Scientists at Northwell Health’s Feinstein Institutes for Medical Research in New York have uncovered a critical mechanism driving acute lung injury (ALI) in sepsis, identifying a novel subset of neutrophils. The team also developed a peptide inhibitor that significantly improves survival in preclinical models of ALI.
The discovery reveals how rogue immune cells fuel deadly ALI in sepsis and paves the way for life-saving treatment. Study findings are detailed in the paper, “DLL4+ Neutrophils Promote NOTCH1-Mediated Endothelial PANoptosis To Exacerbate Acute Lung Injury in Sepsis,” published in the Journal of Clinical Investigation.
According to a press release, a specific subtype of white blood cells, called delta-like ligand 4 (DLL4+) neutrophils, are generated in response to extracellular cold-inducible RNA-binding protein (eCIRP) — a damage-associated molecular pattern prevalent in sepsis. Researchers found significantly elevated levels of DLL4+ neutrophils in the blood and lungs of septic mice and human samples. They also observed that the DLL4+ neutrophils interact directly with pulmonary vascular endothelial cells, triggering PANoptosis — a highly inflammatory form of programmed cell death.
“Sepsis-induced acute lung injury remains a major cause of mortality, and understanding its underlying mechanisms is key to finding new treatment options,” said co-author Ping Wang, MD, professor and chief scientific officer at the Feinstein Institutes. “Our discovery of DLL4+ neutrophils and their direct role in driving PANoptosis in lung endothelial cells allows us to better understand how exactly inflammation devastates organs in sepsis.”
In the study, scientists performed detailed experiments, including transferring DLL4+ neutrophils into septic mice, which confirmed the specific immune cells’ direct role in causing severe lung damage. This destructive process occurs at the point that a protein on the neutrophil (DLL4) directly binds to a receptor on the lung’s endothelial cells, known as Notch1. This was the key trigger for the development of PANoptosis in the lungs.
The research team went on to design a new therapy using a small peptide called the Notch1-DLL4 Inhibitor (NDI) to specially block this harmful molecular connection between the immune cells and lung cells.
In laboratory tests using animal models with sepsis, researchers found the NDI to be highly effective. It successfully stopped the destructive PANoptosis in the lung lining, thereby reducing inflammation throughout the body, alleviating acute lung injury and dramatically improving survival in septic mice.
“Despite exhaustive efforts, specific therapies for sepsis have eluded investigators for decades,” said Kevin J. Tracey, MD, president and CEO of the Feinstein Institutes and Karches Family Distinguished Chair in Medical Research. “The new findings from Dr. Wang and his colleagues suggest a new therapeutic pathway to prevent organ damage during sepsis, laying the foundation for possible future clinical studies.”
