CD11d integrin blockade reduces the systemic inflammatory response syndrome after spinal cord injury

Traumatic injury to the spinal cord triggers a systemic inflammatory response syndrome (SIRS), in which inflammatory cells from the circulation invade organs such as the liver, lung and kidney, leading to damage of these organs. Our previous study (Gris, et al, Exp. Neurol, 2008) demonstrated that spinal cord injury (SCI) activates circulating neutrophils that then invade the lung and kidney from 2 to 24 h after injury, increasing myeloperoxidase activity, cyclooxygenase-2 and matrix metalloproteinase-9 expression and lipid peroxidation in these organs. The present study was designed to ascertain whether a treatment that limits the influx of leukocytes into the injured spinal cord would also be effective in reducing the SIRS after SCI. This treatment is intravenous delivery of a monoclonal antibody (mAb) against the CD11d subunit of the CD11d/CD18 integrin expressed by neutrophils and monocytes. We delivered the anti-CD11d mAb at 2 h post moderate clip compression SCI at the 4th or 12th thoracic segments and assessed inflammation, oxidative activity and cellular damage within the lung, kidney and liver at 12 h post-injury. In some analyses we compared high and low thoracic injuries to evaluate the importance of injury level on the intensity of the SIRS. After T4 injury, treatment with the anti-integrin mAb reduced the presence of neutrophils and macrophages in the lung, with associated decreases in expression of NF-κB and oxidative enzymes and in the concentration of free radicals in this organ. The treatment also reduced lipid peroxidation, protein nitration and cell death in the lung. The anti-CD11d treatment also reduced the inflammatory cells within the kidney after T4 injury, as well as the free radical concentration and amount of lipid peroxidation. In the liver, the mAb treatment reduced the influx of neutrophils but most of the other measures examined were unaffected by SCI. The inflammatory responses within the lung and kidney were often greater after T4 than T12 injury. Clinical studies show that SIRS, with its associated organ failure, contributes significantly to the morbidity and mortality of SCI patients. This anti-integrin treatment may block the onset of SIRS after SCI.