Since the primary function of the lungs is to provide gaseous interchange, there is an innate requirement for the organ to be accessible to both the external and internal environments via inhalation and the circulation, respectively, leading to the evolutionary development of critical structural and physiological relationships between the air passages, respiratory parenchyma, and vascular system. However, an additional consequence is that the intimacy of these relationships together with the ease of access makes the lungs especially susceptible to a multitude of physical, chemical, and biological stressors that appear to be able to disrupt the delicate functional balance of this system with relative ease. Of course, through normal wound healing responses, such an injury may be completely resolved. However, depending on the source and severity, under many circumstances there is progression to a persistent, chronic pathology, which occurs through a complex cascade of processes, beginning with the acute injury and followed by an associated innate inflammatory response, culminating in abnormal remodeling and tissue repair [1
With respect to this article, the pulmonary sequelae that are seen following irradiation
are, indeed, varied and often long-lasting, and include edema, epithelial degeneration and subsequent regeneration, invasion of alveoli by the bronchial epithelium, endothelial sloughing, disruption of the microvasculature, and atelectasis [2
]. Of clinical concern, the lung consequences, radiation pneumonitis and pulmonary fibrosis, that can develop in the normal tissue in the months to years after a standard course of radiotherapy obviously affect quality-of-life and may even be lethal in outcome, and are therefore recognized dose-limiting complications in the treatment of thoracic and related tumors [4
], thereby, potentially, compromising cure. In addition, these deleterious downstream effects not only arise following localized high-dose pulmonary irradiation, but also are seen subsequent to the use of low-dose whole body irradiation used, for example, as part of preconditioning regimens for bone marrow transplantation [6
]. As a result, the development of pharmaceutical agents that can protect against, mitigate, or treat the development and expression of such morbid conditions has long been an aim for many investigators due to the potentially significant clinical benefit. Recently, this goal has gained further attention due to a perceived threat from nuclear or radiological terrorism, since accidental radiation exposures also have been shown to lead to the induction of these same lethal outcomes [8
], indicating the need for a countermeasure against late effects in normal lung tissue for use following detonation of a dirty bomb or similar devices.
As demonstrated at both the bench and patient/victim level, the response to radiation injury in the lung is associated with a well-characterized progression: there is an apparent “delay” subsequent to the immediate injury (the so-called “latent period”), followed by an acute phase of alveolitis/pneumonitis, and a final late/chronic stage of pulmonary fibrosis [10
]. A similar sequence of events is seen in the majority of mammals, including humans [12
], which has allowed for the use of both small and large animal models in the study of dose-response relationships and the temporal development of the radiation-induced tissue injury. Such studies have spanned the majority of the last century and continue up until the present day [13
] and yet, despite this breadth of data, the critical underlying mechanisms that lead to either radiation pneumonitis or pulmonary fibrosis remain elusive, thereby confounding the identification of agents that could effect a successful therapeutic strategy. This failure may be partly the result of the inherent limitations of extrapolating animal data to humans, but it also may reflect an incomplete comprehension of the available human data, which have suffered from a lack of standardized endpoints, limited follow-up, and patient and observer variability [14
In this review, we will attempt to present an overview of our current understanding of the progression of events, both pathological and molecular, that are involved in the lungs’ response to radiation injury, identifying potential targets for intervention. This will include past and current areas of interest, although we hope to offer insight into some potential areas that may yet be explored.