Abstract
Radiation-induced lung injury (RILI) is a potential complication of thoracic radiotherapy that can result in pneumonitis or pulmonary fibrosis and is associated with significant morbidity and mortality. The pathobiology of RILI is complex and includes the generation of free radicals and DNA damage that precipitate oxidative stress, endothelial cell (EC), and epithelial cell injury and inflammation. While the cellular events involved continue to be elucidated and characterized, targeted and effective therapies for RILI remain elusive. Sphingolipids are known to mediate EC function including many of the cell signaling events associated with the elaboration of RILI. Sphingosine-1-phosphate (S1P) and S1P analogs enhance EC barrier function in vitro and have demonstrated significant protective effects in vivo in a variety of acute lung injury models including RILI. Similarly, statin drugs that have pleiotropic effects that include upregulation of EC S1P receptor 1 (S1PR1) have been found to be strongly protective in a small animal RILI model. Thus, targeting of EC sphingosine signaling, either directly or indirectly, to augment EC function and thereby attenuate EC permeability and inflammatory responses, represents a novel and promising therapeutic strategy for the prevention or treatment of RILI.
Highlights
Radiation-induced lung injury (RILI) represents a dose-limiting toxicity associated with thoracic radiotherapy for which effective treatments remain non-existent
These findings strongly support the idea that SphK1 ubiquitination by ubiquitin c-terminal hydrolase L1 (UCHL1) is an important determinant of the elaboration of RILI and suggest that strategies aimed at increasing UCHL1 activity could confer RILI protection
Consideration of previously under-recognized mechanisms that drive RILI pathobiology is warranted in the hope of identifying novel and effective therapies
Summary
Radiation-induced lung injury (RILI) represents a dose-limiting toxicity associated with thoracic radiotherapy for which effective treatments remain non-existent. RILI encompasses a clinical spectrum of disease manifested early (6–12 weeks after radiation) by pneumonitis and later (at 6–12 months) by fibrosis associated with irreversible impairment of lung function [1]. Reports of the incidence of RILI after radiotherapy are highly variable due to differences amongst patient populations at risk including the underlying disease, the specific radiation protocols administered, and the existence of any number of comorbidities known to contribute to risk [2]. Variable incidences of RILI are associated with variable radiation treatment parameters including the percentage of total lung volume dose, the mean lung dose, and the normal tissue complication probability derived from the lung dose–volume histogram [3]. The lack of effective RILI treatment represents an important, unmet medical need and discovery of effective therapies would yield significant clinical benefits to a wide range of potential patients
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