Radiation-induced pulmonary fibrosis: roles of therapy-induced senescence and microRNAs

Abstract

Purpose

Progressive, irreversible radiation-induced pulmonary fibrosis (RIPF) is a clinically significant intermediate- to a late-occurring side effect of radiotherapy. Known mechanisms of RIPF include oxidative stress-induced activation of TGF-β with activation of SMAD signaling, TNF-α elaboration, and activation of the Angiotensin Converting Enzyme (ACE) mediated production of angiotensin II with resulting activation of profibrotic cytokine signaling and vasoconstriction. The pioneering work of John Moulder, to whom this paper is dedicated, and several of his colleagues demonstrated that inhibiting the conversion of ACE with drugs such as Captopril, Enalapril, and Losartan can ameliorate radiation fibrosis in various tissues. While this work led several groups to probe mechanism-based pharmacological mitigation of RIPF, in this article, we explore and discuss the roles of microRNAs (miRNA) and therapy-induced senescence (TIS) in the pathogenesis of and potential biomarkers for RIPF.

Conclusion

Our analysis of the published literature in the last decade on RIPF, miRNA, and TIS identifies TIS as a mechanism in the onset and progression of RIPF, which is regulated through several miRNAs. This work may lead to the discovery and development of the next generation of miRNA therapeutics and/or the repurposing of approved pharmaceutical agents and the development of early biomarker panels to predict RIPF.

Keywords:

• Radiation
• radiotherapy
• fibrosis
• senescence
• microRNA

Author contributions

PGSP designed, acquired, analyzed, interpreted the data, and drafted the initial version of the manuscript. MA contributed to the design, acquisition, analysis, and interpretation of the data on miRNAs and biomarkers. DEC contributed to the design and validated the data on therapy-induced senescence and miRNAs, and critically reviewed the manuscript. CNC contributed to the design, research, and interpretation of the data, reviewing the draft, and drafting the epilog. All authors approved the final version of the manuscript.

Disclosure statement

The views and opinions expressed in this article are those of the authors and do not reflect the views, opinions, or policies of the NCI, NIH, or HHS. Authors have no competing interests to declare.

Additional information

Funding

This work was supported by the Radiation Research Program, Division of Cancer Treatment and Diagnosis, and the Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.

Notes on contributors

Pataje G. S. Prasanna

Pataje G. S. Prasanna, PhD, is a Program Director in the Radiation Research Program, Division of Cancer Treatment and Diagnosis, at the National Cancer Institute, Bethesda, Maryland.

Molykutty Aryankalayil

Molykutty Aryankalayil, PhD, is a Research Scientist in the Experimental Therapeutics Section, Radiation Oncology Branch at the National Cancer Institute, Bethesda, Maryland.

Deborah E. Citrin

Deborah E. Citrin, MD, is a Senior Investigator in the Radiation Oncology Branch of the Center for Cancer Research, National Cancer Institute, in Bethesda, Maryland.

C. Norman Coleman

C. Norman Coleman, MD, is Associate Director of the Radiation Research Program, Division of Cancer Treatment and Diagnosis, Senior Investigator, Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, and Senior Medical Advisor, Administration for Strategic Preparedness and Response, Department of Health and Human Services, Washington DC.