Advances in Molecular Mechanisms and Treatment of Radiation-Induced Pulmonary Fibrosis

Abstract

Radiation-induced pulmonary fibrosis (RIPF) is a common complication in patients with lung cancer and breast cancer after receiving thoracic radiotherapy. The average incidence of RIPF is 16%-28% after radiotherapy. RIPF includes a heterogeneous group of lung disorders characterized by progressive and irreversible destruction of lung architecture and disruption of gas exchange. The clinical signs of RIPF include increasing dyspnea, deteriorating lung function, and accumulation of interstitial fluid, eventually leading to respiratory failure. No medical therapy for RIPF has been approved for routine clinical use despite the apparent need for an effective treatment. Numerous signaling pathways are involved in the initiation and progression of RIPF. Also, various approaches for RIPF treatments have focused on several aspects of the current understanding of the molecular pathology of RIPF. This review used the mechanistic categories of associated cell signaling pathways, epithelial cell dysfunction and senescence, abnormal lung remodeling, and aberrant innate and adaptive immunity to review the published literature on RIPF to date and then to identify potential areas for the effective treatment of RIPF.

Figure 1

Associated cell signaling pathway and related potential therapeutic areas. Integrin avβ6 interacts with the amino acid sequence RGD, which is located near the C-terminus of LAP. TGF-β can be activated after release from LAP. The inhibition of avβ6-mediated TGF-β activation prevents RIPF. Both LY2109761, a small molecule TGF-β receptor 1 serine/threonine kinase inhibitor, and galunisertib, a highly selective inhibitor of TGFβR1, attenuate RIPF by inhibiting TGF-β–associated downstream targets. Further, 2-methoxyestradiol (2-ME) effectively inhibits the action of HIF-1α, reducing EndMT, EMT, and concomitant deposition of vascular collagen and eventually attenuating the development of RIPF. PDGF receptor tyrosine kinase inhibitors (imatinib, SU9518, and SU11657) markedly attenuated the development of fibroblast foci and subsequent remodeling of lung architecture.

Figure 2

Epithelial cell injury, abnormal lung remodeling, and related potential therapeutic areas. Diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase (NOX), prevents AECII senescence and markedly reduces RIPF. Rapamycin inhibits radiation-induced signaling downstream of mTOR; reduces expression of profibrotic, proinflammatory, and senescence-associated cytokines in irradiated lungs; and prevents RIPF. Forkhead box M1 (Foxm1) can decrease the expression of Snail1 mRNA and protein and attenuate RIPF by repressing EMT. MiR-140 inhibits myofibroblast differentiation and inflammation and prevents RIPF. MMP13 is relevant with ECM deposition and remodeling of lung architecture. MMP13 knockouts dramatically reduce lung density and shrinkage of lung volume and attenuate RIPF. GATA-3 develops type 2 phenotype and produces type 2 cytokines while inhibiting Th1 cells. Inhibition of GATA-3 attenuates RIPF.