New Hope for Patients with Idiopathic Pulmonary Fibrosis

Until late 2025, one of the most common causes of lung scarring, idiopathic pulmonary fibrosis or IPF, had few treatment options.

Health Lab recently spoke with researcher Sean Fortier, M.D., assistant professor in the Department of Internal Medicine in the Division of Pulmonary and Critical Care, about promising developments for IPF, a rare but devastating lung disease.

What is IPF and Why is it So Hard to Treat?

Fortier: IPF is a devastating disease characterized by stiffening of lung tissue due to progressive scarring (fibrosis).

This scarring leads to difficulty breathing, reduced blood oxygen levels, and ultimately respiratory failure. The primary cause of lung fibrosis in IPF is unknown (or idiopathic).

Progressive fibrosis in IPF and other fibrotic diseases results from an inappropriate response to injury in which normal tissue repair has become dysregulated.

Lung injury isn’t uncommon because the lungs are directly exposed to the outside world through every breath.

Inhaling pollution, toxins, or infectious agents are all examples of exposures that can lead to lung injury.

Due to a combination of genetics and/or repeated exposure, injury from these sources can then cause cells in the lungs of certain individuals to react in ways that lead to scarring that gets worse over time.

IPF is challenging to treat because it likely represents a group of diseases with many different unknown causes making the clinical course variable from patient to patient.

As a Basic Science Researcher, What are You Trying to Learn About IPF?

Fortier: We want to know why progressive lung scarring occurs in some individuals but not others.

In other words, what is different between lungs that progressively scar and those that appropriately repair themselves at a molecular and cellular level?

Damage to the body is repaired through a complex series of coordinated phases with one important step being wound closure.

This is accomplished by cells called fibroblasts which produce the components that make up a scar (such as collagens) to physically repair tissue that has been damaged.

Most of the time when an organ like the lung sustains an injury, it does not result in a runaway scarring process. This is because the fibroblasts do their job and then naturally go away, leaving a small amount of scar tissue that does not meaningfully disrupt organ function.

This is observed in animal models such as mice that demonstrate a remarkable ability to spontaneously resolve lung fibrosis after injury.

We have a hypothesis that there are failsafe pathways in lung fibroblasts responsible for telling them to “go away” at the right time after lung injury and that these pathways are dysregulated or absent in IPF.

This results in the persistence of active fibroblasts within the lung, ongoing scar formation, and respiratory failure.

So, if we can understand what is disabled in lung fibroblasts in the context of IPF, then we can determine what might need to be replaced or modulated using targeted therapies.

There has been a paradigm shift over the past five years or so that my mentor Dr. Marc Peters-Golden and I, along with other labs, are implementing in our research.

Instead of focusing on uncovering the cell pathways that cause a lung fibroblast to become more active and make scar, we are interested in understanding how to coax already scar-forming fibroblasts to revert into their normal state and be naturally cleared.

Similarly, in animal models of fibrosis, we are interested in determining the necessary cellular and molecular events that promote normal repair and spontaneous resolution of fibrosis in the lungs after injury.

We have previous published work demonstrating that upregulating the molecular cell messenger cyclic-AMP (cAMP) within lung fibroblasts coaxes these cells into reducing their collagen production and reprograms them to be naturally cleared through programmed cell death.

Most importantly, we have recently shown that cAMP is necessary for the spontaneous fibrosis resolution observed in healthy mice.

This work has been presented at national conferences, and we are now working to package it into a formal publication.

What are the Recent Developments for IPF Treatments?

Fortier: One recently approved drug as of October 2025, called nerandomilast, works by increasing cAMP.

It essentially tells the cells to stop degrading it, thereby increasing its levels and duration of effect inside cells.

This drug helped to slow the progression of pulmonary fibrosis, demonstrated additive effects when combined with current drugs for IPF, and was better tolerated by patients.

There’s now a kind of rush in our pulmonary clinic to get this drug to people who need it.

It’s not a cure, but it’s a huge step in the right direction and it gives us, after 10 years, a new tool to treat IPF.

Also, a recent study found that patients receiving an inhaled drug for pulmonary hypertension (or high blood pressure in the lungs) who also had lung fibrosis did not experience progression of their fibrosis as quickly as patients not receiving the inhaled drug.

This result was just recently confirmed in a dedicated IPF trial, and the drug (treprostinil) is likely to be approved in the upcoming year.

And wouldn’t you know it; treprostinil acts by increasing cAMP levels.

It does so by a fundamentally different mechanism than the recently approved nerandomilast. Instead of preventing its breakdown, it tells cells to make more cAMP.

How do These New IPF Drugs Connect to Your Research?

Fortier: These drugs directly impact the same pathway (cAMP) we have found is necessary for spontaneous fibrosis resolution in mice.

Our findings that cAMP promotes fibrosis resolution through its actions in fibroblasts in an animal model of fibrosis combined with the success of two phase 3 IPF clinical trials provide both mechanistic and real-world evidence that this pathway holds promise to improve outcomes in IPF and other fibrotic lung diseases.

We have evidence from the lab that cAMP reverses the “bad” fibroblasts back into their good form, while the older IPF drugs do not.

What’s great about this pathway is that there are so many molecular locks (cell receptors) and keys (ligands which activate cell receptors) that exist in our body that combine to generate cAMP.

These two new drugs are just two among several that modulate cAMP. Existing drugs utilized in other diseases – such as albuterol for asthma and GLP1 drugs for diabetes and weight loss – also work by leveraging the cAMP pathway in unique ways.

Why Does IPF Research Need More Investment?

Fortier: It’s estimated that more than a third of all chronic diseases have some fibrotic component to them. So, if we crack fibrosis in one organ, it’s very likely we will learn something important that is applicable to other diseases.

I think this work has the potential to go beyond pulmonary fibrosis.

In the context of my work, I like to look at cells and ask: what’s this odd thing they’re doing?’ Because my underlying premise is that cells are not wasting time or energy, I assume that if a process or pathway exists, it is likely to provide a survival advantage.

Applying this heuristic to the observation that there are over 50 different receptors and ligands that can combine to generate cAMP – many of which are expressed in fibroblasts – it stands to reason that cAMP is a fundamentally important pathway in fibrosis with rich therapeutic potential.

The most straightforward application for fibrotic lung diseases is combining oral nerandomilast with inhaled treprostinil to evaluate whether there might be additive benefit as we and others have found that these drug classes have additive anti-fibrotic effects on fibroblasts grown in culture.

Many receptor/ligand pairs influencing cAMP levels have not been pharmacologically explored and might represent new targets for therapy.

Looking forward, the specific mechanisms by which cAMP achieves its antifibrotic effects are of great interest as they could lead to more targeted “downstream” therapies.

Patients should know there is active work being done, we’re starting to slowly provide more options, and the hope is that there’s going to be an explosion in these options, therapeutic and otherwise, in the years to come.