined using a novel experimental set-up to physically separate the rescue signals from the bystander signals. The authors' results showed that the rescue effect was mediated through activation of the nuclear factor-κB (NF-κB) response pathway in the irradiated cells, and that the NF-κB activation inhibitor BAY-11-7082 did not affect the activation of this response pathway in the irradiated cells induced by direct irradiation.

Long-term determination of airborne radon progeny concentrations using LR 115 detectors and the effects of thoron.

The 'proxy equilibrium factor' (F(p)) method has been developed for long-term determination of airborne radon progeny concentrations using LR 115 solid-state nuclear track detectors. In this paper, the effects of (220)Rn on the F(p) method have been studied. The correction to the track density was related to a parameter α which was the ratio of the sum of activity concentrations of alpha-particle emitting radionuclides in the (220)Rn decay chain to the activity concentration of (220)Rn alone. Under commonly encountered circumstances, α could not be smaller than 2. An attempt was made to verify this using the exposure chamber at the National Institute of Radiological Sciences (NIRS), Chiba, Japan. A most interesting observation of α < 2 for very high (220)Rn concentrations and very low equilibrium factors for (220)Rn in the exposure chambers was made. A possible explanation was the substantial deposition of (216)Po under the extreme conditions inside the exposure chambers.