Systemic Administration of an Anti-CD18 Antibody Prevents the Accumulation of Peripheral Leukocytes in Pericontusional Tissue,but Does Not Improve Outcome after Traumatic Brain Injury in Mice

Abstract

The formation of brain edema is one of the key factors that determine patient outcomes following traumatic brain injury (TBI). Despite decades of research, no causal treatment is available to date. Among the many factors discussed, inflammation is believed to facilitate brain edema formation. Following brain trauma, leukocytes become activated, interact with the vascular endothelium, and transmigrate into pericontusional tissue. It was hypothesized that this process may affect the permeability of the blood–brain barrier and facilitate vasogenic brain edema formation. Thus, our study aimed to investigate the role of leukocyte adherence and migration in brain edema formation after experimental TBI by inhibiting the integrin CD18. Male C57BL/6 mice (n = 7/group) underwent controlled cortical impact (CCI) and were randomly assigned to one of three groups: (1) sham operation, (2) CCI + control IgG, or (3) CCI + anti-CD18 antibody. Treatment was administered 30 min before and 24 h after CCI. The anti-inflammatory effect of the anti-CD18 treatment was verified using in vivo two-photon microscopy and immunohistochemistry 48 h after CCI (n = 5/group). Lesion volume and brain edema formation were assessed by T2 and free-water diffusion magnetic resonance imaging longitudinally at 1, 2, 3, 5, and 7 days after the trauma or sham operation. Neurological function was determined daily using the Modified Neurological Severity Score. Vasogenic brain edema formation was detectable up to 7 days after trauma; no edema formation occurred in animals that underwent a sham operation. Anti-CD18 treatment reduced leukocyte–endothelium interaction and leukocyte migration into the brain after trauma to nearly control levels; however, it did not reduce lesion volume or brain edema formation. Preventing the adhesion of circulating leukocytes to cerebral vessels and their migration into the brain parenchyma does not reduce the formation of vasogenic brain edema and lesion volume after TBI in mice.