Effect of Traumatic Brain Injury in Mice Deficient in Intercellular Adhesion Molecule–1: Assessment of Histopathologic and Functional Outcome

Abstract

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule of the immunoglobulin family expressed on endothelial cells that is upregulated in brain as part of the acute inflammatory response to traumatic brain injury (TBI). ICAM-1 mediates neurologic injury in experimental meningitis and stroke; however, its role in the pathogenesis of TBI is unknown. We hypothesized that mutant mice deficient in ICAM-1 (-/-) would have decreased neutrophil accumulation, diminished histologic injury, and improved functional neurologic outcome versus ICAM-1 +/+ wild type control mice after TBI. Anesthetized ICAM-1 -/- mice and wild-type controls were subjected to controlled cortical impact (CCI, 6 m/sec, 1.2 mm depth). Neutrophils in brain parenchyma and ICAM-1 on vascular endothelium were assessed by immunohistochemistry in cryostat brain sections from the center of the contusion 24 h after TBI (n = 4/group). Separate groups of wild-type and ICAM-1-deficient mice (n = 9-10/group) underwent motor (wire grip test, days 1-5) and cognitive (Morris water maze [MWM], days 14-20) testing. Lesion volume was determined by image analysis 21 days following TBI. Robust expression of ICAM-1 was readily detected in choroid plexus and cerebral endothelium at 24 h in ICAM-1 +/+ mice but not in ICAM-1 -/- mice. No differences between groups were observed in brain neutrophil accumulation (9.4 +/- 2.2 versus 11.1 +/- 3.0 per x100 field, -/- versus +/+), wire grip score, MWM latency, or lesion volume (7.24 +/- 0.63 versus 7.21 +/- 0.45 mm3, -/- versus +/+). These studies fail to support a role for ICAM-1 in the pathogenesis of TBI.

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

“…It has previously been shown that treatment with a mAb to CD11d decreases macrophage and neutrophil infiltration into the damaged spinal cord (Mabon et al, 2000;Saville et al, 2004). It has also been demonstrated that endothelial ICAM-1 is expressed on the endothelial surface when exposed to various cytokines and mediates PMNL and endothelial adhesion (Whalen et al, 1999). In addition, the adhesion molecule, E-selectin, is also rapidly expressed on endothelial cells and neutrophils .…”

“…Several laboratories have also used transgenic mice that are genetically engineered to overexpress or knockout various genes of interest in the inflammatory cascade (Tehranian et al, 2002;Whalen et al, 1999). For example, Whalen and colleagues (1999) tested mutant mice deficient in ICAM-1 to assess the importance of neutrophil accumulation on the pathogenesis of TBI.…”

“…Thus, treatments that block the upregulation of these adhesion molecules and reduce inflammatory processes have been shown in some studies to improve outcome in models of brain trauma (Chatizipantelli et al, 2002;Otto et al, 2002;Shohami et al, 1996). After brain injury, leukocyte and monocyte infiltration requires tethering on the surface of endothelial cells (Bevilacqua, 1993;Whalen et al, 1999) followed by the interaction of endothelial cell-adhesion molecules with integrins on the PMNL or monocyte surface (Clark et al, 1996;Mabon et al, 2000;Neish et al, 1995;Shanley et al, 1998) facilitating leukocyte extravasation through the BBB. To prevent this interaction, previous studies in spinal cord injury (SCI) have utilized a monoclonal antibody (mAb) to the CD11d subunit of the CD11d/ CD18 integrin Van der Vieren et al, 1999) to improve outcome.…”

Plasma Interleukin-8 as a Potential Predictor of Mortality in Adult Patients with Severe Traumatic Brain Injury

“…Inflammatory stress response to TBI includes activation of complement (Kaczorowski et al 1995) and up-regulation of adhesion molecules on the endothelium of cerebral blood vessels (Whalen et al 1999), associated with the accumulation of neutrophils and production of cytokines (Yamasaki et al 1997). Interleukin-8 (IL-8) is considered to be one of the pivotal cytokines in the pathophysiology of TBI.…”

Concussive Injury before or after Controlled Cortical Impact Exacerbates Histopathology and Functional Outcome in a Mixed Traumatic Brain Injury Model in Mice

“…3 Controlled cortical impact (CCI) has been widely used to model cerebral contusion in mice. [4][5][6][7][8] Because the head is held fixed in a stereotaxic frame, CCI does not impart acceleration/deceleration forces characteristic of concussive TBI, which is characterized by linear or angular acceleration of the head. [9][10][11] We recently published a closed head injury (CHI) model of concussive TBI in mice in which the head freely rotates in the anterior-posterior plane.…”