A discovery in the lab of Youyang Zhao, PhD, offers a potential new therapeutic approach to life-threatening lung injury caused by sepsis. The study, “Unexpected Protective Role of Thrombosis in Lung Injury via Endothelial Alox15,” was published in Circulation Research.
People who have sepsis — an infection that causes rampant inflammatory response and organ disfunction — can frequently develop acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). They can also suffer from severe thrombosis or blood clotting.
Youyang Zhao, PhDStanley Manne Children’s Research Institute
Dr. Zhao and his team of researchers from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago have pinpointed a gene called ALOX15 that plays a central role in the mechanisms of disease development.
ALOX15, which is located within the endothelium (inner lining of blood vessels), ciphers a lipid-producing enzyme that helps protect the lungs from injury, especially one caused by sepsis.
According to the researchers, severe lung thrombosis is highly detrimental during sepsis. However, they found that ALOX15, via the protective lipid, reduced the severity of lung injury in mouse models with mild lung thrombosis.
“We provide unequivocal evidence that mild lung thrombosis unexpectedly inhibits sepsis-induced lung injury,” Dr. Zhao said in a news release. “This is a paradigm shift, since we know clinically and from our experiments that either too much blood clotting or not enough increases lung damage from sepsis. The key turned out to be the extent of ALOX15 gene expression.”
Dr. Zhao developed and patented an endothelium-targeted nanoparticle gene delivery system — a technology to augment ALOX15. He said he plans to validate the safety and efficacy of the new therapeutic approach in mouse models and hopefully begin clinical trials in two to three years.
“Our discoveries point to novel therapeutic strategies for lung injury caused by sepsis, especially for patients who have too much blood clotting or not enough,” Dr. Zhao said. “Treatments via enhancement of ALOX15 gene expression or via ALOX15-dependent protective lipids could potentially be effective.”
Dr. Zhao is director of the Genetic Medicine and Nanotechnology Development Center at Manne Research Institute and head of the section for injury repair and regeneration research. He holds the William G. Swartchild Jr. Distinguished Research Professorship at Lurie Children’s Hospital and is professor of pediatrics (critical care), medicine (pulmonary and critical care) and pharmacology at Northwestern University Feinberg School of Medicine.
