All for one, though not one for all: team players in normal tissue radiobiology

Abstract

Purpose: As part of the special issue on 'Women in Science', this review offers a perspective on past and ongoing work in the field of normal (non-cancer) tissue radiation biology, highlighting the work of many of the leading contributors to this field of research. We discuss some of the hypotheses that have guided investigations, with a focus on some of the critical organs considered dose-limiting with respect to radiation therapy, and speculate on where the field needs to go in the future.

Conclusions: The scope of work that makes up normal tissue radiation biology has and continues to play a pivotal role in the radiation sciences, ensuring the most effective application of radiation in imaging and therapy, as well as contributing to radiation protection efforts. However, despite the proven historical value of preclinical findings, recent decades have seen clinical practice move ahead with altered fractionation scheduling based on empirical observations, with little to no (or even negative) supporting scientific data. Given our current appreciation of the complexity of normal tissue radiation responses and their temporal variability, with tissue- and/or organ-specific mechanisms that include intra-, inter- and extracellular messaging, as well as contributions from systemic compartments, such as the immune system, the need to maintain a positive therapeutic ratio has never been more urgent. Importantly, mitigation and treatment strategies, whether for the clinic, emergency use following accidental or deliberate releases, or reducing occupational risk, will likely require multi-targeted approaches that involve both local and systemic intervention. From our personal perspective as five 'Women in Science', we would like to acknowledge and applaud the role that many female scientists have played in this field. We stand on the shoulders of those who have gone before, some of whom are fellow contributors to this special issue.

Keywords: Normal tissue radiobiology; brain; cardiovascular system; immune system; lung.

Figure 1.

Examples of the evolution in hypotheses and approaches taken to decipher the mechanisms underlying normal tissue radiation responses. (A) A paradigm of tissue compartments communicating through unspecified channels (Rubin et al. 1998); (B) An holistic overview of radiation disrupting a tissue’s homeostatic balance, resulting in autocrine and paracrine expression of chemokines and cytokines (McBride et al. 2004); (C) A simplified overview of the potential integration of -omics data at the DNA (genes, red), RNA (transcripts, dark blue) and protein (red) levels, as well as the regulation (red broken lines) at the transcription (yellow) miRNA (orange) and epigenetic (green) levels (modified from Unger 2014.).

Figure 2.

The feed-forward loop between radiation-induced inflammation, bone marrow myeloid skewing and persistent tissue damage. This illustrates the link between the initial tissue damage, which signals danger to the immune system, and the recurring waves of inflammatory responses, driven by persistent DNA damage and senescence-associated phenotypes. Positive feed-back to the bone marrow leads to hematopoiesis being adjusted toward emergency myelopoiesis, thereby maintaining a pool of inflammatory myeloid cells that prevents resolution and, instead, causing further inflammatory-related collateral tissue damage. Red circle = self-renewing hematopoietic stem cells.

Figure 3.

The development of radiation-induced lung injury is biologically complex. Of the 90+ cell types in the lung, there is no single target cell that initiates the response, although several are currently considered candidates. Progression to the early (pneumonitic) and late (fibrotic) phases involves multiple, parallel events, including initial and/or delayed hypoxia due to occlusion and permanent loss of blood vessels, respectively, waves of inflammatory cell recruitment and activation (including macrophages, lymphocytes and platelets), and chronic oxidative stress. Adapted from Bentzen 2006, Schaue et al. 2012 and Leiva-Juárez et al. 2018.

Figure 4.

Research in preclinical models and analyses of patient samples have identified several cell types and cellular mechanisms that may contribute to the development of cardiovascular dysfunction after exposure to ionizing radiation. Additional insight into biological mechanisms needs to be obtained. ER: Endoplasmic Reticulum; MPTP: mitochondrial permeability transition pore.

Figure 5.

Clinical and preclinical research supports several mechanisms underlying RIBI and subsequent cognitive deficits, including apoptotic cell death, neuroinflammation, genetic/epigenetic changes, and changes to the neuronal microenvironment, which are prolonged by continued neuroinflammation and vascular damage. Damage depends on total dose delivered, fractionation, and dose-rate, and not all models display all changes. NSC: neural stem cell; LTP: long-term potentiation; NT: neurotransmitter.