Less mucus, more neutrophils: alternative view of CF

A conventional view of cystic fibrosis (CF) and its effects on the lungs is that it’s all about mucus. The inherited disease leads to an accumulation of mucus in the lungs, which appears to be connected with inflammation, susceptibility to infection and loss of lung capacity.

Immunologist Rabin Tirouvanziam has an alternative view, centered on neutrophils. They are a type of immune cell that is very numerous, yet often overlooked, he says.

Rabindra Tirouvanziam, PhD

A new paper, published in Journal of Leukocyte Biology, substantiates his ideas about cystic fibrosis and harnesses them for future diagnostic and therapeutic advances. Tirouvanziam is an assistant professor of pediatrics at Emory University School of Medicine and Emory Children’s Center. He and his colleagues have developed a system for studying neutrophil behavior in a specialized culture, a model of a cell layer in the lung.

Neutrophils behave differently in the diseased lung environment, compared with when they are in the blood. The culture system makes the neutrophils pass through a layer of lung cells, under the influence of lung fluids obtained from CF patients. The culture system opens up the opportunity of testing fluids from patients to mark disease progression, as well as drug discovery: looking for compounds that could deprogram the neutrophils.

Neutrophils are generally thought to be short-lived, and their nuclei have a distinctive appearance under microscopes because their chromatin (where the DNA is located) is highly condensed.

“Neutrophils make up 60 percent of the cells in the bone marrow, and they dominate in immune responses to bacteria,” Tirouvanziam says. “Yet immunologists often discard them on their way to isolating lymphocytes.”

His theory (more in this review) is that in the lungs of people with CF, neutrophils are triggered early on to come in and clean up an abnormal state. But then the cells stay around, and begin to run the show. It is a vision out of the “Sorcerer’s Apprentice” section of the movie Fantasia, when Mickey Mouse finds he cannot control the enchanted marching brooms.

“This started several years ago, because I didn’t understand why neutrophils would enter the lung and release all these enzymes with harmful effects, such as elastase and myeloperoxidase,” he says. “Other people in the field thought that neutrophils were simply dying once they reached the lungs, and that’s why their contents were being released. We’ve shown that they are actually staying alive to cause trouble.”

Once the neutrophils have migrated into the lung environment, they display an array of characteristics, which Tirouvanziam has coined an acronym for: GRIM. This stands for Granule Release, Immunomodulatory activity, and Metabolic changes.

Tirouvanziam says neutrophils are key because the problem with the lung environment starts even before mucus accumulates. And it explains why not all of the lung succumbs to dysfunction at the same time – it depends upon the arrival of the neutrophils.

The insight could extend beyond CF, into lung diseases such as COPD (chronic obstructive pulmonary disease) and asthma, which share the feature of mucus obstruction. Researchers have observed that COPD appears to be “acquired CF”, because the CFTR molecule, defective in CF, is also dysfunctional in COPD.

Photo from commencement celebrations. Osric Forrest with psychology professor Patricia Bauer

The first author of the paper is graduate student Osric Forrest, in the Immunology and Molecular Pathogenesis program. Forrest recently obtained his doctorate and was honored with the Eleanor Main Graduate Award, recognizing mentorship.

Co-authors at Emory include Joanna Goldberg, PhD, professor of pediatrics and Vin Tangpricha, MD, professor of medicine. Amit Gaggar, MD at University of Alabama, Birmingham also contributed to the paper.

Tirouvanziam’s research was supported by the Cystic Fibrosis Foundation, the National Heart Lung and Blood Institute (R01HL126603), and the Georgia Clinical & Translational Science Alliance.

Posted on by Quinn Eastman in Immunology Leave a comment

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Quinn Eastman

Science Writer, Research Communications qeastma@emory.edu 404-727-7829 Office

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