Are you aware of pulmonary fibrosis's biological complexities and its root causes? In 2023, out of every 10,000 people around the world, 13 to 20 individuals were diagnosed with pulmonary fibrosis, with a majority of cases affecting 50-70-year-olds.¹ Although the figures may not seem staggering, the prevalence of this lung condition is increasing every year. This article provides an overview of the definition of pulmonary fibrosis, the different causes of pulmonary fibrosis, and the methods to treat and manage symptoms of this lung condition. 

Definition of pulmonary fibrosis 

Pulmonary fibrosis occurs when lung tissue is scarred or damaged, leading to the stiffening of the lungs which disrupts the normal functioning of the lungs. As a result, patients may experience breathing complications like shortness of breath, fatigue and dry cough. Symptoms may worsen over time, but the rate at which this occurs varies between individuals.² When the cause of pulmonary fibrosis is unknown, it is classified as idiopathic pulmonary fibrosis (IPF). Nevertheless, studies have shown that IPF may be linked to various causes including exposure to harmful particles and smoking. Whether or not these factors are the direct causation of IPF is still being researched. ³

Impact on lung function (Pathophysiology)

Fibrogenesis may be due to repeated injury to the epithelial cells, particularly in the alveoli where gas exchange occurs. As a result, myofibroblasts, which disrupt normal lung architecture and functioning, are activated. Myofibroblasts are responsible for depositing extracellular matrix, leading to a change in the structure and loss of function 

of the alveoli.⁴ Moreover, as apoptosis (regulated cell death) is dysregulated, the apoptosis of the alveoli epithelial cells increases while the apoptosis of myofibroblasts decreases, leading to the damage of the connective tissues located between the alveoli and surrounding blood vessels.⁵ The thickening of the lung connective tissue causes difficulty in lung expansion so patients will find it harder to breathe. Lung volumes are 

reduced and lung compliance decreases. As there is no cure, prolonged symptoms will eventually lead to death.⁶

Diagnosis of pulmonary fibrosis 

Healthcare professionals will look at the high-resolution images taken from different angles and produced from CT scans. This allows them to obtain an overview of the extent of the lung tissue damage. In addition to CT scans, pulmonary function tests are done to understand lung function. For instance, pulse oximetry measures the oxygen percentage in the patient’s blood.⁷ The patient may also perform spirometry; the patient will exhale forcefully into a tube that measures the forced vital capacity (FVC) which is the maximum volume of air that the patient can exhale. The forced expiratory volume (FEV) is also measured to show the rate at which air moves out of the lungs. A lower-than-normal FVC and FEV indicate restricted breathing caused by pulmonary fibrosis.⁸

Environmental factors 

Environmental pollutants are a major risk factor for various illnesses and deaths. About 91% of the world’s population lives in areas where air pollution exceeds the limits recommended by WHO. Air contaminated by particulate matter and high nitrogen dioxide and sulfur dioxide content is responsible for the majority of respiratory diseases including pulmonary fibrosis.⁹

Effect of different air pollutants and toxins 

Particulate matter can be generated naturally from forest fires and volcano eruptions. It can also be produced from anthropogenic processes like burning fossil fuels for vehicles and power stations. Particulate matter can range from less than 0.1 micrometres to 10 micrometres in diameter. When pollutant gases and particulate matter mix in the 

atmosphere, smog is formed, causing severe air pollution.¹⁰ The entering of particulate matter into the lungs damages alveolar epithelium and increases the deposition of extracellular matrix. Restoration of normal lung architecture is impeded and the remodelling of lung structure is stimulated Thus, there is an impairment in gas exchange at the alveolar-capillary interface.⁹

Besides that, smoking is proven to be closely linked to pulmonary fibrosis. Lung damage and emphysema (alveoli damage) can also be seen in tobacco smokers who are diagnosed with pulmonary fibrosis. Tobacco smoking not only increases mucus production but also causes lung inflammation and collapse due to unregulated apoptosis.  This disrupts the absorption of oxygen from the alveoli into the bloodstream.¹¹ It is still unclear which particular component in tobacco smoke is responsible for putting a smoker at risk of developing pulmonary fibrosis.¹²

Occupational exposure 

Common industries and exposure to certain hazardous materials

Exposure to dust, gases, and fumes increases the risk of developing pulmonary fibrosis. According to NCBI, it is stated that a quarter of pulmonary fibrosis cases were caused by occupational exposure. Common industries where workers inhale hazardous materials like organic dust, iron dust and silica dust over a long period include the construction, mining and agriculture industries. Metal dust induces the conversion of alveolar cells to mesenchymal cells, subsequently causing an immune-inflammatory response and scarring of lung tissue. An imbalance of the mesenchymal cell population leads to many lung diseases.¹³ Exposure to silica dust causes a similar debilitating effect, but lung function deteriorates much more rapidly. When silica dust comes into contact with the alveoli surfactant, the immune system is stimulated. Macrophages are recruited to clear the lung of the harmful debris. Continuous stimulation of immune response leads to inflammation and damage of lung tissue, reducing lung surface area for gas exchange.¹⁴ A recent study showed that metal dust and silica dust were found in the lymph nodes and lung tissue of patients diagnosed with pulmonary fibrosis.¹⁵ Furthermore, exposure to asbestos is prevalent in construction and automotive repair as it is usually woven into materials to produce brakes and roofing materials. The use of asbestos has been banned in certain industries in the U.S., but it is still widely used in low and middle-income countries. Asbestos exposure not only causes pulmonary fibrosis but also lung cancer.¹⁶

Autoimmune diseases

Pulmonary fibrosis may also be a secondary effect of an overreaction of the immune system that attacks one’s body cells. This is because a person’s own immune system fails to recognise his or her body cells and sees them as foreign. This leads to inflammatory responses that result in the scarring of lung tissue (fibrosis). The risk factors of autoimmune diseases include smoking or inheriting certain genetic mutations or markers.¹⁷

Rheumatoid arthritis 

Rheumatoid arthritis (RA) is a condition in which a patient experiences chronic joint pain. Evidence shows that 40% of patients with RA are typically also diagnosed with pulmonary fibrosis to a certain extent after several years of living with RA. Patients may experience complications like respiratory failure and a collapsed lung, leading to the development of RA-related lung disease.¹⁸ Patients with RA have autoantibodies like rheumatoid factor and anti-cyclic citrullinated peptide (CCP) that circulate in the bloodstream. It has been proposed that stimulated production of inflammatory cytokines and immune response that damages lung tissue.¹⁹ Studies have shown that smoking and contact with environmental pollution are some of the most significant environmental factors that increase the risk of a patient with RA developing pulmonary fibrosis. This demonstrates the interaction between environmental risk factors and autoimmune diseases in pulmonary fibrosis.¹¹ Cigarette smoking increases the production of RA autoantibodies.¹⁹

Systemic sclerosis

Moreover, scleroderma-associated interstitial lung disease is when patients with scleroderma experience inflammation and scarring in the walls of the alveoli in the lungs. Scleroderma is when the skin on the fingers and other body parts thickens due to the dysregulation of the immune system. How systemic sclerosis develops is still a question that is being researched and studied.²⁰ In the U.S., the number of scleroderma cases is 50-300 for every 1 million people, with almost 90% of the cases developing interstitial lung disease.²¹ Over time, patients may experience shortness of breath as lung function deteriorates and the severity of pulmonary fibrosis increases. This is because as scleroderma progresses, high levels of anti-fibroblast antibodies are produced. Fibroblasts are then activated and converted to myofibroblasts, inducing the production of an extracellular matrix that alters lung architecture.²²

Sjogren’s syndrome

Sjodren’s syndrome is an autoimmune disease that affects the secretory gland tissue. Like other autoimmune diseases, it is associated with impaired immune response and genetic and environmental factors. These factors trigger the activation of B and T lymphocytes within the glands.²³ About 9-22% of patients with Sjogren’s syndrome also develop respiratory symptoms including pulmonary fibrosis which usually occurs in smokers.²⁴ The dysregulated activation and proliferation of B and T cells and local inflammation damage the lung tissue in some patients as observed in pulmonary fibrosis.²³

Prevention and mitigation 

There is a need for novel therapies to treat pulmonary fibrosis because conventional therapy has limited efficacy or an unfavourable safety profile. There are also no FDA-approved therapies available.¹¹ To slow down the progression of pulmonary fibrosis, risk factors need to be identified and mitigative efforts should be taken to prolong the patient’s survival.

Reducing environmental exposure

As there is growing evidence of the close association between exposure to environmental hazards and smoking, removing repetitive stimuli of lung injury is a cost-effective method for reducing the incidence of pulmonary fibrosis. Regulations must be enforced to reduce the negative environmental impact of factory plants and subsequently to improve the air quality index. Residents living in areas with heavily polluted air are encouraged to wear facemasks when outdoors to filter out harmful particulate matter. To improve respiratory function, public health measures must be implemented to encourage the cessation of active and second-hand smoking. This must be emphasized, particularly in patients with chronic respiratory conditions. Mitigating environmental exposures seems to be the most cost-effective strategy.¹³

Prioritising workplace safety

Over recent decades, the rise in automation and mechanisation has reduced the occupational exposure of industrial workers to toxic dust and fumes. For instance, the mining industry in the majority of the European countries has been shrinking as a result of environmental policies. Moreover, as mentioned earlier in this article, asbestos is highly hazardous to lung function. Since the late 1990s, its usage has been banned in most of Europe.²⁵ Many workplaces have made significant progress in identifying occupational hazards and taking stringent measures such as reducing dust concentrations to ensure the health and safety of their workers. As workers in certain industries are more likely to be exposed to occupational hazards, regular health screenings should be provided to allow the early diagnosis of respiratory diseases.²⁶

Management and treatment of autoimmune diseases 

The most common treatment is taking immunosuppressive medications to regulate the activity of the immune system. Common options include methotrexate, azathioprine or cyclophosphamide to slow the progression of autoimmune diseases and reduce lung inflammation. Azathioprine works by inhibiting DNA replication in lymphocytes. However, these drugs may not be effective and are not well tolerated by patients. Some patients may even need to resort to lung transplantation when appropriate to restore their breathing abilities.²⁷ Another option is to prescribe patients anti-inflammatory agents like corticosteroids, which include pirfenidone and nintedanib which are both FDA-approved. Corticosteroids aim to reduce the rate at which fibrosis appears in the lungs. They interfere with leukocytes and restrict access to inflamed tissues.¹⁷ However, in the past decade, the use of corticosteroids for the treatment of pulmonary fibrosis has been strongly discouraged due to adverse outcomes.²⁸ In the future, chimeric antigen receptors (T-cells) can be used to treat autoimmune diseases. T-cells can be genetically engineered to express antigens on their surface to target and destroy autoantibodies that cause autoimmune diseases.²⁹

Conclusion

Identifying the risk factors such as environmental exposure, occupational hazards and autoimmune diseases is crucial to assess the risk of an individual developing pulmonary fibrosis. This way, we can better tailor preventive strategies and treatments to patients. This includes reinforcing public environmental and health measures and workplace regulations to minimise exposure to hazardous materials and managing symptoms of autoimmune diseases.