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. Author manuscript; available in PMC: 2022 Apr 1.

Biology of Radiation Induced Lung Injury

Soumyajit Roy1,Kilian E Salerno1,Deborah E Citrin1,1
1Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
1

Corresponding author: 10 CRC, B2-3500, Radiation Oncology Branch, National Institutes of Health, Bethesda, MD 20892, Phone (301) 496-5457, Fax (301) 480-5439,citrind@mail.nih.gov

PMCID: PMC7905704  NIHMSID: NIHMS1650771  PMID:33610273
The publisher's version of this article is available atSemin Radiat Oncol

Abstract

Radiation induced lung injury (RILI) encompasses radiation induced pneumonitis, inflammation of the lung which may manifest as a dose-limiting acute or sub-acute toxicity, and radiation induced lung fibrosis, a late effect of lung exposure to radiation. This review aims to highlight developments in molecular radiation biology of radiation induced lung injury and their implications in clinical practice

INTRODUCTION

Radiation exposure of the lungs is common during a course of therapeutic radiation for thoracic malignancies. In some cases, this exposure leads to inflammation that progresses to clinically apparent pneumonitis or fibrosis. Radiation induced lung injury (RILI) is a term describing both radiation pneumonitis (RP) and radiation induced lung fibrosis (RILF). Identifying the processes involved in development of RILI may afford opportunity to prevent injury, especially in those at highest risk, and to develop effective treatment strategies.

Radiation changes in the lungs are often asymptomatic, with reported rates of clinically significant RILI varying widely in the literature from approximately 5–25% of patients treated with radiation (RT) for thoracic and mediastinal malignancies and 1–5% of those receiving RT for breast cancer.1 This review will provide an overview of RILI with focus on its biologic basis and therapeutic opportunities.

PATHOLOGY:

A discussion of the pathobiology of RILI requires a basic understanding of the anatomy of the alveolus, the site of gas exchange within the lung. The alveolus is composed of a thin wall covered by a single layer of airway epithelial cells (AEC), with Type I AEC interspersed with the relatively rare Type II AEC. Type II AEC produce surfactant, and after alveolar injury, they also give rise to both Type I and Type II AEC to repopulate the alveolar epithelium. Alveolar macrophages surveil for pathogens and contribute to alveolar homeostasis. Capillaries, interstitial immune cells, and fibroblasts surround the alveolar wall in a delicate structure that maximizes gas exchange.

Following radiation, three phases of histopathologic change in the lung have been described.2 The early/latent phase occurs within a month after radiation and is characterized by loss of Type I AEC, alveolar transudates, interstitial edema, and Type II AEC morphologic changes. The acute exudative phase, clinically known as RP, occurs between 3 weeks and up to 6 months after exposure and is characterized by a fibrin rich alveolar exudate, interstitial edema, pronounced Type II AEC atypia, and accumulation of alveolar macrophages. The late or fibrotic phase begins approximately 6 months after radiation and is characterized by further Type I AEC loss, capillary loss, and progressive collagen deposition.

RADIOBIOLOGY

In classic radiobiology, the lung is considered a non-regenerating tissue in which the functional subunits, the terminal airway and the alveoli it serves, exist in parallel.3 Historically, lung tissue is considered to have a tolerance dose of 18–20 Gy.3 Beyond this dose damage to the functional subunit of the lung, the terminal airway and associated alveoli, occurs and prevents effective gas exchange.3 The α/β ratio of lung is reported to be approximately 3 Gy.3

Increasing knowledge of the molecular events that occur in normal tissue following radiation exposure has complemented the classic radiobiological concepts of dose threshold, α/β ratio, and classification of tissue hierarchy. The rapid cell killing caused by RT initiates changes in cellular function, liberation of cytokines and chemokines, local inflammation, and matrix remodeling that may be perpetuated in the months to years after exposure (Figure 1). Selected key processes involved in the progression of RILI are highlighted below.

Figure 1. Time course of radiation induced lung injury.

Figure 1.

The phases of lung injury can be divided into 3 main phases: the early/latent phase, the acute phase (pneumonitis), and the late phase (fibrosis). Pathologic findings and biological processes contributing to each phase are described.

Oxidative Stress

After the initial direct and indirect damage from radiation, secondary reactions result in the generation of reactive oxygen species (ROS). The resulting damage and inflammation further perpetuate oxidative injury and generation of reactive nitrogen species.4 Endothelial cells, epithelial cells, and inflammatory cells can contribute to oxidative stress though production of superoxide and nitric oxide.5,6 Highly toxic superoxide directly damages DNA or other cellular components and generates harmful secondary radical species. Delivery of superoxide dismutase (SOD), a detoxifying enzyme, or SOD mimetics has been demonstrated to reduce markers of inflammation, oxidative stress, and RILI in animal models.7,8 Some clinical trials evaluating SOD and SOD mimetics as treatment for radiation injury have demonstrated encouraging findings, while others have shown no benefit or allergic reactions.9–12

Cytokines and chemokines

Numerous pro-fibrotic, mitogenic, immunomodulatory, and pro-inflammatory mediators, such as platelet derived growth factor (PDGF), tumor necrosis factor alpha (TNF-α), transforming growth factor-β (TGF-β), vascular endothelial growth factor (VEGF), Interleukin-1 (IL-1), IL-6, and IL-13, are elaborated in irradiated lung tissue and have been implicated as drivers of RILI.13,14 TNF-α and TGF-β play a dominant role in RP and RILF, respectively, and are further highlighted here.

Tumor necrosis factor alpha (TNF-α) is an acute phase inflammatory cytokine that may impact and regulate a broad range of inflammatory cells. Activated macrophages, a prominent component of RILI, serve as a major source of TNF-α.15 TNF-α is known to exhibit rapid and persistently increased expression in irradiated lung.16 Mice deficient in TNF-α signaling have substantially reduced sensitivity to RILI, demonstrating an important role of TNF-α signaling in RP.17,18 Agents targeting TNF-α are in clinical use for the treatment of rheumatologic diseases, providing an opportunity for clinical translation in RILI.

TGF-β is a cytokine with demonstrated importance in conditions characterized by tissue remodelling and inflammation, including RILI. TGF-β is rapidly activated after irradiation in a dose dependent fashion, followed by cyclic waves of increased expression in the following days, weeks, and months.19,20 TGF-β signaling through the Smad family of transcription factors regulates the expression of genes involved in cell proliferation, epithelial to mesenchymal transition, matrix remodeling (matrix metalloproteinases), immune modulation, and inflammation.21 TGF-β activity stimulates differentiation of fibroblasts to myofibroblasts, resulting in deposition of collagen, fibronectin, and proteoglycans, leading to loss of tissue elasticity and obliteration of alveolar spaces.

In clinical trials, increased plasma TGF-β concentrations correlate with risk of RILI, although the utility of plasma TGF-β as an independent predictor of RILI is uncertain.22 Extensive laboratory data supports a critical role of TGF-β in RILI, with inhibition of TGF-β signaling sufficient to prevent RILI in rodents.14,23 Despite the success of TGF-β signaling inhibition in pre-clinical models, the toxicity observed with chronic dosing of these agents has tempered excitement for clinical use for RILI.24

Inflammation

Inflammation is a key element of RILI. Although neutrophils may be observed rapidly and transiently, the characteristic histopathologic inflammation of RILI is an accumulation of alveolar and interstitial macrophages.13,25 Macrophages, known to play a key role in tissue repair and wound healing, are also implicated in the pathogenesis of autoimmune diseases and fibrosis.26

Activated macrophages exhibit an altered phenotype in response to cues from the microenvironment.27 This polarization of activated macrophages has been described as classically activated (M1) and alternatively activated (M2) phenotypes, although this is understood to be an oversimplification of a spectrum of phenotypes. M2 macrophages can be subdivided further based on secreted factors, surface markers, and conditioning stimuli, although the overlap between M2 subtypes is substantial. The profibrotic subset of M2 macrophages, generated after exposure to IL-4 and IL-13, secrete TGF-β and mitogenic factors.26 In contrast, regulatory or suppressive M2 macrophages act in an immunoregulatory fashion through secretion of IL-10 and other cytokines.26

Mice with varying sensitivity to RILI exhibit marked differences in the accumulation of alveolar and interstitial M2 macrophage subsets after pulmonary irradiation, suggesting that the cytokines that stimulate M2 polarization, IL-4 and IL-13, may play an important role in RILI.28 Studies in mice deficient in IL-4 have demonstrated that IL-4 impacts recovery of macrophage subpopulations after radiation, but does not alter the progression of RILI.25 In contrast, deficiency of IL-13 is sufficient to largely prevent RILI and M2 macrophage accumulation after radiation, while simultaneously reducing TGF-β activity and the expression of fibrosis associated genes.13 An array of pharmacologic agents targeting M2 macrophages and the cytokines that drive their polarization are in varying stages of clinical development for the treatment of asthma, autoimmune disorders, and allergic disease, providing an opportunity for eventual clinical translation in the setting of RILI.

Although macrophages are the most prevalent inflammatory cell in RILI, shifts in the proportion of T-cell subsets and T-cell polarization, have been implicated in RILI progression.29 Shifts in the balance of T-cell subsets or T-cell polarization can impact inflammation in a broad fashion through elaboration of cytokines and T-cell interactions with other inflammatory cells. The events responsible for altered T-cell subset balance after irradiation remains uncertain, however relative sensitivity and recovery rates of each subset after radiation have been suggested to be contributory.29

CD4+ T helper (Th) cells can further differentiate into Th1, Th2, and Th17 lineages, each with differing effector responses. Rodent studies have implicated CD4+ T-cells, especially the Th2 helper subset, as playing a role in the progression of RILF.30 Th17 subsets have also been implicated in RILI. A recent study of mouse strains with differing tendencies towards RILI noted an increase in Th17 cells in strains that develop both RP and RILF compared to strains that only develop RP, suggesting Th17 cells and the IL-17 that they secrete may drive RILF but not RP.31 As expected from these observations, IL-17 targeted therapy has shown efficacy in reducing RILI in animal models.32 In contrast, the depletion of immunosuppressive regulatory T cells increased Th17 responses but resulted in reduced RILI.33 Collectively, these studies highlight the complexity of Th responses and suggest there remains much to be learned about these subsets in RILI.

Senescence in RILI

Senescence has recently been implicated as a contributor to RILI.6,34 Senescence is a state of permanent growth arrest that may occur in normal development or in response to stress, such as exposure to DNA damaging agents or oxidative stress. Although senescence may be observed in multiple cell types in the lung after radiation, the senescence of Type II AEC may be particularly harmful given that it results in loss of stem cell capacity and inability to replenish Type I and Type II AEC in damaged lung.6

Senescent cells can further impact irradiated tissues through elaboration of the senescence associated secretory phenotype (SASP), a complex mixture of immunomodulatory, pro-inflammatory, angiogenic, and mitogenic molecules.35 Several molecules secreted as part of the SASP have been independently implicated in RILI, such as IL-1, IL-6, TGFβ, IL-13, EGF, VEGF, and TNF-α. The SASP elaborated by senescent Type II AEC can induce secondary senescence in undamaged Type II AEC and can enhance polarization of macrophages towards a pro-fibrotic M2 phenotype.6,36 Thus, senescent cells may further propagate normal tissue injury in a paracrine fashion via elaboration of the SASP. Several agents that prevent senescence or selectively kill senescent cells (senolytic therapy) have demonstrated efficacy in preventing or reversing RILI in pre-clinical models and may hold promise for clinical translation.34

FLASH Radiation and RILI

Dose rate is well known to impact radiobiologic response of cells and tissues. Recently, ultra-high dose rate irradiation (>40 Gy/second) delivered in short pulses, also known as FLASH radiation, has been described to have remarkable tumor selectivity of cell killing37 resulting in minimal normal tissue injury at tumoricidal doses. Most striking, even with a single whole thorax FLASH dose as high as 17 Gy, rodents do not develop pulmonary fibrosis.

The mechanism of the extreme tumor selectivity of FLASH remains uncertain, although reduced senescence of progenitors and oxygen consumption have been implicated.38 FLASH exposures led to less apoptosis in multiple normal tissue cell types in lung compared to the same conventional dose.37 Delivery of TNFα prior to FLASH increased apoptosis and pulmonary edema, but did not lead to RILF, suggesting that a reduction in apoptosis relative to that observed at similar doses with conventional radiation is not the primary mechanism of reduced normal tissue effects with FLASH. The initiation of clinical trials of FLASH will likely lead to numerous interesting radiobiologic observations.

RISK FACTORS FOR RILI:

Identification of factors predictive of moderate to severe RILI may provide important biologic insights. Assessment of RILI severity is often complicated by the presence of comorbidities, such as pre-existing pulmonary disease or infection, that confound comparisons across published series.39

Clinical Factors Inform Biology

Clinical predictors of RILI can give insight into the underlying pathobiology of RILI. Increasing age has been associated with increased risk of RILI,40 with no clear age threshold. It is unclear if this association is driven by age-associated comorbidities. Higher rates of RILI with increasing age suggest that aged lung may be less capable of repairing radiation injury and it could be hypothesized that this predisposition to RILI may be linked to age related senescence in the lung stem cell compartment.

The presence of interstitial lung disease (ILD) is an important risk factor for developing severe RP. Several studies have demonstrated a significantly increased risk of moderate, severe, or fatal RP in patients with pre-existing ILD treated with radiation for thoracic malignancies.41 The biologic rationale for the increased toxicity observed in patients with ILD is uncertain. Idiopathic pulmonary fibrosis (IPF), the largest subtype of ILD, has been linked to shortened telomeres.42 IPF and RILI share several common findings, such as AEC loss, Type II AEC senescence, increased TGF-β expression, and myofibroblast differentiation and activation. Although speculative, ILD and the associated “aging” of the lung may act synergistically with radiation to increase the progression of lung injury.

In contrast to ILD, studies have shown conflicting results on chronic obstructive pulmonary disease (COPD) as a risk factor for RILI. Some studies suggest that patients with COPD may have milder RP compared to those with normal lungs.43 Severe COPD is associated with smoking, and, perhaps counterintuitively, smoking has been described as protective from RILI. Thus, patients with severe COPD may have less severe RILI due to the protective effect of smoking.44 Alternatively, this finding could be due to difficulties in attributing symptoms to RILI versus COPD after RT and/or unique aspects of the underlying pathobiology of COPD.

Treatment Related Risk Factors

Lung dosimetry has consistently been found to be predictive of risk of RILI. A comprehensive review of the applicable literature and associated guidelines is outside the scope of this article, however some key findings and radiobiologic considerations are highlighted. The quantitative analysis of normal tissue effects in the clinic (QUANTEC) report summarized more than 70 publications pertaining to risk of lung injury with conventionally fractionated 3D-CRT, and concluded that the volume of lung receiving ≥20 Gy (V20) and MLD were the two most important dosimetric predictors for RP.45 The QUANTEC report also noted that there were no evident dose/volume thresholds, in conflict with traditional radiobiologic models.

Since the release of the QUANTEC report, there has been a shift from 3D-CRT techniques to intensity modulated radiotherapy (IMRT), stereotactic body radiation therapy (SBRT), and proton beam based approaches. These techniques may result in differences in dose distributions compared to 3D-CRT, such as a larger volume of lung receiving doses below the classical lung threshold of 18–20 Gy.46 The clinical impact of these sub-threshold exposures and their contribution to risk of RILI varies in the literature, potentially due to confounders of technique, comorbidity, and concurrent therapy. There are clinical data in which the volume of lung exposed to 5 Gy (V5) and 10 Gy (V10) are also highly predictive of risk of RILI. The findings of the QUANTEC report support that the alveoli can be injured after exposure to a sub-threshold doses,46 and demonstrate the need to supplement the classic radiobiological model of lung injury to account for the impact of low dose exposures.

Recent data suggests that there is spatial variation in risk of RILI and prioritization of overall spatial dose distribution may be more relevant than the typical approach of dose-volume threshold-based plan optimization. Exposure of the medial and superior lung may be less harmful in terms of risk of RILI than similar exposures in the lower lungs and heart.47 Recent studies have integrated functional and spatial variation of lung function into dosimetric modeling.48 Current radiobiologic models do not account for spatial variation or prioritization of functional subunits based on location within the lung.

The demonstrated impact of cardiac dose on RILI and outcomes after thoracic RT is also not accounted for in current radiobiologic models. Although the cause of this relationship is uncertain, irradiation of the cardiac vasculature may lead to myocardial stunting and diastolic dysfunction, in turn increasing pulmonary venous pressures and exacerbating pulmonary edema and transudate. Including cardiac exposure in preclinical modeling may further elucidate these interactions and inform clinical practice.49

Much of the data suggesting a clinical impact of sub-threshold exposures included patients who received systemic therapy with RT (concurrent or sequential), which may impact risk of RILI through independent pulmonary toxicity pathways, potentiation of radiation (sensitization), and/or by impairing regenerative capacity. These mechanisms effectively lower the radiation dose threshold of the alveolar-terminal airway unit. Numerous chemotherapeutic agents have been implicated in increasing risk of RILI such as bleomycin, paclitaxel/carboplatin doublet, gemcitabine, anthracyclines, and tyrosine kinase inhibitors.44 The growing use of immune checkpoint inhibitors (ICI) in patients who have received thoracic RT raised concerns regarding the possibility of increased risk of RILI as some ICI can independently initiate autoimmune pneumonitis. Based on existing evidence however, the rate of moderate to severe RP does not seem to be synergistically increased with the combination.50

MANAGEMENT OF RILI

RP is a diagnosis of exclusion and must be distinguished from tumor progression, infectious or post-obstructive pneumonia, chemotherapy/immunotherapy induced pneumonitis, or acute exacerbation of co-existing COPD. Many patients may have asymptomatic radiographic changes. Treatment is generally only indicated in patients with symptoms attributable to RILI, with inhaled steroids and anti-inflammatory medications used for mild symptoms, and high dose glucocorticoids with slow taper utilized for more symptomatic disease.51 Complete symptomatic recovery is possible with prolonged treatment, however relapse is possible. For those unresponsive to or intolerant of steroids, alternative immunosuppressive therapies, including azathioprine and cyclosporine, have been used.51

Glucocorticoids function by binding to the intracellular glucocorticoid receptor and initiating or supressing transcription of a wide array of pro- and anti- inflammatory genes.52 Glucocorticoids impact post-translational modification of transcripts encoding genes involved in inflammation and immune cell function, thus altering transcript stability. As a result, the expression of several cytokines and enzymes involved in RILI, such as IL-1α, IL-1β, IL-6, IL-10, and COX-2, are impacted by glucocorticoid treatment.52 As a consequence, glucocorticoids reduce leukocyte adhesion, impair neutrophil and macrophage phagocytosis, impair macrophage antigen presentation and effector functions, and alter the T cell balance towards an anti-inflammatory state.52 These diverse anti-inflammatory effects are accompanied by substantial systemic toxicity, including metabolic derangements, loss of bone mineral density, susceptibility to infection, hypertension, and adrenal insufficiency.

Alternative treatments have been investigated to avoid the substantial toxicity of prolonged glucocorticoid treatment. To date, the efficacy of these agents has not supported routine clinical use. Amifostine, pentoxifylline, and angiotensin converting enzyme inhibitors have all been reported to have efficacy in preventing or treating RILI in small series, however larger validation studies have not been conducted, have been plagued by inadequate accrual, or have not confirmed efficacy.51 Additional agents currently in clinical use for the treatment of ILD have also entered clinical testing for the treatment of RILI, including nintedanib, a multi-kinase inhibitor, and pirfenidone.

In comparison to the treatment strategies described for RP, there is at present no effective therapy for RILF. Treatment approaches aim to optimize pulmonary function and provide symptomatic relief. As highlighted previously, there are numerous recently identified candidates for clinical testing in the prevention and treatment of RILF (Figure 2). Because many agents have been shown to prevent but not reverse RILF in preclinical models, their effective use would require identification of patients at highest risk. To do so requires an improved capacity to predict risk of severe RILF, either with imaging/radiomics, genetic profiles, dosimetry, or other biomarkers. In contrast, the capacity of senolytic therapy to reverse established RILF raises a unique opportunity that would allow early treatment initiation in those manifesting RILI, as opposed to broader prevention strategies.

Figure 2. Biological events that contribute to radiation induced lung injury.

Figure 2.

Numerous processes contribute to radiation lung injury and may interact directly and indirectly. Examples of contributing cytokines that may be targeted for therapeutic purposes are highlighted in blue. Additional investigational targets described in the text are highlighted in green.

FUTURE DIRECTIONS:

A deeper understanding of the molecular pathways and processes driving RILI may allow identification of novel predictive biomarkers or suggest potentially effective mitigators or therapeutics. Several promising targets for treatment or mitigation have recently been identified. Clinical evaluation of these agents as a method to treat RP in a fashion that does not interfere or interact with diverse types of cancer therapies is likely to be a future challenge.

The capacity to personalize treatment planning by integrating dosimetry with known predictors of RILI, such as concurrent therapies, underlying lung function, and cardiopulmonary comorbidity, could more seamlessly account for varying threshold for RILI in individual patients. Exciting progress has been made incorporating spatial variation and regional variation in lung function into dosimetric modeling,48,53 and in integrating biomarkers or genomic predictors with predicted effective dose.54,55 A major challenge in modern normal tissue radiobiology is formulating a unifying model that accounts for many diverse factors predictive of injury, and identifying those that can be modified to prevent harm. A customized algorithm incorporating clinical and demographic factors, tumor location and volume, dosimetric and radiobiological metrics, biomarkers, information on systemic agents and their radio-equivalent impact, radiogenomics and findings from pre-treatment molecular, anatomic and functional scans might lead to a better predictive tool for RILI. Integration of deep neural network and machine learning might pave the way for developing such algorithms. Such efforts are likely to require large, robust datasets for development, necessitating cooperative efforts.

CONCLUSION:

In summary, RILI is a complex biological process that includes interactions and contributions of diverse cell types, with inflammation and chronic oxidative stress playing a prominent role. Classical radiobiological models of RILI are evolving to incorporate molecular findings and clinical observation that alter our understanding of the radiation response of lung.

Acknowledgments

This work was supported by the Intramural Research Program of the CCR, NIH.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of interest: none.

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