Hepatic veno-occlusive disease may develop in secondary iron overloaded mice after allogeneic hematopoietic stem cell transplantation with total body irradiation

Mi Young Yeom; Yoo Jin Kim; Nack Gyun Chung; Jae Wook Lee; Pil Sang Jang; Bin Cho; Chul Seung Kye; Dae Chul Jeong

doi:10.5045/br.2015.50.3.140

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Original Article

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Blood Res 2015; 50(3):

Published online September 22, 2015

https://doi.org/10.5045/br.2015.50.3.140

Hepatic veno-occlusive disease may develop in secondary iron overloaded mice after allogeneic hematopoietic stem cell transplantation with total body irradiation

Mi Young Yeom¹, Yoo Jin Kim², Nack Gyun Chung³, Jae Wook Lee³, Pil Sang Jang³, Bin Cho³, Chul Seung Kye⁴, and Dae Chul Jeong^3,5*

Author Info. +

¹Department of Clinical Research Laboratory, Incheon St. Mary's Hospital, Incheon, Korea.

²Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

³Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁴Department of Radiation Oncology, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁵Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Correspondence to : Correspondence to Dae Chul Jeong, M.D., Ph.D. Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpodaero, Seocho-gu, Seoul 06591, Korea. Tel: +82-2-2258-6180, Fax: +82-2-537-4544, dcjeong@catholic.ac.kr

Received: July 3, 2015; Revised: August 11, 2015; Accepted: August 11, 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Background

The outcome of hematopoietic stem cell transplantation (HSCT) is poor in patients with secondary iron overload (SIO). We evaluated the relationship between SIO and veno-occlusive disease (VOD) in an animal model with radiation for HSCT.

Methods

We used a 6-week-old female BDF1 (H-2^b/d) and a male C57/BL6 (H-2^b) as recipient and donor, respectively. Recipient mice were injected intraperitoneally with 10 mg of iron dextran (cumulative doses of 50 mg, 100 mg, and 200 mg). All mice received total body irradiation for HSCT. We obtained peripheral blood for alanine transaminase (ALT) and liver for pathologic findings, lipid hyperoxide (LH) as reactive oxygen species (ROS), and liver iron content (LIC) on post-HSCT day 1 and day 7. The VOD score was assessed by pathologic findings.

Results

ALT levels increased depending on cumulative iron dose, with significant differences between days 1 and 7 for mice loaded with 200 mg of iron (P<0.01). LH levels significantly increased in mice loaded with 200 mg of iron compared to those in other groups (P<0.01). For mice loaded with 100 mg of iron, the LH level depended on the radiation dose (P<0.01). There was a statistically significant relationship among ALT, LH, and LIC parameters (P<0.05). Pathologic scores for VOD correlated with LIC (P<0.01).

Conclusion

Livers with SIO showed high ROS levels depending on cumulative iron dose, and correlations with elevated liver enzyme and LIC. The pathologic score for VOD was associated with the LIC. Our results suggest that SIO may induce VOD after HSCT with irradiation.

Keywords Iron overload, Hepatic veno-occlusive disease, Radiation, Reactive oxygen species

Article

Original Article

Blood Res 2015; 50(3): 140-146

Published online September 22, 2015 https://doi.org/10.5045/br.2015.50.3.140

Hepatic veno-occlusive disease may develop in secondary iron overloaded mice after allogeneic hematopoietic stem cell transplantation with total body irradiation

Mi Young Yeom¹, Yoo Jin Kim², Nack Gyun Chung³, Jae Wook Lee³, Pil Sang Jang³, Bin Cho³, Chul Seung Kye⁴, and Dae Chul Jeong^3,5*

¹Department of Clinical Research Laboratory, Incheon St. Mary's Hospital, Incheon, Korea.

²Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea.

³Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁴Department of Radiation Oncology, College of Medicine, The Catholic University of Korea, Seoul, Korea.

⁵Vaccine Bio Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.

Correspondence to: Correspondence to Dae Chul Jeong, M.D., Ph.D. Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222, Banpodaero, Seocho-gu, Seoul 06591, Korea. Tel: +82-2-2258-6180, Fax: +82-2-537-4544, dcjeong@catholic.ac.kr

Received: July 3, 2015; Revised: August 11, 2015; Accepted: August 11, 2015

Abstract

Background

Methods

Results

Conclusion

Keywords: Iron overload, Hepatic veno-occlusive disease, Radiation, Reactive oxygen species

Abstract

Fig 1.

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Figure 1.

A comparison of the levels of alanine transaminase (ALT) at post-HSCT days 1 and 7. ALT (IU/L) increased according to the cumulative iron dose. The ALT in mice that have been loaded with 200 mg of iron was highest among all the other groups at post-HSCT day 7 (P<0.01). All mice received 1,100 cGy (N=6). ^a)P<0.01 in t-test, ^b)P<0.01 in ANOVA.

Blood Research 2015; 50: 140-146https://doi.org/10.5045/br.2015.50.3.140

Fig 2.

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Figure 2.

The lipid hyperoxide (LH) levels according to the cumulative iron dose (A) and radiation dose (B). (A) LH (µM) was highest in the mice that received 200 mg of iron at post-HSCT day 7 (P=0.01). All mice (N=6) treated with allogeneic HSCT received 1,100 cGy. (B) LH was highest in the recipients of 1,100 cGy (P<0.01) of radiation. All mice (N=6) treated with allogeneic HSCT had cumulative iron levels of 100 mg. Beeswarm boxplots show the median values and the quartiles, and single measurements are shown as open circles. The middle bar in the box denotes mean value. ^a)P<0.01 in t-test, ^b)P<0.01 in ANOVA.

Blood Research 2015; 50: 140-146https://doi.org/10.5045/br.2015.50.3.140

Fig 3.

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Figure 3.

The pathologic findings in the liver (H-E stain; ×200). (A) The findings show the hepatic pathology according to cumulative iron dose. There is no evidence of veno-occlusion in allogeneic transplantation without iron load. However, there are iron deposits, sinusoidal hemorrhages, hepatic necrosis, and endothelial damage in the iron loaded group. (B) The hepatic findings in mice that received 100 mg of iron are shown according to radiation dose. Damage to hepatocytes and sinusoidal hemorrhages are not significantly different according to radiation dose.

Blood Research 2015; 50: 140-146https://doi.org/10.5045/br.2015.50.3.140

Fig 4.

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Figure 4.

A comparison of the individual correlations between lipid hyperoxide (LH), alanine transaminase (ALT), liver iron content (LIC) levels, and pathologic score, respectively. (A) Correlation between LH and ALT levels (P<0.01, r²=0.911). (B) Correlation between ALT and LIC (mg/gm) (P=0.014, r²=0.548). (C) Correlation between LIC and LH (^P=0.019, r²=0.564), and (D) pathologic score (P<0.01, r²=0.0597), respectively.