International Journal of Radiation Oncology*Biology*Physics
Critical reviewRadiation pneumonitis and fibrosis: Mechanisms underlying its pathogenesis and implications for future research
Introduction
Radiation pneumonitis and subsequent radiation pulmonary fibrosis (RPF) are the two main dose-limiting factors when irradiating the lung. As such, they limit the therapeutic ratio in one of the most common and life-threatening cancers—lung cancer—and, furthermore, can complicate the quality of life of long-term survivors, such as patients who have undergone radiotherapy (RT) for breast cancer or Hodgkin’s disease. Finally, radiation pneumonitis can be the most devastating complication of total body RT.
Although the advent of more sophisticated RT techniques, such as conformal RT or intensity-modulated RT, can permit dose escalation by limiting the normal tissue complication probability, radiation pneumonitis and RPF have not been eliminated, and therapy for these entities presents a challenging problem for ameliorating the survival rates and the quality of life of these patients.
Although intensive research in the past few decades has revealed many interesting aspects of the underlying mechanisms, we are far from proposing a reliable pathogenetic model. This is mainly because, first, it is not evident that the results from research addressing the idiopathic conditions leading to lung fibrosis can be extrapolated to radiation pneumopathy. Second, despite the plethora of reports using different animal models and fibrogenic agents, it is unclear whether the biologic pathways described also apply to radiation pneumonitis and RPF.
This critical review has combined the existing laboratory and clinical research evidence in an attempt to provide a background of the mechanisms underlying the pathogenesis of radiation pneumonitis and RPF.
Section snippets
Terminology
The term radiation pneumopathy refers to a continuing process triggered after lung RT. This comprises two distinct, still tightly connected, abnormalities (1). One is radiation pneumonitis, an early inflammatory reaction involving alveolar cell depletion and inflammatory cell accumulation in the interstitial space that occurs within 12 weeks after lung RT. The second is a late phase of radiation fibrosis, considered until recently as irreversible, that consists mainly of fibroblast
Incidence, clinical characteristics, measurement
The incidence of radiation pneumopathy varies widely among reports. Differences in radiation technique, awareness, method of reporting, and the evaluation of the symptoms themselves may account for this variability. The scoring of radiation pneumonitis is difficult, because coexisting medical conditions challenge the reliability of laboratory measurements. Also, with combined modality therapy with cytotoxic agents steadily being incorporated into clinical RT practice, a greater incidence of
Pathogenetic mechanisms
The process of radiation pneumopathy is undoubtedly one of the most thought-provoking radiobiologic phenomena. Interstitial inflammation leading to, or accompanying, lung fibrosis is a complex process involving proinflammatory and profibrotic cytokines produced by damaged and activated cells of the interstitium and the alveolus, leading to the loss of normal architecture within the lung (15). Furthermore, similar genetic and molecular changes, such as those observed after RT, have also been
Transforming growth factor-β
Transforming growth factor (TGF)-β is a key cytokine in the fibrotic process that induces phenotypic modulation of human lung fibroblasts to myofibroblasts (30, 31). TGF-β is a potent stimulator of collagen protein synthesis (32). TGF-β gene expression has been shown to increase dramatically at 1–14 days after RT, in parallel with changes in fibroblast gene expression of collagens I/III/IV and fibronectin (33, 34). Although inflammatory cells are the source of TGF-β, pneumocytes and fibroblasts
Interleukins
The ILs originate from lung macrophages, as well as from a variety of nonmacrophage cellular sources (e.g., alveolar epithelial cells, fibroblasts, mast cells). Studies of TNF-α and IL-1, the early response cytokines, established the primacy of these mediators in the upregulation of lung vascular adhesion molecules. The IL-8 family of cytokines has chemotactic activity for leukocytes and angiogenic activity. They also induce collagen synthesis and cell proliferation (28). Although most
Cytoprotection
The cellular antioxidant response seems to play an important role in the development of post-RT lung fibrosis. Superoxide dismutase (SOD) gene therapy studies in animals have shown a protective SOD effect from radiation lung toxicity (106). Three types of SOD exist: MnSOD (SOD2), CuZnSOD (SOD1), and extracellular SOD (EC-SOD), which is also referred to as SOD3 (87). EC-SOD is the predominant extracellular antioxidant enzyme and, in the lung, is primarily localized to Type II pneumocytes and
Conclusions
In many ways, irradiated tissue responds to injury in a manner similar to that of normal wound healing. In the case of irradiated tissues, however, the wound does not heal normally but instead enters a “death spiral,” containing features of hypoxia, angiogenesis, cell death, proliferation, and macrophage infiltration (147). Ultimately, this spiral leads to the total replacement of the tissue by collagen, leaving few, if any, cellular elements.
We believe that the process of acute pneumonitis and
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