As a full-time investigator in the Division of Critical Care Medicine, I’m committed to advancing basic science research to clinical application in healthcare. Since joining Cincinnati Children’s more than 25 years ago, my laboratory — which is funded by the National Institutes of Health (NIH) and other federal agencies — has focused on delineating the pathophysiological mechanisms of organ injury in sepsis and trauma. Our research programs span from basic science investigation in pre-clinical models of sepsis and trauma to translational science investigation in clinical studies of pediatric patients with sepsis.
During medical school, in addition to completing mandatory clinical clerkships, I enrolled in a two-year research internship at the University of Messina Institute of Pharmacology in Italy. That’s where I learned about research methods in cardiovascular physiology. After starting my residency in medical toxicology, also at the University of Messina, I realized how many unsolved medical problems impact the care of critically ill patients. As a physician, I felt a sense of obligation to further pursue research efforts in this field. This experience motivated me to enroll in a PhD program in experimental medicine, so I could launch my career as a clinician-scientist.
With my PhD program's support, I came to Cincinnati Children’s in 1995 to expand my research in molecular mechanisms of organ failure. My expertise with in vivo pre-clinical models of critical illnesses became an important asset to the trauma and sepsis research program within the Division of Critical Care Medicine. After completing my PhD in 1997, I was recruited as a faculty member and became a full-time basic science investigator.
Today, my research focuses on mechanisms of dysmetabolism and systemic inflammation that lead to multiple organ dysfunction syndrome (MODS) in patients with sepsis, major trauma or hemorrhagic shock. MODS develops in association with serious illness or injury and is the leading cause of morbidity and mortality in the intensive care unit.
Although MODS treatment relies on fluid resuscitation, supportive care and sometimes antibacterial or antiviral agents, there are limited effective therapies to reduce inflammation and promote healing of the failing organs. Furthermore, the outcomes of critically ill patients, especially in the adult population, are significantly impacted by age and male gender — which are also risk factors for higher mortality.
The molecular mechanisms that link age and gender to recovery are unknown, and modern medicine has mostly ignored them as different therapeutic targets. To that end, our laboratory investigates the cellular events that promote organ recovery in critical illnesses. We also seek to understand the biological variables of age and sex to design personalized treatments tailored to each patient.
To date, we’ve identified anti-inflammatory transcription pathways regulated by the nuclear hormone receptors called peroxisome proliferator activated receptors. These are major regulators of glucose and lipid metabolism and can counteract inflammatory and innate immune responses. We discovered that during sepsis, trauma and hemorrhagic shock, these important receptors are markedly downregulated in several tissues and immuno-competent cells. This down-regulation is also exacerbated by the aging process and correlates with the severity of inflammatory response and organ injury.
In deciphering these receptors' upstream regulatory mechanisms, my laboratory is also investigating the age-related dysfunction of the AMP-activated protein kinase (AMPK), a crucial regulator of energy production in the cell. This kinase controls the production and function of mitochondria.
One of our major discoveries is that despite different etiologies (i.e., sepsis, trauma or hemorrhagic shock), infectious or sterile inflammatory responses are characterized by similar alterations of mechanisms of mitochondrial quality control. We are also testing the hypothesis that utilizing pharmacological tools to improve mitochondrial function subsequently improves metabolic recovery of injured organs. In moving toward clinical application, these basic science discoveries have served as the scientific rationale for a prospective randomized phase I clinical trial to study the safety of treatment with pioglitazone — an FDA-approved PPARγ ligand — in pediatric patients with sepsis.
Outside of my research activities, I have a special commitment to medical education. I enjoy teaching medical students, residents and critical care fellows. Trainees rotating through my lab participate in hands-on bench research and learn about cutting-edge research technologies related to the pathophysiological mechanisms of organ injury.
I have received numerous awards and honors from the Shock Society and the Society of Critical Care Medicine for distinguished service and scientific contributions. I also received the Alumni Award for International Excellency from the University of Messina in 2019.
Over the years, I have served as a member or chair in grant review panels at the National Institutes of Health (NIH), in study sections related to the critical care field. These include the sections of Surgery, Anesthesiology and Trauma, Technology and Surgical Sciences, and Bioengineering. I also serve as reviewer with the Defense Medical Research & Development Program for the Department of Defense.
In 2012, I served a one-year term as president of the Shock Society, a nonprofit organization comprised of physicians and scientists that promotes research into the basic biology of trauma, shock and sepsis. I’m currently the General Secretary for the International Federation of Shock Societies (2016-2022). This federation includes the United States Shock Society, as well as shock societies located in Europe, China, Japan, Indonesia, Brazil and Russia. I’m honored to have this opportunity to advocate for educational programs and encourage research in the field of critical care.
MD: School of Medicine, University of Messina, Italy, 1990.
PhD: Experimental Medicine, School of Medicine, University of Messina, Italy, 1997.
Residency: Medical Toxicology, School of Medicine, University of Messina, Italy, 1990-1992.
Certification: General Medicine (Italian), 1990.
Signal transduction mechanisms regulating the inflammatory response in sepsis, hemorrhage, ischemia and reperfusion injury; inflammatory bowel disease with focus on the role of the nuclear enzyme poly (ADP-ribose) polymerase and the nuclear peroxisome proliferator activated receptors; development of novel therapeutic approaches for the treatment of sepsis and trauma
Circulating extracellular vesicles are associated with the clinical outcomes of sepsis. Frontiers in Immunology. 2023; 14:1150564.
Expert consensus on the monitoring and treatment of sepsis-induced immunosuppression. Military Medical Research. 2022; 9:74.
Colivelin, a synthetic derivative of humanin, ameliorates endothelial injury and glycocalyx shedding after sepsis in mice. Frontiers in Immunology. 2022; 13:984298.
Candidate Biomarkers for Sepsis-Associated Acute Kidney Injury Mechanistic Studies. Shock. 2022; 57:687-693.
Deficiency of AMPKα1 Exacerbates Intestinal Injury and Remote Acute Lung Injury in Mesenteric Ischemia and Reperfusion in Mice. International Journal of Molecular Sciences. 2021; 22:9911.
Administration of GDF3 Into Septic Mice Improves Survival via Enhancing LXRα-Mediated Macrophage Phagocytosis. Frontiers in Immunology. 2021; 12:647070.
First Do No Harm: A Proposal of an Expert-Guided Framework of Surrogate Humane Endpoints in Preclinical Models of Acute Lung Injury. Critical Care Medicine. 2021; 49:373-375.
AC6 regulates the microtubule-depolymerizing kinesin KIF19A to control ciliary length in mammals. The Journal of biological chemistry. 2020; 295:14250-14259.