Lethal lung disarming of the immune system

Photo: CSHL researchers have found that treating mice with a candidate drug that inhibits a protein called PTP1B can prevent fatal lung inflammation in mice. Shown here are 3D images of mouse lungs treated (left) and without (right) the PTP1B inhibitor drug filter. The candidate drug prevented a lethal amount of lung damage, shown in cyan, from overactive immune cells called neutrophils.
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Credit: Tonks lab/CSHL, 2022

Neutrophils, the most abundant type 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 use various weapons to protect the body. But if these weapons are overly activated, they can damage the body’s tissues. Lung tissues are saturated with blood vessels, which makes them more susceptible to attacks of neutrophils. If the lung injuries are severe enough, it can lead to acute respiratory distress syndrome (ARDS), the leading cause of death from COVID-19.

Nicholas TonksKarel Boys, Professor of Cancer Research at Cold Spring Harbor Laboratory (CSHL) and his team have found a candidate drug that can prevent fatal lung inflammation in mice by inhibiting a protein called PTP1B. Their discovery may help develop better treatments for severe inflammatory conditions such as sepsis and COVID-19.

“When you think of COVID-19, acute lung infection and acute respiratory distress syndrome underlie the potentially lethal aspects of the disease,” Tonks says. “So, when the epidemic spread, we were wondering if there was anything we could do to help, to provide an understanding of this aspect of the disease and to suggest ways it could be treated.”

Donjian Song, a graduate student at Tonks, investigated whether the use of a candidate drug PTP1B inhibitor could inhibit fatal consequences of neutrophil overactivity in mice. It found that pretreating mice with a PTP1B inhibitor reduced lung tissue damage. When untreated, less than half of the mice survived acute lung injury and acute respiratory distress syndrome. But when they were cured, they all survived.

The researchers exploited a natural process, called neutrophil aging, which the body uses to control the lifespan of an immune cell. As they get older, neutropenia becomes less dangerous. Tonks’ team discovered that inhibiting PTP1B accelerated neutrophil aging. “An elderly justice is like a soldier without a weapon,” Song explains. “So, no matter how many neutrophils flood the area, they won’t be able to cause serious damage.”

This project was part of the COVID-related research program at CSHL. Tonks says collaborate with CSHL professor Michala Egbladand postdoc Jose M. Adrover, and research assistant professor at CSHL Scott Lyons were essential to this discovery. Going forward, he and Song are working to further understand how PTP1B inhibitors affect the immune system. Tonks hopes that his lab’s ongoing research will lead to new treatments and preventative measures for various inflammatory diseases. His lab is currently working with DepYmed, Inc. To take PTP1B inhibitor drugs in clinical trials.

Tonks’ lab studies signal transduction, the process that controls how cells respond to signals from their environment. In particular, they focus on the PTP protein family, which Discover Tonks over 30 years ago. Since then, he has sought to develop small-molecule drug candidates that target these proteins, which could provide new avenues for treating major human diseases including cancer, metabolic and neurodegenerative diseases.

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