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How tissues respond to damage at the cellular level: orchestration by transforming growth factor- (TGF-)

Life Sciences Division, Lawrence Berkeley National Laboratory, 1 Cyclotron Road, Berkeley, CA 94720, USA

When the human body is exposed to high doses of radiation, a complex, rapidly evolving, deleterious biological response is initiated that may culminate in multi-organ failure (MOF). Although this process begins with energy deposits in cellular targets, it is propagated and amplified by the tissue response to cell damage. I will argue that if the biology of wound healing is at the root of MOF following surgical trauma, and inflammation is the basis for MOF in sepsis, then the biology of the irradiated tissue uniquely initiates radiogenic MOF. The present review summarises data suggesting that tissue response to radiation damage is initiated and co-ordinated by extracellular signalling. In particular, research from the author's laboratory demonstrates that transforming growth factor-1 orchestrates the biology of irradiated tissue via a novel function as a tissue level sensor of oxidative stress, and is integral to the cellular DNA damage response. Thus, the means to therapeutically control radiogenic MOF lies in the mechanisms by which tissues respond to global cellular damage.