Transient blockage of the CD11d/CD18 integrin reduces contusion volume and macrophage infiltration after traumatic brain injury in rats

Abstract

The early inflammatory response to traumatic brain injury (TBI) may result in secondary damage. The purpose of this study was to evaluate the effects of a transient treatment employing a blocking monoclonal antibody (mAb) to the CD11d/CD18 integrin on histopathological outcome and macrophage infiltration following TBI. A parasagittal fluid percussion (FP) brain injury (1.8 -2.1 atmosphere) was induced in male Sprague-Dawley rats. Rats were randomized into two trauma groups, treated (N=7) and nontreated (N=8) animals. In the treated group, a mAb to the CD11d subunit of the CD11d/CD18 integrin was administered 30 minutes, 24 and 48 hours after brain injury. Control animals received an isotype-matched irrelevant mAb using the same dose and treatment regimen. At three days after TBI, animals were perfusion-fixed for histopathological and immunocytochemical analysis. The anti-CD11d mAb treatment reduced contusion areas as well as overall contusion volume compared to vehicle-treated animals. For example, overall contusion volume was reduced from 2.7 ± 0.5 mm 3 (mean ± SEM) to 1.4 ± 0.4 with treatment (p<0.05). Immunocytochemical studies identifying CD68 immunoreactive macrophages showed that treatment caused significant attenuation of leukocyte infiltration into the contused cortical areas. These data emphasize the beneficial effects of blocking inflammatory cell recruitment into the injured brain on histopathological outcome following traumatic brain injury.

A CD11d Monoclonal Antibody Treatment Reduces Tissue Injury and Improves Neurological Outcome after Fluid Percussion Brain Injury in Rats

“…This acute modification of the inflammatory cell population within the injured brain had long-lasting effects on the 4-week behavioral outcomes, as well as normalizing the glial and neuronal population responses at this time. Our data also confirm a preliminary study that demonstrated reduced contusion volume and macrophage infiltration in CD11d mAb-treated rats after TBI (Utagawa et al, 2008). Despite the reduction of the macrophage population in the injured brains in our CD11d mAb-treated animals, they had no infections in the CNS or elsewhere.…”

“…The following groups were tested: anti-CD11d-SR, n = 25; anti-CD11d-LR, n = 14; 1B7 control-SR, n = 24; 1B7 control-LR, n = 14; sham-SR, n = 24; and sham-LR, n = 14. To provide brain tissue for histological analysis of leukocyte infiltration after injury (Carlos et al, 1997;Clark et al, 1996;Donnelly and Popovich, 2008;Utagawa et al, 2008), approximately half of the SR rats were perfused 24 h post-injury after the completion of elevated-plus maze testing. All other rats were perfused immediately after the completion of behavioral testing approximately 72 h or 30 days post-injury.…”

Post-Traumatic Hypoxia Exacerbates Brain Tissue Damage: Analysis of Axonal Injury and Glial Responses

“…In this study, we have shown that microglia have a resting morphology throughout the brain parenchyma at day 1 in TAI and TAI þ Hx animals, followed by a sharp increase in the numbers of activated amoeboid macrophages and microglia at day 7 post-injury, with a further increase at day 14 in TAI-alone animals. These observations were similar to those of previous studies done by ourselves and others on TAI as well as focal TBI (Bye et al, 2007;Csuka et al, 2000;Czigner et al, 2007;Kelley et al, 2007;Li et al, 2009;Semple et al, 2010;Urrea et al, 2007;Utagawa et al, 2008a). More importantly, we have shown that post-traumatic hypoxia results in exacerbated microglial activation and macrophage infiltration in the corpus callosum at both 7 and 14 days, which corresponded with the regional distribution of retraction bulbs and swollen axons.…”

CD11d integrin blockade reduces the systemic inflammatory response syndrome after traumatic brain injury in rats

“…In a study performed independently by in a different institution (Utagawa et al, 2008) the antiCD11d treatment reduced the density of macrophages and the contusion volume at a fluid percussion brain injury site in rats. More recently, in a model of three repeated mild lateral fluid percussion injuries, each separated by a 5-day interval, we have shown that intravenous antiCD11d integrin treatment at 2 h and 24 h after each injury also reduced the neutrophil and macrophage presence in the injured brain with attendant decreases in lipid peroxidation, astrocyte activation, amyloid precursor protein accumulation, and neuronal loss (Shultz et al, 2013).…”