Pulmonary fibrosis (PF) is a lung disease in which normal lung tissue is replaced with scar tissue due to chronic damage which in time leads to progressive lung failure. The most common form of PF, idiopathic pulmonary fibrosis (IPF), affects over a million people worldwide and dramatically increases mortality in the affected population¹ with a 5-year survival rate of about only 20-30% from the point of diagnosis.² In this article we will cover the treatment options for people with PF.

What is fibrosis?

Fibrosis is a process of tissue remodelling and hardening caused by excessive deposition of scar tissue that occurs in response to tissue damage. It plays a major role in wound healing by increasing the integrity of injured organs making them more resilient to injury. Whenever there is wound formation, a cocktail of immune cells and signalling molecules -commonly referred to as ‘inflammation’- gathers at the site of injury and activates specialised cells called fibroblasts. Activated fibroblasts start patching up the damaged tissue by producing a fibrous network of proteins known as the extracellular matrix. The main purpose of this newly formed tissue is to act as a ‘crutch’ for the affected organ. While the physiological role of fibrosis in wound healing is undeniable, when this process gets out of hand, i.e. in chronic organ inflammation, it can lead to loss of function and irreversible organ failure, as seen in pulmonary fibrosis.³

What causes pulmonary fibrosis?

Many factors can cause PF – any chronic exposure to exogenous factors that damage the lungs can with time cause fibrosis. Causes of PF can be classified into the following groups:⁴

• Occupational and environmental – observed in people with occupational exposure to fine dust particles such as coal workers, talk miners, agricultural workers, and poultry workers.^4,5
• Radiation-induced – as a side effect of radiation treatment.⁴
• Autoimmune – PF can be a complication of some autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus.^4,6,7
• Drug-induced – some medicines may produce chronic lung inflammation leading to PF.⁴ Amiodarone, a drug used for different types of arrhythmias, can precipitate PF by causing a buildup of phospholipids inside alveolar macrophages.⁸ Cyclophosphamide and bleomycin, two anticancer drugs, and nitrofurantoin, a drug used for urinary tract infections, may cause fibrosis by inducing oxidative stress in alveolar cells.^9,10,11

Even with the variety of factors causing PF, the most prevalent form of PF is idiopathic pulmonary fibrosis, i.e. PF with no known cause. Some risk factors for developing IPF are smoking, genetics, age (above 60 years), and male sex.¹²

What are the symptoms and complications of pulmonary fibrosis?

The first symptom that becomes apparent in patients with PF usually is a persistent dry cough. With time, patients develop oxygen deficiency presenting as shortness of breath, blue tinting of the lips and skin (cyanosis) and nail clubbing. Further lung tissue damage causes an increase in blood pressure in the pulmonary veins (pulmonary hypertension) that increases the heart’s workload, leading to myocardial hypertrophy and potentially fatal arrhythmias.¹³

What are the current treatment options for pulmonary fibrosis?

Anti-inflammatory agents

As stated above, inflammation plays a major role in the development of pulmonary fibrosis. Thus, reducing inflammation is one of the main therapeutic options for slowing the progression of pulmonary fibrosis. The most used anti-inflammatory agents in PF are steroids, azathioprine, cyclophosphamide, and mycophenolate mofetil, suppressing the immune system and slowing down fibrosis progression.¹⁴

Symptom control in pulmonary fibrosis

• Treatment of cough – people with PF often experience dry irritating cough, especially in those who also suffer from gastroesophageal reflux disease (GERD). Dry cough can be relieved with the help of different cough suppressants such as dextromethorphan and hydrocodone.¹⁴
• Treatment of GERD – a very commonly observed comorbidity in patients with PF. H2-blockers (e.g., famotidine) and proton pump inhibitors (e.g., esomeprazole) are used to relieve symptoms of acid reflux.¹⁴
• Treatment of depression – depression is a common condition in patients with PF as the daily struggles of affected people can often be overwhelming.¹⁵ It is important to apply routine early screening for depression in patients with PF and if needed refer them to a healthcare provider specialised in depression management in people with chronic diseases.¹⁵

Anti-fibrotic agents

Anti-fibrotic agents are a relatively new class of medications that target molecules involved in fibrosis. Currently, there are two medicines in this group – nintedanib and pirfenidone. They are approved for use in idiopathic pulmonary fibrosis in the EU and the US. Nintedanib acts by inhibiting a group of receptors located on the surface of activated fibroblasts, known as growth factor receptors (GFRs), i.e. FGFR, VEGFR, and PGFR. Pirfenidone acts by inhibiting key activators of fibroblasts – TGF-β1 and TNF-α. Both drugs have been shown to slow down the disease progression of PF in clinical trials.^16,17

Oxygen therapy 

Supplemental oxygen can compensate for the complications of chronic lung failure seen in PF and help them feel less breathless. Oxygen can be administered through masks or nasal tubes. Usually, the way that oxygen supplementation machines are arranged allows for people to easily go on with their lives which in turn improves quality of life.¹⁴

Pulmonary rehabilitation 

The goal of pulmonary rehabilitation is to improve lung function and quality of life in patients with chronic pulmonary diseases. It comprises a combination of inspiratory muscle training, neuromuscular electrical stimulation, nutritional care, and psychosocial counselling.¹⁸

Lung transplantation 

Lung transplantation is a life-saving and live-prolonging treatment option usually reserved for terminal patients with PF. Lung transplantation can dramatically restore lung function and improve quality of life. As with any other transplantation procedure, it has some severe drawbacks: increased risk of bleeding or formation of clots, need for immunosuppressant therapy increasing the risk of infection, rejection of the transplanted lung with potentially fatal consequences etc.¹⁹ It is of no less significance that many patients with PF die before making it on the waiting list for lung transplantation due to many of them being referred to transplant units with advanced disease.²⁰ 

Various pulmonary and extrapulmonary comorbidities associated with PF may have an unpredictable effect on disease prognosis and clinical outcomes for patients.²¹ It is therefore necessary to improve early diagnosis of PF and provide adequate supportive care to patients who need lung transplantation.²⁰ Notably, many countries have an underdeveloped organ transplantation system which results in unequal access to healthcare in terminal patients with PF.

Novel treatment options for pulmonary fibrosis

Emerging anti-fibrotic agents

Currently, experimental treatments are undergoing clinical assessment for potential applications in the management of PF. Many genes and therefore many signalling molecules are associated with the process of fibrosis. 

Studies conducted in patients with IPF have shown the potential of some molecules targeting important fibrosis-promoting molecules to slow down the progression of the disease. One such molecule is TD139 – a potent targeted inhibitor of a fibrogenic molecule known as galectin-3. This compound was studied as an inhaled formulation for the treatment of IPF and has been shown to reduce both concentrations of galectin-3 in alveolar macrophages and plasma levels of biomarkers for fibrosis with a well-defined safety profile compared to placebo.²²

Stem cell therapy

The idea behind using stem cells as a treatment for PF emerges from the ability of these ‘Jack of all trades’ cells to differentiate into practically every cell type and potentially regenerate the normal functioning lung tissue in people with PF.²³ This is the premise on which a phase 1 study conducted by researchers at the University of North Carolina is based. The study aims to assess the safety and efficacy of autologous Lung Spheroid Stem Cells administered by intravenous infusion in patients with IPF. The results of this study are yet to be published.²⁴

Gene therapy

Having in mind that IPF has a genetic component, it is only intuitive to attempt curing this disease by manipulating human DNA. This highly innovative idea however is still in very early stages of research as it also raises very controversial ethical questions.²⁵ A potential delivery of therapeutic genes targeting the underlying cause of IPF via inhaled therapeutic genes may offer an opportunity to treat lung tissue locally without altering the genome of other organs.²⁶

Summary

PF is a debilitating disease that carries a poor prognosis for affected people. It has no cure and current treatment guidelines are not well defined; and focus on controlling symptoms and slowing down disease progression rather than eradicating the underlying cause. This unmet need poses a serious medical challenge which rapidly drives scientific research for PF. As fibrosis is a very complex biological process with many cell types and signalling molecules involved, molecular markers for the progression of PF are still not well understood which hinders the identification of proper primary endpoints for treatment of patients with PF in clinical trials.²⁷ Gene and stem cell therapies still need to undergo vigorous research before being implemented in clinical practice but may have the potential to reverse PF.