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(Chest. 2001;120:S63-S64.)
© 2001 American College of Chest Physicians

Role of c-Jun N-Terminal Kinase in Radiation-Induced Lung Fibrosis*

Soo-taek Uh, MD; Do Jin Kim, MD; Seung Hyuk Moon, MD; Yong Hoon Kim, MD; Uk Seok Kim, MD; Doo Ho Choi, MD and Choon Sik Park, MD

* From the Departments of Internal Medicine (Drs. Uh, D.J. Kim, Moon, Y.H. Kim, and Park) and Radiation Oncology (Drs. U.S. Kim and Choi), Soon Chun Hyang University Hospital, Seoul, Korea.

Correspondence to: S. Uh, MD, Department of Internal Medicine, Soon Chun Hyang University Hospital, 657–58 Hannam-Dong, Yongsan-Ku, Seoul, 140-743, Korea

The underlying pathogenesis of radiation-induced lung fibrosis (RTLF) has not been defined very well. However, the role of transforming growth factor (TGF)-ß has been focused on the generation of RTLF because of its increased expression in irradiation-induced fibrotic lung lesions,1 and TGF-ß messenger RNA and protein preceded RTLF.2 The downstream signal after TGF-ß stimulation-resulting lung fibrosis includes the activation of a lot of mediators, like Smad and c-Jun N-terminal kinase (JNK) through TAK1.3 We hypothesized that the activation of JNK may have a pivotal role in the pathogenesis of RTLF through the increased transcription of fibrogenic cytokines. The present study evaluates the activity of JNK in alveolar macrophages after radiation, and the relationship with the activity of JNK and the amount of collagen in lung tissues.

C57BL/6 mice (20 to 25 g, male) received chlorotetracycline, 2 g/L, in drinking water 1 week before irradiation and continuously afterwards. The mice were irradiated once with 1,400 cGy of 60CO{gamma}-ray on the whole chest.4 We measured the cellular composition of whole-lung BAL fluids, the elastin expression of lung tissues, the level of hydroxyproline in lung tissues, and in vitro JNK assay before and 1, 4, and 8 weeks after irradiation.

The volumes of retrieved BAL fluid from instilled 4 mL of saline solution with 2% heparin were 3.7 to 3.8 mL in each group. The cell numbers were similar before (4.1 x 104/mL) and 1 week after (3.1 x 104/mL) after irradiation. At 4 weeks and 8 weeks after irradiation, the cell numbers reached 14 x 104/mL and 10 x 104/mL, respectively. We could not find any change of lymphocyte and neutrophil populations in BAL fluid after irradiation. Hematoxylin-eosin stain of lung tissues did not show any structural and fibrotic change in lung tissues at 4 weeks and 8 weeks after irradiation, and the amounts of elastin and collagen were not different on Verhoeff stain of lung tissues from before to 8 weeks after irradiation. The content of hydroxyproline was measured with the left lung dissected from left main bronchus. The lungs were homogenized and hydrolyzed with 6 N HCl for 12 h at 110°C and then measured as previously described.5 The content of hydroxyproline, standardized with lung protein concentration, reached peak at 4 weeks after irradiation, and thereafter showed plateau (Fig 1) . In vitro JNK assay using c-Jun1–79-GST (a gift from Gary Johnson, National Jewish Medical and Research Center, Denver, CO) sepharose beads was performed with the alveolar macrophages obtained from BAL.6 The JNK activity was not detected before irradiation; however, the JNK activity increased from 1 week after irradiation and reached its peak 4 weeks after irradiation (Fig 2) .



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  		Figure 1. Contents of hydroxyproline in lung tissues after irradiation.

 


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  		Figure 2. In vitro JNK assay.

 
These results indicated that JNK may be involved in the pathogenesis of RTLF because the JNK activity showed a similar pattern with the content of hydroxyproline. However, it is needed to clarify whether JNK increases the transcription of fibrogenic cytokines through the transcription factor.

Footnotes

Abbreviations: JNK = c-Jun N-terminal kinase; RTLF = radiation-induced lung fibrosis; TGF = transforming growth factor

Supported by a grant from 1999 Soon Chun Hyang University Foundation for Hyonam Kidney Laboratory.

References

  1. Franko, AJ, Sharplin, J, Ghahary, A, et al (1997) Immunohistochemical localization of transforming growth factor-ß and tumor necrosis factor-{alpha} in the lungs of fibrosis-pone and "non-fibrosing" mice during the latent period and early phase after irradiation. Radiat Res 147,245-256[ISI][Medline]
  2. Yi, ES, Bedoya, A, Lee, H, et al (1996) Radiation-induced lung injury in vivo: expression of transforming growth factor-ß precedes fibrosis. Inflammation 20,339-352[CrossRef][ISI][Medline]
  3. Shirakabe, K, Yamaguchi, K, Shibuya, H, et al (1997) TAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinase. J Biol Chem 272,8141-8144[Abstract/Free Full Text]
  4. Finkelstein, JN, Johston, CJ, Baggs, R, et al (1994) Early alterations in extracellular matrix and transforming growth factor-ß gene expression in mouse lung indicative of late radiation fibrosis. Int J Radiat Oncol Biol Phys 28,621-631[ISI][Medline]
  5. Eitzman, DT, McCoy, RD, Zheng, X, et al (1996) Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-i gene. J Clin Invest 97,232-237[ISI][Medline]
  6. Chan, ED, Winston, BW, Jarpe, MB, et al (1997) Preferential activation of the p46 isoform of JNK/SAPK in mouse macrophages by TNF-{alpha}. Proc Natl Acad Sci U S A 94,13169-13174[Abstract/Free Full Text]




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