The role of mast cells and the underlying mechanisms in the formation of deep vein thrombosis in asthmatic mice

Abstract

Rationale

Asthma-induced inflammation has been shown to increase the risk of deep vein thrombosis (DVT), but the underlying mechanisms remain unclear.

Objective

To verify the associations between asthma exacerbation and the occurrence and development of DVT and explore the potential pathophysiological mechanisms at the molecular level.

Methods and results

By coculturing activated and unactivated mast cells with endothelial cells, we found that activated mast cells could lead to an increase in inflammatory factors. In contrast, this effect was significantly attenuated when we cocultured toll-like receptor 4 (TLR4)-knockdown mast cells with endothelial cells. In a mouse model of DVT induced by partial ligation of the inferior vena cava, we demonstrated that asthma exacerbates DVT in mice. DVT was significantly attenuated in vivo after the administration of mast cell degranulation and TLR4 inhibitors to asthmatic mice, whereas the infusion of differentiated MCs into mice exacerbated thrombosis. However, thrombosis was not significantly aggravated after the infusion of TLR4-knockdown mast cells. Inhibition of MC degranulation as well as TLR4 receptor expression attenuated local and systemic inflammation in asthmatic mice, and reinfusion of NC-MCs reversed this effect, whereas the reversal and degranulation of MCs were attenuated after reinfusion of TLR4-knockdown MCs. The infusion of differentiated MCs into asthmatic mice with inhibited MC degranulation and systemic TLR4 resulted in significant increases in AKT, P38, JNK, and ERK, whereas the infusion of TLR4-knockdown MCs resulted in significantly reduced increases in AKT, P38, JNK, and ERK.

Conclusions

Asthma may exacerbate DVT via mechanisms related to mast cells, which may exacerbate DVT through endothelium inflammation and the upregulation of AKT, P38, JNK, etc., which is mediated, at least in part, by TLR4.