**3. Pathology of TBI**

A traumatic brain injury may be defined as an injury to brain tissue caused by direct external force [10]. The physical impact of TBI initiates a plethora of downstream processes with deleterious effects on neuronal and glial tissue. Overall, the pathophysiology of a TBI can be divided into primary and secondary phases of injury [5, 10–12]. The primary phase of injury includes the cellular damage caused at the instant of injury by the direct mechanical impact of trauma. Primary injury can manifest as cell death, hemorrhage, and/or diffuse axonal injury. First, neurons and supporting vasculature can be directly torn by the shear forces of injury. This damage to the neurovascular network results in intracranial hemorrhage, which can lead to increased intracranial pressure as blood builds up inside the skull. Intracranial bleeding can also generate hematomas. Both increased intracranial pressure and hematoma formation have negative impacts on neural recovery [11, 13]. Primary injury can also encompass diffuse axonal injury. Diffuse axonal injury is damage to neurons going beyond the initial lesion area, caused by dynamic forces spreading through the brain from the primary impact [11]. These physical forces resulting from traumatic brain injury can be either linear accelerational forces or rotational forces. Since neural tissue is elastic and does not have a strong internal structure, the brain has little tolerance for this disruption and is very susceptible to injury from these forces [12]. Primary injury also disturbs autoregulation of cerebral blood flow and cellular metabolism. Normal control mechanisms for blood flow and metabolism fail due to the cellular damage of TBI, resulting in cellular effects similar to those seen in ischemic stroke. As the massive damage overwhelms cellular metabolism, ATP production cannot match demand, and neuronal and glial supplies of ATP become inadequate to fuel cellular ion pumps. The resulting dysregulation of ion flow initiates various downstream pathways leading to necrosis, apoptosis, and oxidative damage [14]. Additional mechanisms of secondary injury have been described and

**17**

*Peripheral Immune Response Following Traumatic Brain Injury*

include the long-term changes resulting from the physiological processes triggered

Neuroinflammation plays a major role in the secondary phase of injury. While all resident brain cells are involved in some way in the response to TBI, the role of microglia, the resident immune cells of the brain, in neuroinflammation has been particularly well-studied. When brain injury occurs, cells damaged in the primary phase of injury release cell signals known as damage-associated molecular patterns (DAMPs). In the early stages of injury, resident microglial cells are activated by these DAMPs and migrate to the injury site [7, 15]. These cells have a profound effect

on both acute and chronic injury processes as they secrete both pro- and anti-

inflammatory cytokines and can remain activated for up to 18 years after TBI [7, 16]. Cytokines released by microglia have a plethora of effects including alteration of local blood flow and modification of the blood-brain barrier (BBB) [15]. Microglia also assist in walling off the injured area in a protective effort to prevent the spread of bleeding and cellular damage. However, these cells can also generate additional reactive oxygen species (ROS) with damaging effects on cells [17]. While glial cell activation is a key part of the secondary phase of TBI, there is also an important role for the peripheral immune system in TBI recovery. The central nervous system is typically viewed as an immune-privileged site, with few or no peripheral-derived immune cells present. However, following TBI, the blood-brain barrier is damaged, allowing infiltration of peripheral-derived circulating immune cells including neutrophils, macrophages, and lymphocytes [17]. Glutamate excitotoxicity, oxidative stress, and neuroinflammation all contribute to the cellular damage observed in the secondary phase of injury, and the long-term damage resulting from these processes can be extensive. This secondary phase of injury is the primary target for TBI therapeutics—while efforts can be made to reduce TBI incidence, once a TBI has occurred nothing can be done to treat primary injury. Therefore, potential TBI treatments are aimed at reducing damage from the secondary phase of injury [14].

Multiple rodent models have been used to study the role of inflammation in TBI. Due to the variety of injury causes and individual patient health effects, human TBI exhibits multifaceted disease processes, and different animal models are used to recapitulate different aspects of human injury. Here, we discuss three common mouse models of TBI: weight drop, fluid percussion injury (FPI), and controlled cortical impact (CCI). All three of these models generate TBI by direct impact, either applied directly to the brain through a craniectomy or applied to the intact skull. While each of these models replicate certain features of human TBI, no one

• Weight drop and fluid percussion injury are both used to produce diffuse injury in rodent models of TBI. Weight drop injury relies on gravity-driven fall of the weight to generate injury. Injury severity can be controlled by adjusting both the height of the drop and the mass of the weight used. Modification of injury severity allows this model to reproduce features of mild, moderate, or severe TBI. Weight drop injury results in cortical cell death, cerebral edema, neuroinflammation, and blood-brain barrier compromise, and this method of

*DOI: http://dx.doi.org/10.5772/intechopen.93597*

by the primary phase of injury [12].

**3.1 Neuroinflammation**

**4. Rodent models of TBI**

model fully expresses the varied picture of clinical TBI.

include the long-term changes resulting from the physiological processes triggered by the primary phase of injury [12].
