Neutrophils, probably the most abundant sort of white blood cell, are the body’s first line of defense against infection. Foreign pathogens can stress the body and activate neutrophils. When activated, neutrophils employ various weapons to guard the body. But when overactivated, these weapons can damage the body’s own tissues. Lung tissue is saturated with blood vessels, making them very liable to neutrophil attacks. If severe enough, acute lung injuries can result in acute respiratory distress syndrome (ARDS), the leading reason for death as a consequence of COVID-19.
Nicholas Tonks, Caryl Boies professor of cancer research at Cold Spring Harbor Laboratory (CSHL), and his team have found a drug candidate that may prevent lethal lung inflammation in mice by inhibiting a protein called PTP1B. Their discovery may help develop higher treatments for severe inflammatory conditions like sepsis and COVID-19.
“When you concentrate on COVID-19, acute lung injury and ARDS underlie the fatal elements of the disease,” Tonks says. “And so, when the pandemic took hold, we were wondering whether there was anything we could do to assist, to supply an understanding of this aspect of the disease and suggest ways it might be treated.”
Tonks’ graduate student Dongyan Song investigated whether using a PTP1B inhibitor drug candidate could dampen the lethal consequences of overactive neutrophils in mice. She found that pretreating mice with the PTP1B inhibitor reduced lung tissue damage. When untreated, lower than half of the mice survived acute lung injuries and ARDS. But when pretreated, all of them survived.
The researchers exploited a natural process, called neutrophil aging, that the body uses to manage the immune cell’s lifespan. As they age, neutrophils develop into less dangerous. Tonks’ team discovered PTP1B inhibition quickens neutrophil aging. “An aged neutrophil is sort of a soldier with out a weapon,” Song explains. “So no matter what number of neutrophils flood an area, they will not give you the option to do serious damage.”
This project was a part of a program of COVID-related research at CSHL. Tonks says collaborations with CSHL Professor Mikala Egeblad, postdoc Jose M. Adrover, and CSHL Research Associate Professor Scott Lyons were essential to this discovery. Going forward, he and Song are working to extend the understanding of how PTP1B inhibitors affect the immune system. Tonks hopes his lab’s continued research results in latest treatments and preventative measures for various inflammatory diseases. His lab is currently working with DepYmed, Inc. to take PTP1B inhibitor drug candidates into clinical trials.
Tonks’ lab studies signal transduction, the method that controls how cells reply to signals from their environment. Specifically, they give attention to the PTP protein family, which Tonks discovered over 30 years ago. Since then, he’s sought to develop small molecule drug candidates that concentrate on these proteins, which may provide latest approaches for treating major human diseases including cancer and metabolic and neurodegenerative diseases.
Source:
Cold Spring Harbor Laboratory
Journal reference:
10.1172/jci.insight.158199