Dexamethasone Protects Against Tourniquet-Induced Acute Ischemia-Reperfusion Injury in Mouse Hindlimb

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.

Bilobalide protects against ischemia/reperfusion-induced oxidative stress and inflammatory responses via the MAPK/NF-κB pathways in rats

“…It has been reported that ischemic preconditioning [ 9 ], ischemic postconditioning [ 21 ], controlled reperfusion [ 22 ], hypothermia [ 23 ], light-emitting diode therapy [ 24 ] and some other physical therapies can relieve skeletal I/R injury [ 25 ]. In addition, several agents, such as dexamethasone [ 10 ], curcumin [ 26 ], salvianolic acid [ 8 ], silibinin [ 27 ], simvastatin [ 28 ], cyclosporine A [ 29 ], hydrogen-rich saline [ 30 ] and lipoxin A4 [ 4 ], have been shown to be effective in attenuating skeletal I/R injury. In cases of traumatic injuries in which I/R is not predictable and early intervention is desired, such strategies are not as relevant.…”

“…Under oxidative stress or inflammatory response conditions, the MAPK and NF- κB pathways can be activated [ 10 ]. Recent studies have shown that in some I/R injury models, including the skeletal I/R injury model, the p38, ERK1/2, JNK and p65 pathways are active [ 4 , 8 ].…”

“…In addition, ROS-induced injury can promote the formation and release of many inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β) [ 4 – 9 ]. Under oxidative stress or inflammatory conditions, the nuclear factor kappa-B (NF-휅B) and mitogen-activated protein kinase (MAPK) pathways can be activated [ 10 ]. Many I/R injury models have been reported to elicit activation of the p38, JNK, ERK1/2 and p65 pathways [ 8 , 9 ].…”

Can lessons learned about preventing cardiac muscle death be applied to prevent skeletal muscle death?

“… 2 While ischaemia often causes the initial insult, reperfusion leads to a second-hit, intense inflammatory response that can cause muscle apoptosis and necrosis in what has been termed the ischaemia-reperfusion (IR) injury. 3 Other causes of skeletal muscle IR injury include elective or emergent tourniquet use, acute or chronic compartment syndrome, and vascular injury requiring repair. 4 Preventing IR injury has been an area of interest in cardiology after myocardial infarction (MI) but has not been aggressively pursued in the orthopaedic realm.…”

Transcutaneous Electrical Acupoint Stimulation Attenuates Lung Injury Caused by Tourniquet-induced Limb Ischemia/reperfusion During Lower Extremity Surgery: A Randomized Controlled Trial

“…Reperfusion of the acute ischemic tissue triggers a potent production of reactive oxygen species (ROS) and cytokines, which promotes a proin ammatory state and subsequently increases lung vulnerability to further injury [1,4,7,8]. Although several treatment strategies have been proposed to attenuate the remote organ injury following tourniquet use, most of them were limited to animal experiments and no ideal treatment was proved to improve prognosis [9,10]. Therefore, to reinforce the anti-in ammatory response and endogenous protective effect would be a new strategy for improving the prognosis.…”