Vitamin D Helped Reduce Lung Fibrosis in IPF Mice

Marta Figueiredo, PhD avatar

by Marta Figueiredo, PhD |

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Vitamin D lessenened lung scarring (fibrosis) in a mouse model of idiopathic pulmonary fibrosis (IPF) by suppressing the activity of the PSAT1 enzyme, and subsequently the mitogen-activated protein kinase (MAPK) pathway, a study shows.

PSAT1 is an enzyme that links metabolic and amino acid production pathways. The MAPK pathway is involved in several cellular functions, such as metabolism and cell growth, and is activated by inflammatory and stress signals. Amino acids are the building blocks of proteins.

These findings shed light on the underlying mechanisms of vitamin D’s previously reported anti-fibrotic properties, and add to previous data showing that in IPF these properties are linked to the suppression of the renin-angiotensin system (RAS), which is known to activate MAPK signaling.

The study, “Vitamin D3 alleviates pulmonary fibrosis by regulating the MAPK pathway via targeting PSAT1 expression in vivo and in vitro,” was published in the journal International Immunopharmacology.

Besides its well-known role in regulating calcium balance and bone health, vitamin D — also known as the sunshine vitamin — has been reported to have antioxidant, anti-inflammatory, and anti-fibrotic effects.

Notably, vitamin D deficiency previously was associated with a higher risk of death among people with IPF, a form of pulmonary fibrosis with no clear cause that is characterized by excessive wound healing leading to lung scarring.

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Oral vitamin D supplements also have been shown to lessen lung fibrosis in a mouse model, but the underlying mechanisms of its anti-fibrotic effects remain poorly understood.

A previous study showed that vitamin D’s anti-fibrotic action involved the blockage of RAS, a signaling pathway known mainly for its role in regulating blood pressure, fluid, and salt balance in the body, but also is involved in lung fibrosis.

Now, a team of researchers in China strengthened these findings by providing evidence that the anti-scarring effects are associated with the suppression of MAPK signaling, which is regulated by RAS.

Researchers used a mouse model of induced IPF and — distinct from most previous studies — assessed vitamin D’s effects on lung fibrosis at the time of, rather than before, its establishment.

They first found that treatment with vitamin D3, a major precursor of vitamin D, after the establishment of lung fibrosis prolonged animals’ survival and eased lung inflammation and scarring, relative to no treatment.

Vitamin D3 also was able to reduce lung infiltration of pro-inflammatory cells, lung cell death, and deposition of collagen — a protein essential for wound healing that is produced excessively in fibrosis-related conditions.

To identify potential targets of vitamin D, researchers conducted several types of omics analyses to identify proteins modulated by vitamin D3 treatment in this mouse model of IPF. Omics studies characterize and quantify pools of biological molecules.

They found the levels of 251 proteins were significantly different between both healthy and IPF mice, and vitamin D3-untreated and treated animals, thereby likely representing the most relevant targets of vitamin D.

These target proteins were found to be involved in “acute inflammation, response to oxidative stress, antioxidant activity, and extracellular matrix regulation,” the researchers wrote.

The extracellular matrix is the network of molecules and proteins, such as collagen, that surrounds and supports cells, while oxidative stress is a form of cellular damage resulting from an imbalance in the production and accumulation of harmful oxidant molecules.

Further analyses revealed that PSAT1 was a “candidate target related to IPF disease and [vitamin D3] treatment” and that the MAPK signaling pathway was “the most probable candidate pathway” behind vitamin D3’s benefits in IPF.

PSAT1 plays an important role in linking metabolic pathways and serine production pathways. Serine is an amino acid essential for collagen production and a target of MAPK enzymes. The stress response-MAPK pathway previously was shown to be involved in fibrosis in several organs, such as the heart, kidney, and lungs.

PSAT1 levels were found to be increased in lung tissue from people and mice with IPF relative to their healthy counterparts. Moreover, using mice with IPF and lab-grown human lung cells, researchers confirmed that vitamin D3 treatment suppressed activation of the MAPK pathway and found this was dependent on PSAT1 suppression.

These findings highlight vitamin D3 as a potential therapeutic agent for IPF “by down-regulating the MAPK signaling pathway via targeting the expression of PSAT1,” the team wrote.

“This research not only provided a scientific basis for further research and application of [vitamin D3] but also proved that multi-omics analysis could be a powerful method for drug mechanism research,” they wrote.

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