Recent studies suggest that resuscitated hemorrhagic shock leads to an inappropriate or """"""""dysfunctional"""""""" increase in the expression of a portfolio of inflammatory mediators, including tumor necrosis factor (TNF), interleukin-1beta (IL-1b), interleukin-6 (IL-6) and nitric oxide (NO), which can in turn provoke a number of deleterious effects in the heart, most notably LV dysfunction. Inflammatory mediators are principal effector proteins of the """"""""innate immune system,"""""""" a phylogenetically conserved early warning system that enables the host to rapidly discriminate """"""""danger signals"""""""" (e.g. ROIs) in the environment. Studies from this and other laboratories have identified the presence of a family of innate immune receptors in the heart termed Toll-like receptors (TLRs). Importantly, these studies have shown that Toll-like receptor mediated signaling activates proinfiammatory mediators in the heart in response to a variety of different forms of environmental stress, including oxidative stress. Our preliminary studies in mice that are deficient in TLR-2 mediated signaling (TLR-2D) show that TLR-2 mice have less reperfusion induced expression of inflammatory mediators and are resistant to the deleterious effects of ischemia-reperfusion injury on LV function. Based upon the foregoing observations the immediate specific objective of this proposal will be to test the following hypotheses: (1) Signaling through Toll-like receptor 2 (TLR-2) amplifies reperfusion-induced expression of inflammatory mediators in the heart through a MyD88/TIRAP dependent pathway, and (2) TLR-2 mediated amplification of inflammatory mediators exaggerates the LV dysfunction that supervenes following resuscitated hemorrhagic shock. These hypotheses will be tested using mutually complementary murine model systems of low-flow ischemia reperfusion (LF-I/R) ex vivo and resuscitated hemorrhagic shock (R-H/S) in vivo.
Four Aims are envisioned.
In Specific Aim 1 we will test the hypothesis that signaling through TLR-2 amplifies the expression of inflammatory mediators in the heart following LFI/ R injury through a MyD88/TIRAP dependent signaling pathway.
Specific Aim 2 will test the hypothesis that TLR-2 mediated signaling exaggerates the left ventricular (LV) dysfunction that occurs following low-flow ischemia/reperfusion LF-I/R through increased expression of inflammatory mediators.
In Specific Aim 3, we will test the hypothesis that signaling through TLR-2 amplifies the expression of inflammatory mediators in the heart following resuscitated hemorrhagic shock (R-HS) through a MyD88/TIRAP dependent signaling pathway.
Specific Aim 4 will test the hypothesis that TLR-2 mediated signaling exaggerates the left ventricular (LV) dysfunction that occurs following R-HS through increased expression of inflammatory mediators. Taken together, Specific Aims 1-4 should provide definitive new information regarding the mechanisms of activation, as well as the role of the innate immune system in resuscitated hemorrhagic shock.
Showing the most recent 10 out of 19 publications
