Grant: Project Grant

Sepsis (ie. blood poisoning) is triggered by harmful microorganisms or their toxins in the blood or tissues. These harmful agents can cause a vicious cycle of blood clot formation and inflammation, which may lead to multiple organ failure and death even after the microorganisms have been cleared with antibiotics. In Canada, there are approximately 90,000 patients with sepsis each year. Of these, 30% to 50% of these patients will die. Many anti-sepsis drugs have been tested in humans, but all of these clinical studies have failed. This suggests that some fundamental knowledge is lacking in our current understanding of why sepsis kills patients. In recent years, neutrophils (a type of white blood cells) have been shown to release web-like structures (called NETs) to capture and kill microorganisms. NETs consist of DNA, histones, and neutrophils enzymes. However, NETs can also cause collateral damage to the body. We have previously shown that the DNA and histone components of NETs can trigger blood clotting and prevent blood breakdown. We have also shown that high levels of DNA in the blood of septic patients is a strong predictor of death. In a mouse model of sepsis, injection of DNAse (an enzyme that breaks down DNA) results in improved organ function and improved survival rates. In the current proposal, we plan to further study how DNA and histones triggers blood clots and inflammation in sepsis. We will perform studies of blood cells and blood molecules in test tubes. By comparing blood samples from septic and non-septic ICU patients, we can identify the precise biological pathways that lead to high levels of DNA in septic patients. We will also perform studies in a mouse model of sepsis to see if removal of DNA and/or histones from the blood can improve survival in septic mice. Our research thus has the potential to identify new anti-sepsis strategies that will improve the lives of septic patients.