Background  Deep hypothermic circulatory arrest (DHCA) can cause systemic inflammatory response (SIR) and ischemia-reperfusion (I/R) injury, potentially exacerbating organ failure. Ulinastatin (UTI) is a frequently employed anti-inflammatory medication in clinical practice, but different timing and dosage may influence its protective efficacy. Methods 24 rats were randomly divided into four groups. Three different doses of UTI (3/10/30 × 104 U/kg; low/medium/high dose) were administered in the DHCA rat model, with a control group that underwent DHCA without UTI administration. Inflammatory markers and routine clinical indicators of myocardial, hepatic, and renal tissue injury were evaluated. All rats underwent the standard DHCA procedure. Results Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and neutrophil elastase (ELA-2) levels in rats exposed to DHCA gradually increased after rewarming. Compared with the DHCA-only group, both the low dose of UTI (UTI-L) and the medium dose of UTI (UTI-M) significantly reduced IL-6 (p = 0.017, p = 0.022 ), TNF-α (p = 0.003, p < 0.001), ELA-2 levels ( p = 0.018, p = 0.001), and elevated IL-10 levels ( p < 0.001, p < 0.001) 4 h post-weaning from cardiopulmonary bypass (CPB). In addition, compared with the DHCA group, both the UTI-L and UTI-M group showed significantly lower levels of cardiac troponin I (p = 0.001, p = 0.001), creatine kinase muscle and brain isoenzyme (CK-MB) (p < 0.001, p < 0.001), creatinine (p < 0.001, p < 0.001), blood urea nitrogen (p = 0.002, p = 0.021), aspartate transaminase (p < 0.001, p < 0.001) and alanine aminotransferase (p < 0.001, p < 0.001) at the end of the experiment. The hematoxylin-eosin staining results of kidney and liver tissue damage were alleviated in the UTI-L and UTI-M groups. The high dose of UTI (UTI-H) group did not exhibit dose-dependent anti-inflammatory effects and was associated with aggravated injury to the heart, liver, and kidney. Conclusion This study demonstrated that the administration of low to medium doses of UTI during DHCA significantly attenuated the levels of IL-6, TNF-α, and ELA-2, elevated the level of the anti-inflammatory factor IL-10, and provided protective effects on myocardial, hepatic, and renal tissues.

Effects of different doses of ulinastatin on organ protection of deep hypothermic circulatory arrest in rats

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2025年3月20日

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Yuan Teng,
Jing Wang,
Zhiyuan Bo,
Tianlong Wang,
Yuan Yuan,
Guodong Gao,
Bingyang Ji,
Qiang Hu

摘要

Background

Deep hypothermic circulatory arrest (DHCA) can cause systemic inflammatory response (SIR) and ischemia-reperfusion (I/R) injury, potentially exacerbating organ failure. Ulinastatin (UTI) is a frequently employed anti-inflammatory medication in clinical practice, but different timing and dosage may influence its protective efficacy.

Methods

24 rats were randomly divided into four groups. Three different doses of UTI (3/10/30 × 10⁴ U/kg; low/medium/high dose) were administered in the DHCA rat model, with a control group that underwent DHCA without UTI administration. Inflammatory markers and routine clinical indicators of myocardial, hepatic, and renal tissue injury were evaluated. All rats underwent the standard DHCA procedure.

Results

Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α) and neutrophil elastase (ELA-2) levels in rats exposed to DHCA gradually increased after rewarming. Compared with the DHCA-only group, both the low dose of UTI (UTI-L) and the medium dose of UTI (UTI-M) significantly reduced IL-6 (p = 0.017, p = 0.022 ), TNF-α (p = 0.003, p < 0.001), ELA-2 levels ( p = 0.018, p = 0.001), and elevated IL-10 levels ( p < 0.001, p < 0.001) 4 h post-weaning from cardiopulmonary bypass (CPB). In addition, compared with the DHCA group, both the UTI-L and UTI-M group showed significantly lower levels of cardiac troponin I (p = 0.001, p = 0.001), creatine kinase muscle and brain isoenzyme (CK-MB) (p < 0.001, p < 0.001), creatinine (p < 0.001, p < 0.001), blood urea nitrogen (p = 0.002, p = 0.021), aspartate transaminase (p < 0.001, p < 0.001) and alanine aminotransferase (p < 0.001, p < 0.001) at the end of the experiment. The hematoxylin-eosin staining results of kidney and liver tissue damage were alleviated in the UTI-L and UTI-M groups. The high dose of UTI (UTI-H) group did not exhibit dose-dependent anti-inflammatory effects and was associated with aggravated injury to the heart, liver, and kidney.

Conclusion

This study demonstrated that the administration of low to medium doses of UTI during DHCA significantly attenuated the levels of IL-6, TNF-α, and ELA-2, elevated the level of the anti-inflammatory factor IL-10, and provided protective effects on myocardial, hepatic, and renal tissues.