Abstract
Extremity injuries with hemorrhage have been a significant cause of death in civilian medicine and on the battlefield. The use of a tourniquet as an intervention is necessary for treatment to an injured limb; however, the tourniquet and subsequent release results in serious acute ischemia-reperfusion (IR) injury in the skeletal muscle and neuromuscular junction (NMJ). Much evidence demonstrates that inflammation is an important factor to cause acute IR injury. To find effective therapeutic interventions for tourniquet-induced acute IR injuries, our current study investigated effect of dexamethasone, an anti-inflammatory drug, on tourniquet-induced acute IR injury in mouse hindlimb. In C57/BL6 mice, a tourniquet was placed on unilateral hindlimb (left hindlimb) at the hip joint for 3 h, and then released for 24 h to induce IR. Three hours of tourniquet and 24 h of release (24-h IR) caused gastrocnemius muscle injuries including rupture of the muscle sarcolemma and necrosis (42.8 ± 2.3% for infarct size of the gastrocnemius muscle). In the NMJ, motor nerve terminals disappeared, and endplate potentials were undetectable in 24-h IR mice. There was no gastrocnemius muscle contraction in 24-h IR mice. Western blot data showed that inflammatory cytokines (TNFα and IL-1β) were increased in the gastrocnemius muscle after 24-h IR. Treatment with dexamethasone at the beginning of reperfusion (1 mg/kg, i.p.) significantly inhibited expression of TNFα and IL-1β, reduced rupture of the muscle sarcolemma and infarct size (24.8 ± 2.0%), and improved direct muscle stimulation-induced gastrocnemius muscle contraction in 24-h IR mice. However, this anti-inflammatory drug did not improve NMJ morphology and function, and sciatic nerve-stimulated skeletal muscle contraction in 24-h IR mice. The data suggest that one-time treatment with dexamethasone at the beginning of reperfusion only reduced structural and functional impairments of the skeletal muscle but not the NMJ through inhibiting inflammatory cytokines.
Highlights
Based on the data from the Center for Disease Control and Prevention, over 14 million persons with extremity injuries visit emergency rooms, with an estimated cost of $80 billion each year (Center for Disease Control and Prevention, 2017)
Acute ischemia-reperfusion (IR) injuries induced by a tourniquet use with subsequent reperfusion usually occur, which include tissue apoptosis and necrosis in the skeletal muscle, and severe structural and functional damage in the neuromuscular junction (NMJ) (Aho et al, 1983; Mohler et al, 1999; Schoen et al, 2007; Tran et al, 2011, 2012; Gillani et al, 2012)
An obvious breakage of muscle fiber was observed in tourniquet-induced IR group of mice, revealed by laminin staining of gastrocnemius muscles in cross-section (Figure 1A)
Summary
Based on the data from the Center for Disease Control and Prevention, over 14 million persons with extremity injuries visit emergency rooms, with an estimated cost of $80 billion each year (Center for Disease Control and Prevention, 2017). Acute ischemia-reperfusion (IR) injuries induced by a tourniquet use with subsequent reperfusion usually occur, which include tissue apoptosis and necrosis in the skeletal muscle, and severe structural and functional damage in the neuromuscular junction (NMJ) (Aho et al, 1983; Mohler et al, 1999; Schoen et al, 2007; Tran et al, 2011, 2012; Gillani et al, 2012) These acute injuries affect long-term recovery of NMJ function and skeletal muscle contraction from IR injuries, even resulting in complete limb paralysis as well as the need for secondary amputation (Kam et al, 2001; Noordin et al, 2009; Vignaud et al, 2010). These complications have led to the deemphasis and limitations of tourniquet use (Clasper et al, 2009; Kue et al, 2015)
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