Inhibiting mitochondrial fission protects multiple organ functions in rats with concomitant explosive blast injury and hemorrhagic shock by improving microcirculation and vascular permeability

To investigate the protective effect of mitochondrial fission inhibitor 1 (Mdivi-1), on organ function in rats with explosive blast injury combined with hemorrhagic shock.

A total of 192 SD rats (half male and half female, 12 weeks old, weighing about 220 g) were randomly divided into 6 groups: Sham group (only surgical incision along the midline of the abdomen), model group (ESH group, thermal radiation and shock wave injury followed by femoral artery hemorrhage), lactated Ringer’s solution resuscitation group (ESH+LR group, LR solution infusion in the femoral vein for resuscitation), and low-, middle- and high-dose Mdivi-1 groups (0.1, 0.5 and 1.0 mg/kg Mdivi-1 intervention after infusion of LR solution). Fluorescent protein tracing was used to determine the leakage amount of fluorescent protein in the lung and kidney tissues to evaluate the vascular permeability. Evans blue dye staining was employed to observe the intestinal permeability and pulmonary vascular permeability. Laser Doppler flowmetry was applied to monitor the tissue blood perfusion in the liver, kidneys, and intestine. Serum levels of cardiac injury marker troponin I (TNI), liver function markers aspartate aminotransferase (AST) and alanine aminotransferase (ALT), and renal function markers serum creatinine (Scr) and blood urea nitrogen (BUN) were detected to evaluate the functions of corresponding organs. The water contents of the lungs and brain were calculated by measuring wet weight and dry weight of the lung and brain tissues. Blood pressure, heart rate, and respiratory rate were monitored. The survival time and 72-hour survival rate were recorded and calculated.

Compared with the Sham group, the ESH group exhibited significantly increased vascular permeability in the lungs and kidneys as well as intestinal tissue (P<0.05), along with obviously elevated water contents in the lungs and brain (P<0.05), and decreased blood perfusion in the liver, kidneys, and intestine by 57.1%, 39.2%, and 43.2% of the Sham group, respectively (P<0.05), elevated levels of TNI, AST, ALT, Scr and BUN (P<0.05), mean survival time of 3.8±1.1 h, and a 72-hour survival rate of 0 (P<0.05). Although LR solution resuscitation reduced vascular permeability and alleviated organ injury in rats with explosive injury combined with hemorrhagic shock, there were no significant differences compared to the ESH group (P>0.05). Mdivi-1 treatment notably decreased vascular permeability in the lungs and kidneys and intestine, and water contents in the lungs and brain when compared with the LR group (P<0.05), with the dose of 0.5 mg/kg demonstrating the most significant effect. Additionally, Mdivi-1 treatment also significantly enhanced organ perfusion, improved organ functions, prolonged survival time, and increased survival rate. The 0.5 mg/kg treatment resulted in a 72-hour average survival time 55.64 h and a survival rate of 62.5%.

Mitochondrial fission inhibitor Mdivi-1 can reduce the permeabilities in the lungs, kidneys and intestine, improve tissue blood perfusion, protect the organ functions of the heart, liver and kidneys, and finally prolong survival time and increase survival rate in rats with concomitant explosive blast injury and hemorrhagic shock.