Research Advances in Idiopathic Pulmonary Fibrosis (IPF)

Idiopathic pulmonary fibrosis (IPF) is a type of chronic lung disease that causes progressively worsening dyspnea (shortness of breath). People with IPF may also experience a dry and persistent cough, progressive fatigue, or unexplained weight loss. The severe breathing difficulties of IPF can lead to disability, and the condition can cause early death.

IPF is not a common disease, but it is not considered rare. About 15,000 people are estimated to die from IPF each year in the United States. It affects men more often than women, smokers more often than non-smokers, and usually people over 50 years of age.

The cause of IPF has not been completely worked out (“idiopathic” means “of unknown cause”), and there is no cure for it. However, research is being done to understand this condition, and to develop effective treatments for IPF. The prognosis for people with IPF has improved in the last few years.

Our Evolving Understanding of IPF

IPF is caused by fibrosis (scarring) of the lung tissue. In IPF, the delicate cells of the alveoli (air sacs) are gradually replaced by thick, fibrotic cells that are unable to perform gas exchange. The chief function of the lungs is exchanging gasses, allowing oxygen from the air to enter the bloodstream, and carbon dioxide to leave the bloodstream. As a result of lung scarring in IPF, this exchange is inefficient.

The gradually worsening ability to get enough oxygen into the bloodstream causes most of the symptoms of IPF.

Inflammation

For many years, the working theory about the cause of IPF was one based on inflammation. That is, it was thought that something caused inflammation of the lung tissue, leading to excessive scarring.

So early forms of treatment for IPF were aimed largely at preventing or slowing the inflammatory process. Such treatments have included corticosteroids, methotrexate, and cyclosporine. For the most part, these treatments were only minimally effective (if at all), and carried significant side effects.

Abnormal Healing

In explaining the cause of IPF, researchers today have largely turned their attention away from a theoretical inflammation-triggering process, and toward what is now believed to be a process of abnormal healing of lung tissue in people with this condition. That is, the primary problem causing IPF may not be excessive tissue damage at all, but abnormal healing from (possibly even normal) tissue damage. With this abnormal healing, excessive fibrosis occurs, leading to permanent lung damage.

The normal healing of lung tissue is an amazingly complex process, involving the interaction of various types of cells and numerous growth factors, cytokines, and other molecules. The excessive fibrosis in IPF is now thought to be related to an imbalance between these various factors during the healing process.

In fact, several specific cytokines and growth factors have been identified that are thought to play important roles in stimulating excessive pulmonary fibrosis. These molecules are now the targets of extensive research, and several drugs are being developed and tested in an attempt to restore a more normal healing process in people with IPF.

Current Treatments

In 2014, the FDA approved two new drugs for the treatment of IPF, Ofev (nintedanib) and Esbriet (pirfenidone). Both drugs have been shown to significantly slow the progression of IPF.

Nintedanib is presumed to work by blocking receptors for tyrosine kinases, molecules that control various growth factors for fibrosis. The exact mechanism of action of pirfenidone is not known, but it's thought to reduce fibrosis by decreasing fibroblast growth and the production of fibrosis-associated proteins and cytokines and may decrease the formation and accumulation of extracellular matrix in response to growth factors.

Pulmospheres

Unfortunately, individuals may respond better to one or the other of these two drugs, and at this time there is no reliable way to tell which drug may be better for which person. However, a promising test may be on the horizon for predicting an individual’s response to these two drugs.

Researchers at the University of Alabama have described a new technique in which they assemble “pulmospheres”—tiny spheres made of tissue from a lung of a person with IPF—and expose the pulmospheres to the anti-IPF drugs nintendanib and pirfenidone.

From this testing, they believe they can determine ahead of time whether the patient is likely to respond favorably to either or both of these drugs. If the early experience with pulmospheres is confirmed with further testing, this eventually may become available as a standard method for pre-testing various drug regimens in people with IPF.

GERD Treatment

In addition, it has now been recognized that many people with IPF (up to 90%) have gastroesphageal reflux disease (GERD) which may be so minimal that they do not notice it. However, chronic “microreflux” may be a factor that triggers minor damage in the lung tissue—and in people who have an abnormal lung healing process, excessive fibrosis may result.

Small randomized trials have suggested that people with IPF who are treated for GERD may experience significantly slower progression of their IPF. While larger and longer-term clinical trials are needed, some experts believe that “routine” treatment for GERD is already a good idea in people who have IPF.

Current Research

Researchers are considering whether combined therapy with nintedanib with pirfenidone could be beneficial for people who have IPF.

A few other drugs that are being tested:

• Imatinib: Imatinib is another tyrosine kinase inhibitor, similar to nintedanib.
• Pamrevlumab/FG-3019: This drug is a monoclonal antibody aimed at connective tissue growth factor, and is designed to limit fibrosis.
• Thalidomide: This drug has been shown to reduce lung fibrosis in animal models, and is being tested in patients with IPF.
  
• PRM-151/Pentraxin 2: A recombinant human serum amyloid P/pentraxin 2 protein.
• GLPG1690: A small molecule selective autotaxin inhibitor.

It is known that many people who develop IPF have a genetic predisposition to this condition. Active research is being done to compare genetic markers in normal lung tissue to genetic markers in the lung tissue of people who have IPF. Several genetic differences in the IPF tissues have already been identified. These genetic markers are providing researchers with specific targets for drug development in the treatment of IPF.

A Word From Verywell

IPF is a very serious lung condition, and it can be devastating to get this diagnosis. However, in just the last few years, a tremendous amount of progress has been made in treating IPF. Two effective new drugs have already been approved for its treatment, several new agents are being tested in clinical trials, and targeted research promises to yield new treatment options soon.

If you or a loved one with IPF is interested in being considered for a clinical trial with one of the new drugs, information on ongoing clinical trials can be found at clinicaltrials.gov.