A drug called disulfiram (DSF), which is used to prevent alcohol abuse, may also help to interrupt the runaway cell death and inflammation that is triggered by severe trauma, according to the results of research by University of Pittsburgh School of Medicine surgeon-scientists. The team’s newly reported study, based on observations in human patients and tested in mice, in addition suggested that treatment may be particularly effective in females.
The findings suggest that inhibiting gasdermin D (GSDMD) may offer a strategy for limiting excessive inflammation and mortality in trauma, and could enable development of therapies that, if given in the first few hours after a severe trauma—such as a fall or vehicle accident—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,” said research lead Timothy Billiar, MD, George Vance Foster Professor and Chair of Pitt’s Department of Surgery. “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.”
Billiar is senior author of the team’s published paper in Science Translational Medicine, titled “Gasdermin D drives the systemic storm and mortality after trauma with hemorrhage to a greater degree in biological females than males,” in which the team wrote, “In conclusion, this study sheds new light on the intricacies of cellular molecular release following severe injury by illuminating the central role of GSDMD in this process.”
In previous research analyzing the interaction of different biological processes, Billiar and colleagues found that there is a fast and massive release of cellular contents in patients suffering from severe bleeding and trauma. “Our previous multiomic analyses of the human injury response revealed an early and massive release of cellular constituents into the circulation of patients with hemorrhagic shock and tissue trauma,” they wrote. 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. “Severe injury accompanied by hemorrhagic shock triggers an early release of cell constituents into the circulation, referred to as the systemic storm,” they continued. “The systemic storm drives the systemic inflammatory response and is associated with increased mortality.”
Their previous analyses had suggested that both passive and active processes are involved in this pattern of release. The broad release of cellular contents can occur through passive processes, such as necrosis, or through active lytic programmed cell death (PCD) mechanisms, including necroptosis, pyroptosis, PANoptosis, or ferroptosis, the authors noted. And while the extent of cell constituent release in addition correlates with both the magnitude of the injuries and patient outcomes, the team further pointed out, “Strategies to prevent the release of cellular constituents early in the management of patients undergoing trauma have remained largely unexplored and limited by a poor understanding of the processes involved in the release patterns.”
To further explore this counterintuitive response to severe injuries and build on their work in human trauma, Billiar and the team turned to a well characterized mouse model of hemorrhagic shock with tissue trauma (HS/T) to mimic the cell constituent release patterns see in humans. However, the researchers did something unusual, in that 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 programmed cell death. All of them partially reversed runaway cell death and inflammation following trauma, but the largest reversal involved blocking gasdermin D (GSDMD), a molecule that triggers pyroptosis cell death by opening up holes in cellular membranes, causing the cellular contents to spill out and encourage inflammation. Disulfiram, the drug the team used to inhibit gasdermin D, is already approved by FDA to treat alcohol use disorder.
The investigators also found that mice engineered to lack gasdermin D (Gsdmd-/- animals) also exhibited a lessened trauma response, further supporting the conclusion that blocking gasdermin D and inhibiting pyroptosis cell death was driving the improved outcomes. “We posit that the protective effects of GSDMD deletion or inhibition is the result of the inhibition of the release of cellular contents into the extracellular environment,” they pointed out. “GSDMD may serve as a central node in the systemic response to severe trauma with hemorrhagic shock, activating both inflammation and coagulation through its roles in pore formation.”
Interestingly, while inhibiting gasdermin D improved recovery and survival in both male and female mice, the benefit was much larger in female mice. “Both GSDMD deletion and the GSDMD inhibitor DSF improved hemodynamic stability and survival after HS/T in mice, effects that were also more pronounced in females,” the investigators stated. Billiar added, “The difference between males and females is striking. 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.”
Noting limitations of their study, the team concluded, “… this study sheds new light on the intricacies of cellular molecule release following severe injury by illuminating the central role of GSMDM in this process … Clarifying the molecular bases for the difference between males and females will require further research; however, both sexes benefited from DFS treatment supporting the further development of GSDMD as a therapeutic target in the resuscitation of female and male patients from severe injury with shock.”
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.
The post Alcohol Abuse Drug May Help Reduce Cell Death Induced by Trauma appeared first on GEN - Genetic Engineering and Biotechnology News.
The findings suggest that inhibiting gasdermin D (GSDMD) may offer a strategy for limiting excessive inflammation and mortality in trauma, and could enable development of therapies that, if given in the first few hours after a severe trauma—such as a fall or vehicle accident—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,” said research lead Timothy Billiar, MD, George Vance Foster Professor and Chair of Pitt’s Department of Surgery. “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.”
Billiar is senior author of the team’s published paper in Science Translational Medicine, titled “Gasdermin D drives the systemic storm and mortality after trauma with hemorrhage to a greater degree in biological females than males,” in which the team wrote, “In conclusion, this study sheds new light on the intricacies of cellular molecular release following severe injury by illuminating the central role of GSDMD in this process.”
In previous research analyzing the interaction of different biological processes, Billiar and colleagues found that there is a fast and massive release of cellular contents in patients suffering from severe bleeding and trauma. “Our previous multiomic analyses of the human injury response revealed an early and massive release of cellular constituents into the circulation of patients with hemorrhagic shock and tissue trauma,” they wrote. 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. “Severe injury accompanied by hemorrhagic shock triggers an early release of cell constituents into the circulation, referred to as the systemic storm,” they continued. “The systemic storm drives the systemic inflammatory response and is associated with increased mortality.”
Their previous analyses had suggested that both passive and active processes are involved in this pattern of release. The broad release of cellular contents can occur through passive processes, such as necrosis, or through active lytic programmed cell death (PCD) mechanisms, including necroptosis, pyroptosis, PANoptosis, or ferroptosis, the authors noted. And while the extent of cell constituent release in addition correlates with both the magnitude of the injuries and patient outcomes, the team further pointed out, “Strategies to prevent the release of cellular constituents early in the management of patients undergoing trauma have remained largely unexplored and limited by a poor understanding of the processes involved in the release patterns.”
To further explore this counterintuitive response to severe injuries and build on their work in human trauma, Billiar and the team turned to a well characterized mouse model of hemorrhagic shock with tissue trauma (HS/T) to mimic the cell constituent release patterns see in humans. However, the researchers did something unusual, in that 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 programmed cell death. All of them partially reversed runaway cell death and inflammation following trauma, but the largest reversal involved blocking gasdermin D (GSDMD), a molecule that triggers pyroptosis cell death by opening up holes in cellular membranes, causing the cellular contents to spill out and encourage inflammation. Disulfiram, the drug the team used to inhibit gasdermin D, is already approved by FDA to treat alcohol use disorder.
The investigators also found that mice engineered to lack gasdermin D (Gsdmd-/- animals) also exhibited a lessened trauma response, further supporting the conclusion that blocking gasdermin D and inhibiting pyroptosis cell death was driving the improved outcomes. “We posit that the protective effects of GSDMD deletion or inhibition is the result of the inhibition of the release of cellular contents into the extracellular environment,” they pointed out. “GSDMD may serve as a central node in the systemic response to severe trauma with hemorrhagic shock, activating both inflammation and coagulation through its roles in pore formation.”
Interestingly, while inhibiting gasdermin D improved recovery and survival in both male and female mice, the benefit was much larger in female mice. “Both GSDMD deletion and the GSDMD inhibitor DSF improved hemodynamic stability and survival after HS/T in mice, effects that were also more pronounced in females,” the investigators stated. Billiar added, “The difference between males and females is striking. 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.”
Noting limitations of their study, the team concluded, “… this study sheds new light on the intricacies of cellular molecule release following severe injury by illuminating the central role of GSMDM in this process … Clarifying the molecular bases for the difference between males and females will require further research; however, both sexes benefited from DFS treatment supporting the further development of GSDMD as a therapeutic target in the resuscitation of female and male patients from severe injury with shock.”
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.
The post Alcohol Abuse Drug May Help Reduce Cell Death Induced by Trauma appeared first on GEN - Genetic Engineering and Biotechnology News.