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Abstract
Background: Heat shock protein 27 (HSP27) is overexpressed during pulmonary fibrosis (PF) and exacerbates PF; however, the upregulation of HSP27 during PF and the therapeutic strategy of HSP27 inhibition is not well elucidated.

Methods: We have developed a mouse model simulating clinical stereotactic body radiotherapy (SBRT) with focal irradiation and validated the induction of RIPF. HSP25 (murine form of HSP27) transgenic (TG) and LLC1-derived orthotropic lung tumor models were also used. Lung tissues of patients with RIPF and idiopathic pulmonary fibrosis, and lung tissues from various fibrotic mouse models, as well as appropriated cell line systems were used. Public available gene expression datasets were used for therapeutic response rate analysis. A synthetic small molecule HSP27 inhibitor, J2 was also used.

Results: HSP27 expression with its phosphorylated form (pHSP27) increased during PF. Decreased mRNA expression of SMAD-specific E3 ubiquitin-protein ligase 2 (Smurf2), which is involved in ubiquitin degradation of HSP27, was responsible for the increased expression of pHSP27. In addition, increased expression of miRNA15b was identified with decreased expression of Smurf2 mRNA in PF models. Inverse correlation between pHSP27 and Smurf2 was observed in the lung tissues of PF animals, an irradiated orthotropic lung cancer models, and PF tissues from patients. Moreover, a HSP27 inhibitor cross-linked with HSP27 protein to ameliorate PF, which was more effective when targeting the epithelial to mesenchymal transition (EMT) stage of PF.

Conclusions: Our findings identify upregulation mechanisms of HSP27 during PF and provide a therapeutic strategy for HSP27 inhibition for overcoming PF.

Affiliations

Seulgi Jeon # 1 2, Hee Jin # 1, Jin-Mo Kim 3 4, Youmin Hur 1, Eun Joo Song 1, Yoon-Jin Lee 5, Younghwa Na 6, Jaeho Cho 7, Yun-Sil Lee 8
1Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea.
2Inhalation Toxicity Research Group, Korea Institute of Toxicology, Jeongeup-si, Jeollabuk-do, 56212, Republic of Korea.
3Department of Radiation Oncology, Yonsei University Health System, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea.
4Department of Manufacturing Pharmacy, Natural Product Research Institute, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
5Korea Institute of Radiological and Medical Science, Seoul, 01812, Republic of Korea.
6College of Pharmacy, CHA University, 120, Haeryong-ro, Pocheon-si, Gyeonggi-do, 11160, Republic of Korea. yna7315@cha.ac.kr.
7Department of Radiation Oncology, Yonsei University Health System, 50, Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea. jjhmd@yuhs.ac.
8Graduate School of Pharmaceutical Sciences, Ewha Womans University, 52, Ewhayeodae-gil, Seodaemun-gu, Seoul, 03760, Republic of Korea. yslee0425@ewha.ac.kr.
#Contributed equally.