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

Abstract

BackgroundThe 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.MethodsWe used a 6-week-old female BDF1 (H-2b/d) and a male C57/BL6 (H-2b) 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.ResultsALT 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).ConclusionLivers 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.

Role of Gut Microbiota and Oxidative Stress in the Progression of Transplant-Related Complications following Hematopoietic Stem Cell Transplantation

“…As the liver is one of the organs in which iron preferentially accumulates, oxidative stress promoted by iron overload in livers after conditioning regimens might be attributed to triggering and exacerbating hepatic injury including SOS in HSCT patients [ 102 ]. Yeom et al demonstrated that ROS levels of the murine liver increased according to cumulative iron dose and correlations with pathologic score for SOS, including sinusoidal hemorrhage and endothelial damage, in HSCT mice with no significant differences between the syngeneic and allogeneic groups [ 103 ]. Mitigating oxidative stress with antioxidants has shown protective effects on SOS-related liver injury in many studies [ 101 , 104 , 105 ].…”

Hepatic sinusoidal obstruction syndrome/veno-occlusive disease after hematopoietic cell transplantation: historical and current considerations in Korea

“…However, multivariate analyses in a recent Korean single-center study showed that a history of significant liver disease or viral hepatitis was not significantly associated with the development of SOS/VOD [29]. Iron overload, as indicated by elevated ferritin level, has been proposed as a risk factor for liver toxicity, including the development of SOS/VOD [36,[49][50][51][52].…”

A Critical Analysis of Experimental Animal Models of Sinusoidal Obstruction Syndrome

“…Yeom et al found that liver iron content increases the severity of SOS after HSCT in mice due to an increase in reactive oxygen species. 49 Meanwhile, Qiao et al also used endothelial progenitor cells concurrently with their HSCT regimen to replace damaged SECs. 48 Endothelial progenitor infusion reduced liver damage by inhibiting platelet activation and decreasing secretion of cytokines Interleukin-6 (IL-6) and Tumor Necrosis Factor-a (TNF-a).…”