Anti-inflammatory effect of tranexamic acid against trauma-hemorrhagic shock-induced acute lung injury in rats

Abstract

It has been demonstrated that tranexamic acid (TXA), a synthetic derivative of lysine, alleviates lung damage in a trauma-hemorrhagic shock (T/HS) model. Nevertheless, the mechanism of TXA against acute lung injury (ALI) has not deeply elaborated. In this study, we generated a T/HS rat model based on previous research, and TXA (50 mg/kg and 100 mg/kg) was intravenously injected into these rats prior to or post T/HS. The results revealed that the decreased survival rate and impaired lung permeability of the rats caused by T/HS were improved by TXA pretreatment or posttreatment. T/HS-triggered over-generation of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in bronchoalveolar fluid and serum was inhibited by TXA, and the enzymatic activity of myeloperoxidase (MPO) in lung tissues was suppressed by TXA as well. Furthermore, TXA treatment deactivated the poly ADP-ribose polymerase-1 (PARP1)/nuclear factor κB (NF-κB) signaling pathway in the lungs of T/HS rats, as evidenced by increased IκBα expression, and decreased cleaved PARP1, p-p65 (Ser276), p-p65 (Ser529), p-IκBα (ser32/ser36), and intercellular adhesion molecule-1. While the expression level of total p65 did not change after T/HS, its DNA binding activity was strengthened. Both TXA pretreatment and posttreatment suppressed this effect on the DNA binding activity of NF-κB. Taken together, our results reveal that administration of TXA effectively relieves T/HS-induced ALI, at least in part, by attenuating the abnormal pulmonary inflammation.

Keywords: NF-κB; acute lung injury; hemorrhagic shock; inflammation; tranexamic acid.

Fig. 1.

Treatment with TXA increased the survival rate of rats with T/HS. The survival of rats following different experimental manipulations was evaluated. a, Sham; b, T/HS group; c, pretreatment with TXA (50 mg/kg) + T/HS group; d, pretreatment with TXA (100 mg/kg) + T/HS group; e, T/HS + posttreatment with TXA (50 mg/kg) group; f, T/HS + posttreatment with TXA group (100 mg/kg).

Fig. 2.

Treatment with TXA relieved ALI of rats caused by T/HS. (A) Lung histological changes were examined by HE staining. (B) The ratio of the percentage of EBD in the BALF to EBD in the plasma. (C) Lung permeability index: BALF protein concentration /plasma protein concentration. a, Sham; b, T/HS group; c, pretreatment with TXA (50 mg/kg) + T/HS group; d, pretreatment with TXA (100 mg/kg) + T/HS group; e, T/HS + posttreatment with TXA (50 mg/kg) group; f, T/HS + posttreatment with TXA group (100 mg/kg). Data are presented as the mean ± SD. *P<0.05; ** P<0.01; ***P<0.001.

Fig. 3.

Treatment with TXA inhibited inflammation of the lung in rats with T/HS. The levels of IL-6 and TNF-α in (A) BALF and (B) serum were detected. (C) MPO activity in lung tissue was evaluated. a, Sham; b, T/HS group; c, pretreatment with TXA (50 mg/kg) + T/HS group; d, pretreatment with TXA (100 mg/kg) + T/HS group; e, T/HS + posttreatment with TXA (50 mg/kg) group; f, T/HS + posttreatment with TXA group (100 mg/kg). Data are presented as the mean ± SD. *P<0.05; ** P<0.01; ***P<0.001.

Fig. 4.

Treatment with TXA attenuated the PARP1/NF-κB signaling pathway.(A) The expression levels of cleaved PARP1, p65, p-p65 Ser276, p-p65 Ser529, IκBα, p-IκBα, and ICAM-1 were detected by western blotting. The bands were semiquantitatively evaluated by densitometry, and the data were normalized to those of the internal control, β-actin. (B) Active p65 was examined through EMSA. The band (active p65) was semiquantitatively evaluated by densitometry. (C) The content of iNOS, MCP-1, COX-2, and VCAM-1 was determined by immunohistochemical analysis. The mean density of staining was calculated as the integrated optical density (IOD) sum/area. a, Sham; b, T/HS group; c, pretreatment with TXA (50 mg/kg) + T/HS group; d, pretreatment with TXA (100 mg/kg) + T/HS group; e, T/HS + posttreatment with TXA (50 mg/kg) group; f, T/HS + posttreatment with TXA group (100 mg/kg). Data are presented as the mean ± SD. *P<0.05; ** P<0.01; ***P<0.001.