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

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

^* To whom correspondence should be addressed. E-mail: ed.conway{at}med.kuleuven.be.

	Abstract

Ischemia-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 anti-coagulant 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 ischemia-reperfusion injury. Using a murine model of lung ischemia-reperfusion injury (90' ischemia, 4 hrs reperfusion), we show 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 IL-1 and 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 LLD of TM to protect the lung against tissue-damaging pro-inflammatory responses following ischemia-reperfusion.

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