Abstract
Blast exposure is a worldwide public health concern, but most related research has been focused on direct injury. Thoracic blast exposure-induced neurotrauma is a type of indirect injuries where research is lacking. As CD28 stimulates T cell activation and survival and contributes to inflammation initiation, it may play a role in thoracic blast exposure-induced neurotrauma. However, it has not been investigated. To explore the effects of CD28 on thoracic blast exposure-induced brain injury and its potential molecular mechanisms, a mouse model of thoracic blast exposure-induced brain injury was established. Fifty C57BL/6 wild-type (WT) and fifty CD28 knockout (CD28−/−) mice were randomly divided into five groups (one control group and four model groups), with ten mice (from each of the two models) for each group. Lung and brain tissue and serum samples were collected at 12 h, 24 h, 48 h, and 1 week after thoracic blast exposure. Histopathological changes were detected by hematoxylin-eosin staining. The expressions of inflammatory-related factors were detected by ELISA. Oxidative stress in the brain tissue was evaluated by determining the generation of reactive oxygen species (ROS) and the expressions of thioredoxin (TRX), malondialdehyde (MDA), SOD-1, and SOD-2. Apoptosis in the brain tissue was evaluated by TUNEL staining and the levels of Bax, Bcl-xL, Bad, Cytochrome C, and caspase-3. In addition, proteins of related pathways were also studied by western blotting and immunofluorescence. We found that CD28 deficiency significantly reduced thoracic blast exposure-induced histopathological changes and decreased the levels of inflammatory-related factors, including IL-1β, TNF-α, and S100β. In the brain tissue, CD28 deficiency also significantly attenuated thoracic blast exposure-induced generation of ROS and expressions of MDA, TRX, SOD-1, and SOD-2; lowered the number of apoptotic cells and the expression of Bax, cleaved caspase-3, Cytochrome C, and Bad; and maintained Bcl-xL expression. Additionally, CD28 deficiency significantly ameliorated thoracic blast exposure-induced increases of p-PI3K and Keap1 and the decrease of Nrf2 expression in the brain. Our results indicate that CD28 deficiency has a protective effect on thoracic blast exposure-induced brain injury that might be associated with the PI3K/Nrf2/Keap1 signaling pathway.
Highlights
Blast exposure is a public health concern all over the world, because it has caused massive injuries to military personnel and civilians in recent wars and conflicts [1]
We examined CD28 knockout (CD28-/-) mice to study whether CD28 could be a therapeutic target in thoracic blast exposure-induced brain injury
Our findings show that Nuclear factor erythroid 2-related factor 2 (Nrf2) was initially upregulated and gradually downregulated and that Keap1 was upregulated in the brain via PI3K phosphorylation after thoracic blast exposure
Summary
Blast exposure is a public health concern all over the world, because it has caused massive injuries to military personnel and civilians in recent wars and conflicts [1]. Cernak et al found that blast waves can cause neuronal damage without direct injury to the head, and they hypothesized that blast waves could be transmitted into the brain through the major blood vessels of the chest, thereby leading to neurological effects that can be slow to appear [7]. One involves the kinetic energy of the blast wave transferred through the large blood vessels in the abdomen and chest to the central nervous system [8]. Cognitive and behavioral changes are caused by blast-induced neurotrauma, victims fail to exhibit the neuropathology expected to initially accompany a traumatic brain injury, which makes it difficult to detect the trauma [11]
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