Vascular and inflammatory factors in the pathophysiology of blast-induced brain injury

Abstract

Blast-related traumatic brain injury (TBI) has received much recent attention because of its frequency in the conflicts in Iraq and Afghanistan. This renewed interest has led to a rapid expansion of clinical and animal studies related to blast. In humans, high-level blast exposure is associated with a prominent hemorrhagic component. In animal models, blast exerts a variety of effects on the nervous system including vascular and inflammatory effects that can be seen with even low-level blast exposures which produce minimal or no neuronal pathology. Acutely, blast exposure in animals causes prominent vasospasm and decreased cerebral blood flow along with blood-brain barrier breakdown and increased vascular permeability. Besides direct effects on the central nervous system, evidence supports a role for a thoracically mediated effect of blast; whereby, pressure waves transmitted through the systemic circulation damage the brain. Chronically, a vascular pathology has been observed that is associated with alterations of the vascular extracellular matrix. Sustained microglial and astroglial reactions occur after blast exposure. Markers of a central and peripheral inflammatory response are found for sustained periods after blast injury and include elevation of inflammatory cytokines and other inflammatory mediators. At low levels of blast exposure, a microvascular pathology has been observed in the presence of an otherwise normal brain parenchyma, suggesting that the vasculature may be selectively vulnerable to blast injury. Chronic immune activation in brain following vascular injury may lead to neurobehavioral changes in the absence of direct neuronal pathology. Strategies aimed at preventing or reversing vascular damage or modulating the immune response may improve the chronic neuropsychiatric symptoms associated with blast-related TBI.

Keywords: animal models; blast; inflammation; traumatic brain injury; vascular pathology.

Figure 1

Altered collagen IV immunostaining in the microvasculature of blast-exposed rats. Shown are sections from a rat sacrificed 10 months after receiving three 74.5 kPa blast exposures delivered on consecutive days. (A) shows a coronal section stained with hematoxylin and eosin. (B,C) show adjacent sections immunostained with collagen IV without (B) or with pepsin (C) treatment. Immunostaining was performed as described in Gama Sosa et al. (57). Pepsin treatment (C) unmasks widespread collagen IV immunostaining. Arrow in (B) indicates a region that shows collagen IV immunostaining without pepsin pretreatment. Scale bar: 1 mm.

Figure 2

Altered collagen IV immunostaining around blast-induced shear-related lesion. Shown are sections from a rat sacrificed 10 months after receiving three 74.5 kPa blast exposures (A–B) or a non-blast exposed control (C–D). Sections were immunostained for collagen IV without pepsin pretreatment (A,C) and counterstained with 4’,6-diamidino-2-phenylindole (DAPI) (B,D) as described in Gama Sosa et al. (57). A focal blast-induced lesion (indicted by asterisks) is apparent in (A,B). Note the vascular staining with collagen IV in the blast-exposed animal despite the lack of pepsin treatment (A) in comparison to the unstained control (C). Scale bar: 250 μm.

Figure 3

Chronic microvascular pathology following blast exposure. In (A) a section of the hippocampal dentate gyrus is shown from a rat sacrificed 6 months after receiving three 74.5 kPa blast exposures. Sections were immunostained for collagen IV without pepsin pretreatment and counterstained with DAPI as in Figure 2. Note the prominent vascular staining despite the lack of pepsin treatment. Arrows indicate strictures in the vessels. In (B) an electron micrograph is shown taken from the frontal cortex of a rat that received three 74.5 kPa blast exposures and was sacrificed 6 months after the last exposure. Note the amorphous material in the lumen creating a near complete occlusion (asterisk). The vessel also becomes narrowed (arrow). The brain parenchyma surrounding the vessel appears normal. Electron microscopy was performed as described in Gama Sosa et al. (57). Scale bar: 25 μm (A); 2 μm (B).

Figure 4

Potential mechanisms relating blast-induced vascular injury to neuroinflammation and neurobehavioral dysfunction. Mechanical injury to blood vessels induces local production of inflammatory mediators including cytokines, chemokines, and cell adhesion molecules through largely cell-mediated mechanisms. Mechanical injury also induces oxidative stress which can be associated with induction of an inflammatory response. Changes in BBB permeability could support initiation of an inflammatory reaction acutely and help sustain a response chronically. Blast-induced damage to the choroid plexus may alter blood-CSF barrier function which has been linked to induction of an inflammatory response. Impaired BBB function and bidirectional signaling between CNS and systemic inflammatory responses could amplify both reactions. Chronic immune activation could lead to neurobehavioral changes in the absence of direct neuronal pathology. Vascular pathology could also disrupt recently described glymphatic pathways that move CSF through the brain parenchyma.