Novel Chemical May Help Prevent Inflammatory Cell Death

by Iswarya on  August 25, 2018 at 11:06 AM Research News
RSS Email Print This Page Comment bookmark
Font : A-A+

New study discovers a way to end the death of immune cells which is linked to multiple diseases, including inflammatory bowel disease (IBD), sepsis, and arthritis. The findings of the study are published in the journal  Science Immunology.
Novel Chemical May Help Prevent Inflammatory Cell Death
Novel Chemical May Help Prevent Inflammatory Cell Death

The findings identify a chemical that potently inhibits inflammatory cell death.

Cells often perforate their own membranes in response to extreme inflammation a type of cell suicide known as pyroptosis. In human cells and animal models, the chemical prevents these deadly holes from forming inside cell membranes. This is a new pharmacologic approach to stopping this destructive process.

"To date, there has been no pharmacologic mechanism to inhibit pyroptotic pore formation directly," said Derek Abbott, MD, Ph.D., Arline H. and Curtis F. Garvin Professor of Medicine at Case Western Reserve School of Medicine and member of the Case Comprehensive Cancer Center, whose lab performed the work.

"We knew necrosulfonamide inhibited another type of pore formation and had a hunch it might work against pyroptosis, too. We found necrosulfonamide is effective in our sepsis models and could be effective to treat diseases worsened by inflammation."

In the new study, mice treated with the chemical necrosulfonamide survived longer than untreated mice, after exposure to bacterial proteins that cause inflammation. The results suggest the chemical alleviates extreme, harmful inflammation associated with bacterial sepsis. Necrosulfonamide has never before been studied as a pharmacologic agent.

Pyroptosis is part of a vicious cycle in many diseases. As dying cells poke holes in their membranes, they leak molecules that recruit more immune cells. The sudden influx of new cells also initiates cell death, and another round of pyroptosis occurs.

Chronic inflammation can result, including the type that underlies arthritis and IBD. Abbott, who is also a professor of pathology and Co-Director of the Medical Scientist Training Program (MSTP) at Case Western Reserve School of Medicine, and his team sought a way to stop pyroptosis while preserving other necessary immune cell functions.

The researchers tested necrosulfonamide by adding it to human cells growing in their laboratory. Even in the face of inflammatory triggers, like bacteria, immune cells exposed to the chemical remained intact. They did not leak dyes or other molecules, and still sent signals to other cells as part of normal, healthy function.

The new study also describes how necrosulfonamide works inside cells. Abbott's team used biochemical analyses to show it directly attaches to gasdermin D--a protein that destroys cell membranes. During pyroptosis, long chains of gasdermin D aggregate inside cell membranes, forming pores. Necrosulfonamide physically gets in the way of this process. With the large chemical attached to it, gasdermin D can't aggregate.

The researchers studied different gasdermin D variations to pinpoint the exact location where necrosulfonamide attaches. They found it attaches to regions where gasdermin D proteins connect to each other. The specific attachment mechanism differs from how the chemical inhibits enzymes involved in other types of cell death.

"Our results suggest gasdermin D inhibitors are clinically possible," said Joseph Rathkey, first author on the study and student in the MSTP at Case Western Reserve School of Medicine.

"We've provided proof of principle that destructive pore formation can be inhibited, and that gasdermin D is a viable pharmaceutical target." He says the "high therapeutic potential" of chemicals like necrosulfonamide could inform future studies in humans.

Source: Eurekalert

Post a Comment

Comments should be on the topic and should not be abusive. The editorial team reserves the right to review and moderate the comments posted on the site.
Notify me when reply is posted
I agree to the terms and conditions
Advertisement

More News on:

Parkinsons Disease Surgical Treatment Death Facts Bereavement Autophagy: Self-Repair Mechanism at Cellular Level 

News A - Z

A B C D E F G H I J K L M N O P Q R S T U V W X Y Z

News Search

Medindia Newsletters

Subscribe to our Free Newsletters!

Terms & Conditions and Privacy Policy.

Find a Doctor

Stay Connected

  • Available on the Android Market
  • Available on the App Store

News Category

News Archive