Ohio State Researchers Launch NIH-Funded Study on Ozone-Induced Pulmonary Inflammation
With no effective pharmacologic treatments currently available for patients suffering from acute respiratory distress syndrome (ARDS) and sepsis, new research by Anasuya Sarkar, PhD, assistant professor of Internal Medicine in The Ohio State University College of Medicine’s Division of Pulmonary, Critical Care and Sleep Medicine, may be a game changer.
The loss of lung endothelial barrier function and endothelial cell (EC) death is a primary pathogenic feature of ARDS. Yet as Dr. Sarkar explains, “Although these fundamental immune cell processes may be at the core of ARDS-mediated vascular injury and dysfunction, the actual mechanism of endothelial cell death regulated by immune cells remains largely unknown. That makes it crucial to understand the precise mechanisms that link immune cell function to vascular dysfunction.
“This knowledge can then support development of a therapy that can prevent uncontrolled inflammation and be used to treat patients with ARDS and other inflammatory diseases.”
Dr. Sarkar’s research is funded by an R01 from the National Institutes of Health and builds upon extensive prior data, including earlier by her team: Microparticulate Caspase-1 Regulates Gasdermin-D and Pulmonary Vascular Endothelial Cell Injury and Circulating Gasdermin-D in Critically Ill Patients. The overarching hypothesis of this current research is that lung endothelial injury during ARDS is linked to the pyroptotic function of monocyte-/macrophage-derived gasdermin D encapsulated in circulating extracellular vesicles (EV GSDMD) in association with the purinergic receptor P2X7.
To determine the specifics of this novel pathway, Dr. Sarkar’s research team will pursue three distinct research aims. First, they plan to delineate the role of monocyte-derived GSDMD in mediating endothelial pyroptosis, or inflammatory cell death, in acute lung injury and ARDS. To accomplish this, they’ll use a murine model, as well as ARDS patient samples to study the role of monocyte-/macrophage-derived GSDMD on pulmonary endothelial damage and dysfunction.
“At Ohio State, I’m able to work with our clinicians to access high-quality, clinically annotated normal and diseased human biospecimens to evaluate our bench-side findings and correlate in a clinically relevant disease setting,” she says. “That’s a tremendous advantage when the ultimate goal of my research program is to develop therapeutics that effectively target a specific disease in actual patients. It definitely enhances the precision of our research.”
Dr. Sarkar’s second aim is to determine how to best regulate the cytopathic function of EV GSDMD. “Inflammation occurs when there is lung injury. The key is figuring out how to prevent an uncontrolled inflammatory response,” says Dr. Sarkar. During this phase of research, her team will study how post-translational modifications of GSDMD regulate its cytopathic behavior and vulnerability to ubiquitin-mediated degradation.
Third, Dr. Sarkar’s lab will work to delineate the role of purinergic receptors in the mechanism of EV GSDMD-mediated endothelial cell death. “Studying these mechanisms will allow us to target the specific cells affected when P2X7 is involved,” she explains.
“If we can be the first to clarify the central role of GSDMD and purinergic receptors in lung cell injury and uncontrolled inflammation, that’s a critical step forward, and it gets us that much closer to finding an effective therapy. It’s exactly why I’ve always wanted to be a translational scientist – to transition findings from bench to bedside – and I’m very optimistic that this research will allow us to do this.”
Learn more about innovations in care and research from the Division of Pulmonary, Critical Care and Sleep Medicine.
