Inhibition of Allergic Bronchial Asthma by Thrombomodulin Is Mediated by Dendritic Cells

Abstract

the results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.

The lectin-like domain of thrombomodulin hampers host defence in pneumococcal pneumonia

“…TM occupies a central role in the regulation of coagulation and inflammation, with responsibility for its specific functions relying on the integrity of its distinct structural domains. Thus, the EGF-like repeats provide cofactor activity for thrombin-mediated activation of protein C and TAFI, resulting in dampening of coagulation, fibrinolysis and complement, while the N-terminal lectin-like domain exhibits a number of anti-inflammatory properties [5][6][7]. Using mouse models to study the host response to bacterial pneumonia, we have previously investigated the role of the EGF-like repeat of TM, which is responsible for protein C activation.…”

“…Thrombomodulin (TM) CD141 is a transmembrane, multidomain glycoprotein receptor that is expressed predominantly on vascular endothelial cells, but also on monocytes, neutrophils, osteoblasts, synovial cells and dendritic cells [5][6][7]. TM exhibits several distinct properties in coagulation, fibrinolysis, innate immunity and inflammation that are based largely on its distinct structural domains.…”

“…The central domain of TM is comprised of six epidermal growth factor (EGF)-like repeats, three of which provide critical cofactor activity for the thrombin-mediated generation of activated protein C (APC) and of activated thrombinactivatable fibrinolysis inhibitor (TAFIa). Protein C activation by thrombin-TM is further augmented by the endothelial protein C receptor [5][6][7]. APC suppresses further generation of thrombin by cleaving and inactivating coagulation cofactors Va and VIIIa.…”

“…TAFIa also inactivates the complement fragments and anaphylatoxins C3a and C5a, thereby dampening the innate immune response [12]. In addition to its pivotal role in activating protein C and TAFI [8,11], TM also has direct anti-inflammatory properties [5][6][7] that are mediated at least in part by its Nterminal C-type lectin-like domain. This structure interferes with neutrophil adhesion, complement activation and cytokine generation [13][14][15], and Although alterations in regulation of the coagulation system have been studied extensively in pneumonia and sepsis [8], there is limited knowledge of the role of TM in the host response to bacterial infection.…”

Eosinophils Promote Epithelial To Mesenchymal Transition Of Bronchial Epithelial Cells

“…The purity of eosinophils was more than 90%. Under pentobarbital anesthesia, mice received intra-tracheally either bone marrow-derived eosinophils (2610 6 /cells in 100 ml saline) or sterile saline (100 ml) on day 0, 7 and 14; for intratracheal instillation, we used high number of eosinophils because we have previously detected between 1 to 2610 6 eosinophils in mouse models of bronchial asthma [34]. Mice were sacrificed and samples were taken either on day 9 or 21 for subsequent analysis.…”