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Abstract
PURPOSE:
Lung fibrosis is a major side effect experienced by patients after lung cancer radiotherapy. However, effective protection strategies and underlying treatment targets remain unclear. In an effort to improve clinical outcomes, pharmacologic treatment of fibrosis is becoming increasingly popular; however, no ideal therapeutic strategy is yet available. Experimental Design/ Results: The expression of Hsp27 (Hsp27 in humans and Hsp25 in mice) was increased during radiation (IR)-induced lung fibrosis in a mouse model following IR. Exacerbation of lung fibrosis by IR was also found in Hsp25 transgenic (TG) mice. Knockdown of Hsp27 in lung epithelial cells inhibited IR-mediated epithelial-mesenchymal transition (EMT). J2, a synthetic small molecule inhibitor of Hsp27, significantly alleviated lung fibrosis by IR in control and TG mice, and the therapeutic effects were better than those achieved with pirfenidone and amifostine. The activation of NFkB pathways via direct interaction between Hsp27 and IkBα resulted in increased expressions of Twist, IL-1β, and IL-6 and facilitated IR-mediated EMT, which was identified as an underlying mechanism of Hsp27-mediated fibrosis after IR. Hsp27 was overexpressed in IR-induced lung fibrosis in an orthotopic lung cancer model and was inhibited by J2 treatment. IR-induced lung fibrotic tissues from patients also showed higher expression of Hsp27 than unirradiated lungs.

CONCLUSIONS:
Collectively, IkBα-NFkB signaling activation by Hsp27 is involved in the EMT process that is tightly connected to the development of IR-induced lung fibrosis. Our findings also suggest that inhibition of Hsp27 has the potential to become a valuable therapeutic strategy for IR-induced lung fibrosis.

Author information

Kim JY1, Jeon S2, Yoo YJ2, Jin H2, Won HY3, Yoon K2, Hwang ES3, Lee YJ4, Na Y5, Cho J6, Lee YS7.
1
radiation oncology, Yonsei University College of Medicine.
2
College of Pharmacy & Division of Life & Pharmaceutical Sciences, Ewha Womans University.
3
College of Pharmacy, Ewha Womans University.
4
Division of Radiation Biomedical Research, Korea Instituteof Radiological and Medical Sciences.
5
College of Pharmacy, CHA University.
6
Radiation Oncology, Yonsei University College of Medicine.
7
College of Pharmacy, Ewha Womans University yslee0425@ewha.ac.kr.

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