Biology of Radiation-Induced Lung Injury

doi:10.1016/j.semradonc.2020.11.006

Seminars in Radiation Oncology

Volume 31, Issue 2, April 2021, Pages 155-161

https://doi.org/10.1016/j.semradonc.2020.11.006 Get rights and content

Radiation-induced lung injury encompasses radiation-induced pneumonitis, inflammation of the lung which may manifest as a dose-limiting acute or subacute 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.

Section snippets

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

Radiobiology

In classic radiobiology, the lung is considered a nonregenerating 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

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

Management of RILI

RP is a diagnosis of exclusion and must be distinguished from tumor progression, infectious or postobstructive 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

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

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.

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CD4⁺CD25⁺ Tregs were isolated from rats, and the supernatant's TGF-β1 level was examined by using enzyme-linked immunosorbent assay (ELISA). Type II alveolar epithelial cells (AECs) were co-cultured with the supernatant of Tregs, and the expression levels of epithelial-to-mesenchymal transition (EMT)-related and TGF-β1/Smad signaling pathway-related proteins were analyzed by using western blotting (WB). Afterward, the Tregs were incubated with different concentrations of JMST. The cell viability and TGF-β1 concentration were confirmed by cell counting kit-8 (CCK-8) assay and ELISA, respectively. The optimized concentration of JMST was applied in vitro and vivo experiments. The specific mechanism was investigated through the combination of using flow cytometry, lung histopathology analysis, ELISA, and WB.
Radiation could promote Tregs to secrete TGF-β1. After radiation, the expression levels of Smad2/3, phosphorylated Smad2/3 (p-Smad2/3), Smad4 and mesenchymal markers Vimentin and α-SMA were all increased, while the expression level of epithelial markers E-cadherin was decreased. The expression levels of these proteins were reversed after interventions involving Treg cell activation inhibition or TGF-β1 receptor inhibitor. JMST reduced the number of Tregs in lung tissue and alleviated the degree of pulmonary fibrosis. The expression of Smad2/3, p-Smad2/3, Smad4, TGF-β1, Vimentin, and α-SMA were significantly downregulated, while the E-cadherin was upregulated, through the intervention of JMST.
Tregs could mediate EMT through TGF-β1/Smad pathway. JMST inhibits EMT via TGF-β1/Smad pathway by regulating Tregs, therefore alleviating RILI.
Cytokine, chemokine alterations and immune cell infiltration in Radiation-induced lung injury: Implications for prevention and management
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Radiation therapy is one of the primary treatments for thoracic malignancies, with radiation-induced lung injury (RILI) emerging as its most prevalent complication. RILI encompasses early-stage radiation pneumonitis (RP) and the subsequent development of radiation pulmonary fibrosis (RPF). During radiation treatment, not only are tumor cells targeted, but normal tissue cells, including alveolar epithelial cells and vascular endothelial cells, also sustain damage. Within the lungs, ionizing radiation boosts the intracellular levels of reactive oxygen species across various cell types. This elevation precipitates the release of cytokines and chemokines, coupled with the infiltration of inflammatory cells, culminating in the onset of RP. This pulmonary inflammatory response can persist, spanning a duration from several months to years, ultimately progressing to RPF. This review aims to explore the alterations in cytokine and chemokine release and the influx of immune cells post-ionizing radiation exposure in the lungs, offering insights for the prevention and management of RILI.
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: Funding: This work was supported by the Intramural Research Program of the CCR, NIH.

: Conflict of Interest: None.

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Published by Elsevier Inc.

Biology of Radiation-Induced Lung Injury

Introduction

Section snippets

Pathology

Radiobiology

Risk Factors for RILI

Management of RILI

Future Directions

Conclusion

Semin Radiat Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Immunity

Immunobiology

Transl Res

Lung Cancer

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Chest

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Clin Chest Med

Pract Radiat Oncol

Radiother Oncol

Radiobiology for the Radiologist

Effects of NOX1 on fibroblastic changes of endothelial cells in radiation-induced pulmonary fibrosis

Mol Med Rep

Role of type II pneumocyte senescence in radiation-induced lung fibrosis

J Natl Cancer Inst

A phase I study of concurrent chemotherapy (paclitaxel and carboplatin) and thoracic radiotherapy with swallowed manganese superoxide dismutase plasmid liposome protection in patients with locally advanced stage III non-small-cell lung cancer

Hum Gene Ther

Orgotein–(bovine Cu-Zn superoxide dismutase), an anti-inflammatory protein drug: Discovery, toxicology and pharmacology

Eur J Rheumatol Inflamm