The lectin-like domain of thrombomodulin protects against ischaemia-reperfusion lung injury.
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)-1beta 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.
Laboratory of Experimental Thoracic Surgery, University of Leuven, Leuven, Belgium.
N
N
Geudens
M
M
Van de Wouwer
B M
BM
Vanaudenaerde
R
R
Vos
C
C
Van De Wauwer
G M
GM
Verleden
E
E
Verbeken
T
T
Lerut
D E M
DE
Van Raemdonck
E M
EM
Conway
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D000925:Anticoagulants / Q000737:chemistry; D001777:Blood Coagulation; D001992:Bronchoalveolar Lavage Fluid; D042783:Endothelial Cells / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D037102:Lectins / Q000737:chemistry*; D055370:Lung Injury / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D011486:Protein C / Q000737:chemistry; D017434:Protein Structure, Tertiary; D015427:Reperfusion Injury / Q000378:metabolism* / Q000517:prevention & control; D018180:Thrombomodulin / Q000737:chemistry*
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D037102:Lectins; D011486:Protein C; D018180:Thrombomodulin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor