Discovery in the lab of YouYang Zhao, PhD, from Stanley Manne Children’s Research Institute at Ann & Robert H. Lurie Children’s Hospital of Chicago, opens promising new directions for treatment of life-threatening lung injury caused by sepsis.
Sepsis, or infection causing uncontrolled inflammatory response and organ dysfunction, often results in acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Patients with sepsis-caused lung injury also commonly suffer from severe thrombosis, or blood clotting, but clinical trials of anticoagulant therapies in sepsis and ARDS patients have failed. Despite improvements in supportive care, including mechanical ventilation and antibiotic therapy, there is currently no effective treatment for sepsis and ARDS, and mortality rates for patients with ARDS are still as high as 40 percent.
Exciting potential for treatment comes from Dr. Zhao’s research that offers new insights into the mechanisms of disease development, uncovering the central role of the gene called ALOX15 within the endothelium (the inner lining of blood vessels). This gene encodes an enzyme that produces lipids, and one of these lipids was found to protect the blood vessels in the lung from sepsis-induced damage, keeping the lung safe from injury.
First, Dr. Zhao discovered that although severe lung thrombosis during sepsis is highly detrimental, mild lung thrombosis surprisingly reduced the severity of lung injury in mouse models. He then found that the favorable effects elicited by mild lung thrombosis are mediated by ALOX15 via a protective lipid.
“We provide unequivocal evidence that mild lung thrombosis unexpectedly inhibits sepsis-induced lung injury. 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,” said Dr. Zhao, senior author on the publication of these findings in the journal Circulation Research.
“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,” added Dr. Zhao. “Treatments via enhancement of ALOX15 gene expression or via ALOX15-dependent protective lipids could potentially be effective.”
Dr. Zhao explained that ALOX15 expression could be augmented through endothelium-targeted nanoparticle gene delivery system – a technology he developed and patented. The lipid-based treatment option could be developed as an oral medication.
Next, Dr. Zhao plans to test the safety and effectiveness of these treatment strategies in mouse models. If the treatments work well, clinical trials could start within two to three years, he said.
At Manne Research Institute, Dr. Zhao is the Director of the Genetic Medicine and Nanotechnology Development Center, as well as Head of the Section for Injury Repair and Regeneration Research. He holds the William G Swartchild, Jr. Distinguished Research Professorship at Lurie Children’s. He also is Professor of Pediatrics (Critical Care), Medicine (Pulmonary and Critical Care) and Pharmacology at Northwestern University Feinberg School of Medicine.
Ann & Robert H. Lurie Children’s Hospital of Chicago is a nonprofit organization committed to providing access to exceptional care for every child. It is the only independent, research-driven children’s hospital in Illinois and one of less than 35 nationally. This is where the top doctors go to train, practice pediatric medicine, teach, advocate, research and stay up to date on the latest treatments. Exclusively focused on children, all Lurie Children’s resources are devoted to serving their needs. Research at Lurie Children’s is conducted through Stanley Manne Children’s Research Institute, which is focused on improving child health, transforming pediatric medicine and ensuring healthier futures through the relentless pursuit of knowledge. Lurie Children’s is the pediatric training ground for Northwestern University Feinberg School of Medicine. It is ranked as one of the nation’s top children’s hospitals by U.S. News & World Report.
Journal
Circulation Research