Esopremazole for Acid Reflux May Ease IPF Inflammation, Scarring

The acid reflux medication esopremazole, commonly used to ease symptoms of gastroesophageal reflux disease (GERD), may be able to reduce lung scarring and inflammation in idiopathic pulmonary fibrosis (IPF), a recent study suggests.

“Esomeprazole favorably regulates a network of genes involved in lung fibrosis [scarring],” according to the researchers, who said the medication “may play [an] antifibrotic role in IPF.”

A proton pump inhibitor or PPI, esomeprazole works by reducing the amount of stomach acid that’s produced by glands in the lining of the stomach.

The study, “Esomeprazole attenuates inflammatory and fibrotic response in lung cells through the MAPK/Nrf2/HO1 pathway,” was published in the Journal of Inflammation.

IPF is a rare but serious lung disease characterized by progressive lung function decline due to the buildup of scar tissue (fibrosis) in the lungs. As scarring occurs over the course of IPF, it is thought that inflammatory, fibrotic, and oxidant processes — those that generate reactive oxygen species, also known as free radicals — become more prevalent.

Although approved antifibrotic medications like Esbriet (pirfenidone) and Ofev (nintedanib) can slow IPF progression, they can neither stop the disease entirely nor reverse the damage it has already caused. This has prompted researchers to continue searching for therapeutic alternatives.

Some scientists think that PPIs like esopremazole — sold as Nexium, among other brand names — and omeprazole, which is marketed as Prilosec, might provide one such option.

These medications were originally developed and approved to reduce stomach acidity and alleviate the symptoms of GERD and stomach ulcers. Yet, some studies suggest they also may improve lung function. Scientists remain uncertain, however, of exactly how various PPIs regulate lung remodeling processes, like fibrosis.

Now, a group led by researchers from Baylor College of Medicine, in Houston, Texas, took a closer look at how esopremazole affects both healthy cells and those taken from the lungs of people with IPF. Their goal was to identify the medication’s biological targets.

Their experiments showed that esopremazole lowered the expression, or production, of enzymes involved in free radical production, while activating one enzyme that plays a key role in lung health. The PPI also was found to activate a biological pathway involved in regulating inflammatory and fibrotic molecules, as well as cell growth and maturation — two processes impaired in IPF.

Specifically, esopremazole reduced the expression of DDAH and iNOS enzymes, which produce free radicals. These enzymes appear to be overactive in lung cells from IPF patients, and have been used in past studies to trigger the onset of IPF in disease models.

At the same time, the medication caused a transcription factor called nuclear factor-like 2 (Nrf2) to move to the cells’ nuclei, where it activated the expression of the heme oxygenase 1 (HO1) enzyme, which is important for cellular health and for maintaining a healthy equilibrium in the lungs. Of note, transcription factors are proteins that are able to regulate the activity of certain genes; nuclei are special compartments that hold cells’ genetic information.

Finally, the team found that esopremazole activated the mitogen-activated protein kinase (MAPK) biological pathway, which cells use for a variety of purposes, including responding to stress and damage. It modulated the levels of inflammatory and fibrotic molecules, and triggered cellular replication and migration, the study found.

The investigators confirmed their findings by specifically inhibiting, or blocking, these apparent targets of esopremazole — such as by deleting the gene that encodes Nrf2, preventing the activation of HO1, or disrupting the MAPK pathway.

In a computational database — the Library of Integrated Network-Based Cellular Signatures (LINCS) — the researchers found additional evidence to support their findings. The data profile how various treatments, including many approved medications like esopremazole, affect the gene expression, or activity, of different cell types.

Besides corroborating the team’s experimental findings, the LINCS data allowed researchers to identify a set of 45 genes that are commonly overactive in IPF and whose activity is reduced by esopremazole. These genes are involved in many pro-fibrotic processes, including the production of collagen and other components of the extracellular matrix (ECM), which is impaired in IPF. The ECM is the network of proteins and other molecules that surrounds and supports cells in tissues.

“PPIs in general and esomeprazole in particular may provide beneficial effect in IPF through upregulation of antioxidant, anti-inflammatory and antifibrotic molecules, as well as suppression of ECM proteins that are involved in collagen metabolism and myofibroblast activation,” the researchers wrote.

“Given the premises of our data and the conditional recommendation of PPIs for the treatment of IPF, randomized controlled clinical trials evaluating the efficacy of PPIs for the treatment of IPF are warranted,” they wrote.