Molecular Mechanisms of Late Normal Tissue Injury James Brush, MS, Scott L. Lipnick, BS, Tiffany Phillips, MS, John Sitko, BS, J. Tyson McDonald, BSE, and William H. McBride, D.Sc Irradiation perturbs the homeostatic network linking parenchymal, mesenchymal, and vascular cells within tissues. Normal communication between cells through soluble, matrix, and cell-associated ligands and receptors is altered so as to set in motion a seemingly inexorable series of events aimed at tissue regeneration and healing. In late responding normal tissues where cell death is not compensated for by rapid regeneration, this process unfortunately often culminates in symptomatic complications of radiation exposure. Cyto- kines and their receptors are prominent in driving the cascade of molecular responses using the balance between seemingly mutually antagonistic molecules to control and direct the healing processes. There is strong evidence from preclinical models for the importance of cytokine-driven pathways in late radiation damage and growing evidence in humans for their relevance to radiation-induced disease. This review aims to show some general aspects of the molecular torrents that drive responses in irradiated tissues before and during the development of late effects. It attempts to collate some of the findings from preclinical models of late lung, central nervous system, skin, and intestinal damage and from clinical studies in the belief that understanding how irradiation perturbs the cellular communication networks will allow rationale intervention for mitigating late radiation tissue damage and carcinogenesis. Semin Radiat Oncol 17:121-130 © 2007 Elsevier Inc. All rights reserved. C ells acknowledge damage from radiation exposure through multiple sensor molecules and structures, in- cluding DNA, receptor tyrosine kinases, lipids, mitochon- dria, and proteasomes. 1 These sensors feed pathways that not only reprogram the cells to make appropriate internal re- sponses but also produce extracellular factors that spread news about the “danger” to the tissue and the body and initiate molecular cascades that aim to orchestrate tissue re- pair processes. These tissue-healing responses contain many highly conserved features that might reflect their essential role in the evolution of multicellular and multitissue organ- isms. Characteristically, responses are highly integrated and show considerable redundancy in their use of effector mole- cules with overlapping functions, as befits such a critical process. Not surprisingly, chemokines 2 and proinflammatory cyto- kines 3 are highly prominent among the panoply of molecules expressed in tissues after irradiation. Perhaps less obvious is the fact that anti-inflammatory cytokines can also be in- creased, some of which may participate in angiogenesis. This yin-yang cytokine balance is a common feature of inflamma- tory responses that is thought to reflect feedback control mechanisms regulated in time and space that allow phase transitions (eg, from proliferative to remodeling phases or for hypoxia-driven angiogenesis that is associated with wound healing). Cytokines, in turn, amplify further coordinated changes in additional cytokines, cell adhesion molecules, prostaglandins and leukotriene species, redox regulating en- zymes and pro- and antioxidant species (manganese super- oxide dismutase, inducible nitric oxide synthase, metallo- thionein, heme oxygenase, gamma-glutamylcysteine synthetase, and myeloperoxidase), matrix remodeling en- zymes and inhibitors, plasminogen activators and inhibitors, and heat shock proteins. These components also often have mutually antagonistic aspects that allow tight control on the inflammatory and tissue-healing responses. In many respects, the tissue responses to irradiation mimic the cytokine storms generated by many other tissue-damag- ing insults, although clinically relevant doses might be said to generate a cytokine breeze rather than storm. It is true that, unlike the low doses used in treating benign conditions, 4,5 the accumulative doses that are used in cancer therapy are proinflammatory but each individual dose generates minimal Roy E. Coats Laboratories, Department of Radiation Oncology, University of California at Los Angeles, Los Angeles, CA. Supported by NIH Grant 1 U19 AI067769. Address reprint requests to William H. McBride, Department of Radiation Oncology, David Geffen School for Medicine, UCLA, Los Angeles, CA90095-1714. E-mail: wmcbride@mednet.ucla.edu 121 1053-4296/07/$-see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.semradonc.2006.11.008