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Peripheral thermal injury causes blood-brain barrier dysfunction and matrix metalloproteinase (MMP) expression in rat
Kathryn Swann1, Jamie Berger, Shane M Sprague
1Plastic and Reconstructive Surgery, USA.
Abstract:
Mortality after serious systemic thermal injury may be linked to significant increases in cerebral vascular permeability and edema due to blood-brain barrier (BBB) breakdown. This BBB disruption is thought to be mediated by a family of proteolytic enzymes known as matrix metalloproteinases (MMPs). The gelatinases, MMP-2 and MMP-9, digest the endothelial basal lamina of the BBB, which is essential for maintaining BBB integrity. The current study investigated whether disruption of microvascular integrity in a rat thermal injury model is associated with gelatinase expression and activity. Seventy-two adult Sprague-Dawley rats were anesthetized and submerged horizontally, in the supine position, in 100 degrees C (37 degrees C for controls) water for 6 s producing a third-degree burn affecting 60-70% of the total body surface area. Brain edema was detected by calculating water content. Real time PCR, Western blot, and zymography were used to quantify MMP mRNA, protein, and enzyme activity levels. Each group was quantified at 3, 7, 24, and 72 h post thermal injury. Brain water content was significantly increased 7 through 72 h after burn. Expression of brain MMP-9 mRNA was significantly increased as early as 3 h after thermal injury compared to controls, remained at 7 h (p<0.01), and returned to control levels by 24 h. MMP-9 protein levels and enzyme activity began to increase at 7 h and reached significant levels between 7 and 24 h after thermal injury. While MMP-9 protein levels continued to increase significantly through 72 h, enzyme activity returned to control level. The increase in MMP-9 expression and activity, associated with increased BBB permeability following thermal injury, indicates that MMP-9 may contribute to observed cerebral edema in peripheral thermal injury.
Insights
Serious thermal injury increases brain edema by disrupting the blood-brain barrier (BBB). Matrix metalloproteinase-9 (MMP-9) expression and activity rise after burns, contributing to BBB breakdown and cerebral edema.
Area of Science:
- Neuroscience
- Physiology
- Biochemistry
Background:
- Systemic thermal injury can lead to mortality, potentially linked to blood-brain barrier (BBB) disruption and subsequent cerebral edema.
- Matrix metalloproteinases (MMPs), particularly gelatinases like MMP-9, are implicated in degrading the BBB's endothelial basal lamina, compromising its integrity.
Purpose of the Study:
- To investigate the association between microvascular integrity disruption and gelatinase expression/activity in a rat model of thermal injury.
- To quantify the temporal changes in MMP-9 mRNA, protein, and enzyme activity following severe burns.
Main Methods:
- Adult Sprague-Dawley rats underwent a standardized third-degree burn (60-70% total body surface area).
- Brain edema was assessed by measuring water content.
- Real-time PCR, Western blot, and zymography were employed to quantify MMP-9 at 3, 7, 24, and 72 hours post-injury.
Main Results:
- Burn injury significantly increased brain water content from 7 to 72 hours post-injury.
- MMP-9 mRNA expression elevated significantly as early as 3 hours post-burn, remaining elevated at 7 hours.
- MMP-9 protein levels and enzyme activity increased between 7 and 24 hours, with protein levels continuing to rise through 72 hours.
Conclusions:
- Elevated MMP-9 expression and activity correlate with increased BBB permeability after thermal injury.
- MMP-9 is a key contributor to the cerebral edema observed following peripheral thermal injury.
- These findings highlight MMP-9 as a potential therapeutic target for mitigating brain injury after severe burns.
