Systemic activation of caspase-1 dependent interleukins and matrix-metalloproteinases in developmental brain trauma
Final Report Abstract
Hypotheses: 1. Infant TBI leads to systemic activation of caspase-1 dependent interleukins and matrix metalloproteinases. This response can be modified by compounds affecting the cholinergic parasympathetic and the sympathetic adrenergic system. 2. Pharmacologic inhibition of the systemic inflammatory response will ameliorate extent of brain injury. Goals of the project: Goal 1: To examine the mechanisms which regulate systemic activation of caspase-1 dependent interleukins and matrix metalloproteinases in the periphery following traumatic brain injury with focus on the cholinergic parasympathetic system and the sympathetic adrenergic system. Goal 2: To examine the cell types which express caspase-1 dependent interleukins, MMP-2 and MMP- 9 in the periphery following infant traumatic brain injury. Goal 3: To determine whether pharmacological inhibition of the systemic inflammatory response following infant traumatic brain injury can affect the extent of brain injury. Results: 1. Infant TBI increases expression of IL-1ß, IL-18, MMP2 and MMP9 in the cortex, liver and lung in a time dependent manner. 2. Infant TBI increases expression of IL-1ß, IL-18, MMP2 and MMP9 in the cortex, liver and lung in a manner that is dependent upon severity of brain injury. 3. Atropine reduces expression of MMP2, MMP9, IL1β and IL18 in cortex, lung and liver tissue following infant TBI. Scopolamine and vagotomy failed to influence cytokine levels. 4. Atropine and right vagotomy did not influence severity of histological injury in the brain following trauma. 6. The above findings could be elicited in only 60% of the experiments, in 40% of the experiments no systemic inflammatory response could be observed following infant TBI. 5. The originally formulated hypotheses could not be confirmed. Surprises: 1. Bilateral vagotomy led to unacceptable mortality following TBI; 2. The pups did not tolerate drugs which lead to impairment of the noradrenergic system after TBI; 3. The results of the study were not consistently reproducible. This raises the possibility that genetic factors may determine whether a systemic inflammatory response occurs following TBI. Due to the low scientific impact of the results and the questions raised by the lack of consistent reproducibility of the findings, we elected to not publish these findings at this time.
