Anti-inflammatory molecule holds promise for acute lung injury

A protein produced in low quantities in response to inflammation may help prevent death in people suffering from acute lung injury, research in laboratory mice suggests.

“There is currently no cure for acute lung injury, so our discovery of how this protein works, and that it dramatically increased survival for mice in sepsis, is very encouraging,” said Manish Mittal, research assistant professor of pharmacology in the University of Illinois at Chicago College of Medicine and first author on the paper, published in the Proceedings of the National Academy of Sciences.

Approximately 200,000 people in the U.S. experience acute lung injury each year, and about 40 percent of all cases prove fatal. In acute lung injury, an overblown immune response causes fluid to leak into the lungs, which can lead to loss of oxygen in the blood.

Mittal and his colleagues wanted to trace the action of a protein called TSG6, for TNF-alpha stimulated gene-6, in a mouse model of acute lung injury. TSG6 is a small protein produced by immune cells called macrophages, but only when they are actively working to resolve inflammation in the body. When there is no injury or inflammation, the protein is not produced.

The researchers found that mice lacking the gene for TSG6 were unable to resolve and survive induced acute lung injury. But when the researchers gave large doses of TSG6 to the mice at the same time they induced acute lung injury, 80 percent survived.

The researchers found that TSG6 works by blocking pro-inflammatory molecules, cytokines and chemokines, in macrophages. Cytokines and chemokines are signaling molecules that help macrophages respond to injury, and when secreted draw more macrophages to the site, which can add to the inflammation, sometimes dangerously so.

The researchers found that when mice are in sepsis, which is what causes acute lung injury, TSG6 blocks the signal triggered by activation of macrophages, so that there is less recruitment of immune cells to infection sites.

“The role of TSG6 is to modulate the immune response and suppress an over-reaction by pro-inflammatory macrophages,” said Mittal. “If we can give doses of TSG6 to people in sepsis or acute lung injury, it could help balance their immune system out, so that the response isn’t contributing to the problem.” Mittal said future studies will look at developing TSG6 into a potential therapy for acute lung injury.

Asrar B. Malik, Chinnaswamy Tiruppathi, Saroj Nepal, You-Yang Zhao, Dagmara Grzych and Dheeraj Soni in the UIC College of Medicine department of pharmacology, and Darwin J. Prockop of Texas A&M University are contributing authors on the paper.

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