Novel function of transglutaminase 2 in extracellular histone-induced acute lung injury

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca2+-dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2−/−) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2−/− mice than that in WT mice. The area of fibrin deposition and the proportion of CD41+CD31+ cells were lower in TG2−/− mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41+CD31+ cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition. Role of transglutaminase 2 (TG2) in the adhesion of platelets to endothelial cells (ECs) and the deposition of fibrin. Extracellular histones induce severe pulmonary haemorrhage, resulting from endothelial barrier damage. To compensate for the loss of the endothelial barrier, TG2 mediates the adhesion of platelets to ECs and the deposition of fibrin. [Display omitted] •Transglutaminase 2 (TG2) did not directly affect platelet aggregation and coagulation abnormalities.•TG2 promoted the platelet adhesion to endothelial cells and the fibrin deposition as novel functions.•TG2 showed the protective contribution to extracellular histones induced-pulmonary haemorrhage.