Journal of Pathology J Pathol 2014; 232: 289–299 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/path.4299 INVITED REVIEW Responses to ionizing radiation mediated by inflammatory mechanisms Debayan Mukherjee,* ,# Philip J Coates, Sally A Lorimore and Eric G Wright Centre for Oncology and Molecular Medicine, University of Dundee Medical School, Dundee, DD1 9SY, UK *Correspondence to: D Mukherjee, Department of Oncology, Sheffield Cancer Research Centre, University of Sheffield Medical School, Sheffield S10 2RX, UK. E-mail: d.mukherjee@sheffield.ac.uk # Current address: Department of Oncology, Sheffield Cancer Research Centre, University of Sheffield Medical School, Sheffield S10 2RX, UK. Abstract Since the early years of the twentieth century, the biological consequences of exposure to ionizing radiation have been attributed solely to mutational DNA damage or cell death induced in irradiated cells at the time of exposure. However, numerous observations have been at variance with this dogma. In the 1950s, attention was drawn to abscopal effects in areas of the body not directly irradiated. In the 1960s reports began appearing that plasma factors induced by irradiation could affect unirradiated cells, and since 1990 a growing literature has documented an increased rate of DNA damage in the progeny of irradiated cells many cell generations after the initial exposure (radiation-induced genomic instability) and responses in non-irradiated cells neighbouring irradiated cells (radiation-induced bystander effects). All these studies have in common the induction of effects not in directly irradiated cells but in unirradiated cells as a consequence of intercellular signalling. Recently, it has become clear that all the various effects demonstrated in vivo may reflect an ongoing inflammatory response to the initial radiation-induced injury that, in a genotype-dependent manner, has the potential to contribute primary and/or ongoing damage displaced in time and/or space from the initial insult. Importantly, there is direct evidence that non-steroidal anti-inflammatory drug treatment reduces such damage in vivo. These new findings highlight the importance of tissue responses and indicate additional mechanisms of radiation action, including the likelihood that radiation effects are not restricted to the initiation stage of neoplastic diseases, but may also contribute to tumour promotion and progression. The various developments in understanding the responses to radiation exposures have implications not only for radiation pathology but also for therapeutic interventions. Copyright  2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: radiation; non-targeted effects; tissue microenvironment; inflammation; macrophages Received 26 September 2013; Revised 30 October 2013; Accepted 5 November 2013 No conflicts of interest were declared. Introduction The deleterious effects of ionizing radiation are con- sidered to result from the deposition of energy in the cell nucleus resulting in DNA damage at the time of exposure. It is well established that radiation pro- duces a wide spectrum of DNA lesions, which include base damage, single-strand breaks (SSBs), double- strand breaks (DSBs) of varying complexity and DNA crosslinks [1]. Similar numbers of base damages and single-strand breaks are induced at approximately 25 times the frequency of double-strand breaks for any given dose of X-rays [2], but most damage can be effectively be repaired by cellular repair pathways. Under conditions of effective repair, the progeny of irradiated cells would be functionally normal and indis- tinguishable from non-irradiated cells. However, DNA double-strand breaks have long been recognized as severe cellular lesions, since if unrepaired they can result in cell death, and if misrepaired they can be initiating events for malignancy [3]. All cells in the body are susceptible to damage by irradiation but the extent of initial damage largely depends on physical parameters [4], with the con- sequences of the damage determined by the ability of cells to detect DNA damage, signal its presence and mediate its repair [5]. Effective repair of damage would result in the progeny of an irradiated cell being functionally normal, but if the damage is misrepaired or unrepaired the progeny of a single irradiated cell would be expected to show radiation-induced genetic changes in all descendant cells, ie the change would be clonal. As clonal mutations have been extensively documented in experimental studies, it has been widely accepted that the production of lethal, mutational or clastogenic lesions is induced in irradiated cells at the time of exposure [6]. The risk of an individ- ual developing malignant disease after exposure to Copyright  2013 Pathological Society of Great Britain and Ireland. J Pathol 2014; 232: 289–299 Published by John Wiley & Sons, Ltd. www.pathsoc.org.uk www.thejournalofpathology.com