Metabolic Pathway a Potential Target to Treat IPF, Early Research Suggests

Metabolic Pathway a Potential Target to Treat IPF, Early Research Suggests

A metabolic process called the mevalonate pathway may be a promising therapeutic target to fight idiopathic pulmonary fibrosis (IPF), according to an early research study using mouse models and lung fluid collected from IPF patients.

Researchers also suggest that lung injury may not be as key to lung fibrosis as had long been thought.

The study, “Increased flux through the mevalonate pathway mediates fibrotic repair without injury,” was published in the Journal of Clinical Investigation.

Lung fibrosis, including IPF, is widely accepted as stemming from abnormal healing in the lungs in response to persistent injury, specifically in cells lining the tiny air sacs of the lungs, known as alveolar epithelia.

In this study, a team led by researchers at the University of Alabama at Birmingham propose a shift in this dogma.

In mouse models of lung fibrosis, researchers found that macrophages — white blood cells directly involved in IPF — can lead to fibrosis in the absence of injury, if a metabolic pathway, the mevalonate pathway, becomes more active than normal.

Macrophages are one of the body’s first lines of defense, specifically in tissues, including the lungs. Alveolar macrophages play an important role in IPF, releasing toxic substances called reactive oxygen species and serving as a critical source of TGF-β1 — a key signaling factor that provokes the destructive lung remodeling associated with IPF.

Using mouse models, researchers found that increased activation of mevalonate pathway shifts, or polarizes, macrophages toward a profibrotic state that promotes lung fibrosis.

The mevalonate pathway is best known for driving the production of cholesterol inside cells. But it also directs the production of many other important cellular compounds, and is involved in several other roles.

Through a sequence of molecular steps, a higher flux on the mevalonate pathway activates a protein called Rac1, which then stimulates the production of toxic reactive oxygen species — leading to macrophage polarization into a profibrotic status and the release of TGF-β1.

Importantly, the team saw that this mechanism can take place in the absence of any lung injury, and appears to occur in patients with IPF, according to tests done in lung fluid samples, or bronchoalveolar lavage fluid, of patients.

“Here, we show a paradigm shift that indicates a critical and essential role for monocyte-derived macrophage/fibroblast [the final cell effectors in fibrosis] crosstalk in the development and progression of fibrosis in the absence of epithelial injury,” A. Brent Carter, MD, pulmonologist and senior author of the study, said in a university news story.

“We propose that monocyte-derived macrophage/fibroblast crosstalk can induce fibrosis without epithelial cell injury, and is the primary driver in mediating disease progression,” Carter said. “These observations suggest that targeting the mevalonate pathway may abrogate the role of macrophages in dysregulated fibrotic repair.”

Ana is a molecular biologist with a passion for discovery and communication. As a science writer she looks for connecting the public, in particular patient and healthcare communities, with clear and quality information about the latest medical advances. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in genetics, molecular biology, and infectious diseases
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Ana is a molecular biologist with a passion for discovery and communication. As a science writer she looks for connecting the public, in particular patient and healthcare communities, with clear and quality information about the latest medical advances. Ana holds a PhD in Biomedical Sciences from the University of Lisbon, Portugal, where she specialized in genetics, molecular biology, and infectious diseases
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