ABSTRACT

Radiation therapy (RT) is an important treatment modality for multiple thoracic malignancies. Incidental irradiation of the lungs, which are particularly susceptible to injury, is unavoidable and often dose-limiting. The most radiosensitive subunit of the lung is the alveolar/ capillary complex, and RT-induced lung injury is often described as diffuse alveolar damage. Reactive oxygen species generated by RT are directly toxic to parenchymal cells and initiate a cascade of molecular events that alter the cytokine milieu of the microenvironment, creating a self-sustaining cycle of inflammation and chronic oxidative stress. Replacement of normal lung parenchyma by fibrosis is the culminating event. Depending on the dose and volume of lung irradiated, acute radiation pneumonitis may develop, characterized by dry cough and dyspnea. Fibrosis of the lung, which can also cause dyspnea, is the late complication. Imaging studies and pulmonary function tests can be used to quantify the extent of lung injury. While strict dose-volume constraints to minimize the risk of injury are difficult to impose, substantial data support some general guidelines. New modalities such as intensity-modulated radiation therapy and stereotactic body radiation therapy provide new treatment options but also pose new challenges in safely delivering thoracic RT.

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Radiation therapy (RT) is an important treatment modality for multiple thoracic malignancies. Incidental irradiation of the lungs, which are particularly susceptible to injury, is unavoidable and often dose-limiting. We presented a review of RT-induced lung injury in this journal in 1994. [1] As this complication continues to be clinically relevant and remains an area of active investigation, we herein provide an updated review.

Molecular Mechanisms

The complex molecular mechanisms underlying RT-induced lung injury are often not considered by the clinician. However, a basic understanding of these processes facilitates an understanding of the clinical and radiologic changes observed after RT.

Immediately after exposure to RT, a cascade of molecular and cellular events is initiated that proceeds during a clinically occult period. The inciting event is the production of free radicals by ionizing radiation (Figure 1). These reactive oxygen and nitrogen species, however, can only produce a limited amount of direct damage. Amplification and propagation of these species is necessary to create a sustained imbalance between oxygen-derived free radicals and cellular antioxidant capacity. [2,3] Chronic oxidative stress is the end result of this persistent imbalance, leading to endothelial dysfunction, increased vascular permeability and edema, monocyte migration, lipid peroxidation, inflammation, and fibrosis. [4-7]

A self-sustaining cycle of inflammation and fibroproliferation ensues, driven by tissue hypoxia, macrophage accumulation and activation, oxidative stress, and profibrogenic (transforming growth factor-beta [TGF-Β]) and proangiogenic (hypoxia inducible factor 1-alpha [HIF-1α], vascular endothelial growth factor [VEGF]) cytokine activity. [4,7] These molecular and cellular events lead to cell death, collagen deposition, and fibrosis in irradiated tissues.

Anatomic Basis of Injury

The lungs are complex organs, consisting of the large central airways such as the trachea and mainstem bronchi, the smaller conducting airways, a complex vascular network, and the alveolar sacs where gas exchange occurs.

The trachea and proximal airways are lined with pseudostratified ciliated columnar...