Compartment syndrome-induced muscle injury is diminished by the neutralization of pro-inflammatory cytokines

Abstract Objectives: Compartment syndrome (CS) is one of the most devastating consequences of musculoskeletal trauma. The pathophysiology of CS includes elevation of intracompartmental pressure (ICP), causing damage to the microcirculation, decreased oxygen delivery, tissue anoxia, and cell death. CS is a combined ischemic and inflammatory condition that induces the systemic inflammatory cascade. In complete ischemia, within the first hour of reperfusion, a peak in the pro-inflammatory cytokine, tumor necrosis factor alpha (TNF-α) has been previously reported. The purpose of this study was to examine the suspected systemic inflammatory cytokine/chemokine release in response to CS, and to evaluate the microvascular dysfunction, tissue injury, and inflammatory response following the neutralization of pro-inflammatory cytokines TNF-α and/or interleukin-1 beta (IL-1β). Methods: Twenty-eight male Wistar rats were randomly assigned into 5 groups: Sham (no CS), CS (with isotype control), CS+TNF-α neutralizing antibody (NA), CS+IL-1β NA, CS+Combo (both TNF-α and IL-1β NA). CS was induced by elevation of ICP above 30 mm Hg through an infusion of isotonic saline into the anterior compartment of the hind limb for 2 hours; NA were administered just prior to fasciotomy. Microvascular perfusion, cellular tissue injury, and inflammatory response within the extensor digitorum longus muscle were assessed using intravital video microscopy for 45 minutes after fasciotomy. Systemic levels of 24 different cytokines/chemokines were also measured, using the xMAP Luminex technology. Results: Of the 24 cytokines/chemokines sampled, 6 were significantly elevated from their baseline levels, and included the pro-inflammatory cytokines TNF-α, IL-1β, growth-related oncogene/keratinocyte chemoattractant (GRO/KC), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1α), and the anti-inflammatory cytokine IL-10. CS resulted in a significant decrease in microvascular perfusion, from 75 ± 2% continuously perfused capillaries in the sham to 31 ± 4% in CS (P < .001), a significant increase in tissue injury (0.33 ± 0.4 versus 0.04 ± 0.01 in sham) and leukocyte activation (14 ± 2 adherent leukocytes/1000 μm2 versus 2 ± 1 adherent leukocytes/100 μm2 in sham, P < .001). CS-associated tissue injury was significantly decreased with TNF-α neutralization (P < .05), both when administered alone or in combination with IL-1β (P < .05). Additionally, TNF-α neutralization blocked CS-associated leukocyte activation (P < .05); IL-1β neutralization also diminished leukocyte adhesion (P < .05). Perfusion remained virtually unchanged in CS animals treated with NA (36 ± 4%, 32 ± 3% and 30 ± 2% in CS+TNF-α, CS+IL-1β and CS+Combo groups, respectively). Conclusion: The results of this study indicate that CS induces a systemic inflammation, as evidenced by upregulation of inflammatory cytokines/chemokines in circulation. Neutralization of TNF-α led to a significant reduction in tissue injury; however, it had no effect on the CS-induced microvascular dysfunction. This suggests a distinct role of TNF-α in the pathophysiology of muscle injury in CS.