Alcohol abuse drug may mitigate trauma-induced damage, especially in females

Runaway cell death and inflammation triggered by severe trauma may be interrupted by a drug used to prevent alcohol abuse – and it may be particularly effective in females, according to new research led by University of Pittsburgh School of Medicine surgeon-scientists and published today in Science Translational Medicine.

The findings, based on observations in human patients and tested in mice, may lead to therapies that, if given in the first few hours after severe trauma – such as a falls or vehicle accidents – could short-circuit further tissue damage, significantly improving survival and shortening hospital stays.

We have dozens of drugs for autoimmune diseases, hundreds for cancer – but there's almost nothing for trauma, the leading cause of death in young people. Our research is leading to a precision medicine, biomarker-based approach to trauma that could result in less organ damage, meaning that patients could get out of the intensive care unit earlier, get into rehabilitation faster and return to their lives."

Timothy Billiar, M.D., Senior Author, George Vance Foster Professor and Chair of Pitt's Department of Surgery

In previous research analyzing the interaction of different biological processes, Billiar and his research colleagues found that there is a fast and massive release of cellular contents in patients suffering from severe bleeding and trauma. That is then followed by inflammation as the body sends immune cells not only to the site of the injury but also to uninjured organs and tissues. While this process can be helpful when localized in minor injuries or infections, in severe traumas it can lead to further damage, such as organ failure and brain swelling.

To further explore this counterintuitive response to severe injuries, Billiar and the team turned to mice. However, the researchers did something unusual: They included female mice in their experiments. Historically, male mice have been favored over female mice in medical research because of concerns that hormonal fluctuations could throw off results.

"If we want to know whether a discovery made in humans has a therapeutic angle, we need to revert that back, in a focused way, to an animal model," said Billiar, who is also chief scientific officer at UPMC. "And we know that women and men respond differently to trauma. So, to understand the human response, our animal model needed to include both males and females."

The mice were treated with four different drugs, each of which inhibited one of the four different types of cell death. All of them partially reversed runaway cell death and inflammation following trauma, but the largest reversal involved blocking gasdermin D, a molecule that triggers pyroptosis cell death by opening up holes in cellular membranes, causing the cellular contents to spill out and encourage inflammation.

The drug that blocked gasdermin D is disulfiram, a medication approved by the U.S. Food and Drug Administration to treat alcohol use disorder.

The team also looked at mice that do not produce the gasdermin D molecule and found that they, too, have a lessened trauma response, further supporting the conclusion that blocking gasdermin D and inhibiting pyroptosis cell death is driving the improved outcomes.

Interestingly, while inhibiting gasdermin D improved recovery and survival in both male and female mice, the benefit was much larger in female mice.

"The difference between males and females is striking," Billiar said. "This could mean that, in a precision medicine approach to trauma, we give gasdermin D inhibitors to women and a different drug or combination of drugs to men."

Next steps will likely involve large animal trials, potentially followed by human clinical trials, to further refine who will most benefit from such treatments. Concurrently, next generation medications could be developed to more selectively target gasdermin D and minimize potential side effects, Billiar said.

Additional authors on this research are Xuejing Sun, M.D., Ph.D., of Pitt and Central South University in China; Sultan S. Abdelhamid, M.D., Zachary Secunda, Robert Voinchet, J.D., Alyssa Gregory, Ph.D., Jacob Scioscia, Mehves Ozel, M.D., Jennifer L. Darby, M.D., Hamed Moheimani, M.D., Qing-De Wang, M.D., Ph.D., Jishnu Das, Ph.D., Matthew D. Neal, M.D., Upendra K. Kar, Ph.D., and Jason L. Sperry, M.D., all of Pitt.

This research was supported by National Institutes of Health grant R35-GM-127027 and R01HL166944.