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The N-terminal lectin-like domain of thrombomodulin reduces acute lung injury without anticoagulant effects in a rat cardiopulmonary bypass model

Abstract

Objectives

Systemic inflammation evoked by cardiopulmonary bypass (CPB) leads to acute lung injury (ALI) and respiratory failure. Although recombinant human soluble thrombomodulin (rTM) consists of three domains (D1–3), is reported to attenuate systemic inflammation through the N-terminal lectin-like domain (D1), anticoagulant domain (D2) may exacerbate coagulopathy after CPB. We investigated the potential of selective D1 against CPB-mediated ALI free from anticoagulant effects using a rat CPB model.

Methods

Rats were divided into three groups: control (CPB alone, n = 5), D1 (CPB + D1, n = 4), and D123 (CPB + D123, n = 6). D1 or D123 was administrated to the rats of each group before CPB establishment. Blood samples are collected before, during and after CPB. Blood coagulability was assessed by a coagulation analyzer. Lung samples are collected at 1 h after the termination of CPB for histological analyses.

Results

D123 group exhibited significantly prolonged glass beads-activated clotting time with heparinase after CPB compared to that in control group, whereas no significant prolongation in control and D1 group (control vs. D1 vs. D123: 65.4 ± 9.2 vs. 65.3 ± 10.9 vs. 83.5 ± 4.6 s, p = 0.036 [control vs. D123], 0.99 [control vs. D1]) indicating the absence of anticoagulant activities of D1. Histological studies revealed less congestion, edema, inflammation, and hemorrhage in both D1 and D123 groups compared to those in control group indicating protective effects of both D1 and D123 against ALI mediated by CPB.

Conclusions

N-terminal lectin-like domain of rTM may reduce the risk of ALI without anticoagulant effects.

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Acknowledgements

We thank Asahi Kasei Pharma Co. for providing the recombinant human soluble thrombomodulin. We thank Dr. S. Kawamoto (Kyoto University) for the technical supports in blood coagulation examinations. We thank Mr. S. Miyake and Ms. Y. Matsubara (Kyoto University) for technical supports in histological assessments. This work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan (to K. Y.) [Grant number 16H05424].

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Correspondence to Hidetoshi Masumoto.

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Itonaga, T., Hirao, S., Yamazaki, K. et al. The N-terminal lectin-like domain of thrombomodulin reduces acute lung injury without anticoagulant effects in a rat cardiopulmonary bypass model. Gen Thorac Cardiovasc Surg 68, 785–792 (2020). https://doi.org/10.1007/s11748-020-01292-8

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Keywords

  • Cardiopulmonary bypass
  • Thrombomodulin
  • Acute lung injury
  • Coagulopathy
  • Animal model