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The lectin-like domain of thrombomodulin protects against ischaemia–reperfusion lung injury

¹ Laboratory of Experimental Thoracic Surgery, ³ Center for Transgene Technology and Gene Therapy, ⁴ Laboratory of Pneumology, ⁵ Dept of Morphology and Molecular Pathology, University of Leuven, ² VIB Vesalius Research Center, and ⁶ Dept of Thoracic Surgery, University Hospital Gasthuisberg, Leuven, Belgium.

CORRESPONDENCE: E. M. Conway, VIB Vesalius Research Center, University of Leuven (KU Leuven), Herestraat 49, B-3000 Leuven, Belgium. Fax: 32 16345990. E-mail: ed.conway{at}med.kuleuven.be

Keywords: Coagulation, inflammation, mouse, protein C system, transplant

Received: November 22, 2007
Accepted May 9, 2008

Ischaemia–reperfusion injury of the lung is a major cause of morbidity and mortality, particularly following lung transplantation, the mainstay treatment for patients with end-stage pulmonary disease. Effective measures to prevent this complication are lacking. Thrombomodulin (TM) is an endothelial cell receptor and cofactor for thrombin-mediated generation of the anticoagulant and anti-inflammatory activated protein C (APC). The N-terminal lectin-like domain (LLD) of TM has no direct effects on coagulation, but has distinct anti-inflammatory properties, interfering with leukocyte adhesion, complement activation and cytokine generation, all of which are hallmarks of ischaemia–reperfusion injury. Using a murine model of lung ischaemia–reperfusion injury (90 min ischaemia, 4 h reperfusion), the present study shows that mice lacking the LLD of TM respond with increased extravasation of neutrophils and macrophages into the lung parenchyma and bronchoalveolar fluid (BALF), with augmented BALF levels of cytokines interleukin (IL)-1β and granulocyte-monocytic colony-stimulating factor (GM-CSF). Pre-treatment of wild-type mice with recombinant LLD, as compared with controls, significantly suppresses protein leakage and accumulation of leukocytes in the BALF.

These novel findings support further evaluation of recombinant lectin-like domain of thrombomodulin to protect the lung against tissue-damaging pro-inflammatory responses following ischaemia-reperfusion.