What is emphysema?

Emphysema is a progressive type of chronic obstructive pulmonary disease (COPD) that gradually damages the structural integrity and function of the lungs.¹ It is a long-term condition that causes symptoms such as:

• Shortness of breath
• Wheezing
• Coughing
• Chest tightness or heaviness
• Fatigue
• Unintentional weight loss

What is the innate immune system?

The innate immune system is the body’s primary line of defense, providing rapid, non-specific protection against pathogens and toxic substances. This includes physical barriers, such as the skin and mucus, as well as immune cells such as macrophages and neutrophils. In emphysema, chronic exposure to toxins, such as cigarette smoke, continuously activates the innate immune system. This article will explain why and how this occurs.²

Pathophysiology of emphysema: how damage is caused

Smoking and pollutants

The leading cause of emphysema worldwide is smoking. Cigarettes contain carcinogenic and toxic substances such as nicotine, tar, carbon monoxide, and heavy metals. These chemicals can become trapped in the lungs and drive the inflammation, oxidative stress, tissue destruction, and impaired immune function often seen in emphysema. Similarly, exposure to pollutants in the air is also a major contributor.³

How toxins and pollutants damage the lungs

Inhaling toxins such as nicotine, tar carbon monoxide, and metals can injure the small sac-shaped structures in the lungs known as alveoli. The alveoli play an essential role in gas exchange, as they take in inhaled air and allow the oxygen to enter the bloodstream while removing carbon dioxide from the body. As toxins enter the alveoli, they can become trapped. The reactive chemicals in these toxins, such as cigarette smoke radicals and ozone, damage the airways and the cell lining of the alveoli. They can also destroy structures known as the cilia, which are responsible for the clearing of unwanted particles from the lungs.³

When alveoli are injured, cells release signals of damage known as damage-associated molecular patterns. These include cytokines such as IL-33, as well as inflammatory transcription factors such as NF-kB. This leads to the activation of additional cytokines and chemokines, which in turn cause further inflammation and tissue damage through the recruitment of white blood cells, in an attempt to heal the damage.⁴

Macrophages and neutrophils are white blood cells attracted to damaged alveoli by chemokines. Alveolar macrophages release matrix metalloproteinases, enzymes that break down the extracellular matrix of alveolar cells, digesting the epithelium (cell lining) and removing elastin and collagen proteins.⁴ This breaks down the alveolar walls and prevents the elastic recoil normally provided by elastin. Elastic recoil helps alveoli return to their original shape after stretching and assists in clearing particles from the lungs. In emphysema, our own immune system causes inflammation and damage in the alveoli, preventing this elastic recoil and impairing efficient gas exchange.

Similarly, neutrophils can produce neutrophil extracellular traps (NETs), which amplify damage. NETs are composed of DNA and proteins that trap pathogens but also promote local injury of alveolar tissue. Continued injury causes apoptosis and necrosis (cell death) of the alveoli and their epithelium. Additionally, the impaired clearance of dead cells (due to loss of elasticity in the alveoli) produces further inflammation. This results in a chronic cycle of inflammation and immune overactivation in response to toxins.⁴

Structural changes to the lungs in emphysema

Over time, the inflammation caused by emphysema and the innate immune response can cause major structural changes in the lungs. The destruction of the alveolar walls by matrix metalloproteinases and other enzymes causes a loss of septa (thin walls) between alveoli, reducing the surface area available for oxygen and carbon dioxide exchange with the bloodstream. The alveoli may also develop enlarged air spaces known as bullae, and the loss of capillary beds within the alveolar walls, further hindering ventilation and gas exchange.⁵

The loss of elasticity in lung tissue reduces elastic recoil, which can cause airway collapse during exhalation due to the lack of structural support. This impairs the effective removal of unwanted particles and can lead to further complications and infections. Additionally, airway narrowing and obstruction can occur due to inflammation and mucus secretion in the bronchioles.⁵

Adaptations to the lung architecture include hyperinflation. This involves an increased residual volume (minimum amount of air in the lungs, normally around 1.2 litres) and the total lung capacity (maximum amount of air that the lungs can hold, approximately six litres in healthy adults). Hyperinflation occurs because air becomes trapped in alveoli at the end of exhalation. In chronic, advanced cases, it can also cause the chest to develop a barrel-shaped appearance.⁶

Diagnosing emphysema

Emphysema is diagnosed using a mixture of strategies, including clinical history investigations, physical examination, imaging, and lung function tests. 

Understanding the cause of a patient’s emphysema is essential. This can be achieved through assessing the patient’s lifestyle. The most common causes are a long history of smoking or prolonged exposure to air pollution. If a patient also presents with symptoms such as shortness of breath, chronic coughing, and wheezing, this can support the diagnosis, although these symptoms alone are not definitive. Physical examinations can be used to identify characteristics of emphysema such as a barrel-shaped chest due to hyperinflation, use of accessory muscles to breathe, and prolonged exhalation.⁷

Pulmonary function tests are considered the gold standard when diagnosing emphysema and other types of COPD. Results will often show an obstructive pattern, such as:

• Decreased forced expiratory volume: total amount of air exhaled from the lungs in one second
• Normal/decreased forced vital capacity: maximum volume of air a person can forcefully exhale after taking a deep breath
• Increased residual volume
• Increased total lung capacity⁷

Imaging techniques such as X-rays and CT scans, can also identify characteristics of emphysema. Chest X-rays can be conducted to identify hyperinflation, flattened diaphragms, reduced vascular markings, and bullae. CT scans are more sensitive and can detect areas where alveoli are destroyed, sites of bullae, and the overall distribution of damage.¹

Laboratory tests can also be used in younger patients or non-smokers who may have emphysema due to a genetic deficiency. Arterial blood gases can also be measured to detect hypoxemia (low oxygen) and hypercapnia (carbon dioxide retention) in advanced cases.⁷

Pharmacological treatment of emphysema

Corticosteroids are a group of drugs sometimes used to treat emphysema. However, the inflammation of COPD is mostly induced by neutrophils and macrophages, which are not fully responsive to corticosteroids. Inhaled corticosteroid therapies ( such as budesonide and fluticasone) are used in combination with bronchodilators to reduce the frequency of exacerbations (symptoms worsening in response to a trigger). This is key in treating patients with frequent flare-ups. Oral corticosteroids are less effective, due to side effects, such as osteoporosis, diabetes, and muscle wasting. They are strictly reserved for acute cases only, typically over the course of 5-7 days.⁸

Phosphodiesterase-4 (PDE-4) inhibitors are a group of drugs which block the PDE-4 enzyme, which normally works to break down cyclic adenosine monophosphate (cAMP) into AMP in inflammatory cells. By inactivating the breakdown of cAMP, there is less inflammatory activity in immune cells. This suppresses the innate immune response and specifically causes neutrophils to release elastase to protect the alveoli while macrophages decrease the secretion of pro-inflammatory chemicals. Roflumilast is the only widely approved oral PDE-4 inhibitor for severe cases of COPD.⁹

Macrolides are a class of antibiotics which have anti-inflammatory effects. They can help to relieve inflammatory symptoms in emphysema patients. Macrolides reduce bacterial colonisation in the airways, lowering the risk of infection-triggered exacerbations. Macrolides also reduce neutrophil recruitment, preventing neutrophil activities such as NET formation. They also suppress the pro-inflammatory cytokines released by macrophages in response to damage. Macrolides are not initially used in emphysema but may be prescribed in cases of frequent exacerbations and patients with a history of long-term smokings. Macrolides commonly used in cases of emphysema are azithromycin and clarithromycin.¹⁰

Challenges and future directions

Emphysema poses a high economic burden due to high hospitalisation rates and long-term drug costs. Although there are various effective diagnostic methods in emphysema, treatment remains challenging. Emphysema is largely driven by the innate immune system, and most of the lung damage and inflammation is caused by white blood cells. This results in a difficulty in prescribing drugs to treat emphysema. Corticosteroids have limited specificity for immune cells, while PDE-4 inhibitors can cause side effects such as diarrhea, abdominal pain anxiety, and depression. Long-term use of macrolides may lead to antibiotic resistance and, in some cases, hearing loss with azithromycin therapy. These limitations restrict current drug options to specific cases. The lack of effective drug treatments means hospitals have to rely on oxygen therapies, pulmonary rehabilitation, and the promotion of smoking cessation to manage emphysema effectively.¹¹

The structural damage in the lungs is irreversible. Alveolar destruction cannot be regenerated, and current treatments only target the symptoms and slow disease progression rather than cure emphysema. Additionally, current drugs do not prevent lung tissue loss so it is essential that new therapies are developed. Areas under research include stem cell therapy and tissue engineering to repair damaged alveoli, as well as growing lung tissue for transplantation to restore lung structure.¹¹

Summary

Emphysema is a chronic, progressive lung disease characterised by the irreversible destruction of the alveolar walls, loss of elasticity, and enlarged air paces. Long-term exposure to toxins, particularly from cigarette smoke, triggers chronic activation of the innate immune system, causing macrophages and neutrophils to release proteases and other chemicals that damage the lung tissue. This results in a lack of air flow within the lungs,  contaminated air being trapped inside the alveoli, and increase in the residual volume of the lungs and impairing gas exchange, Symptoms of emphysema include shortness of breath, chronic cough, wheezing and a reduced exercise tolerance. Diagnosing emphysema involves assessing patient history, imaging with X-rays and CT scans, and conducting lung function tests. Emphysema is incurable, and the damage caused to the lungs is irreversible. However, treatment involves relieving symptoms with drugs such as corticosteroids, PDE-4 inhibitors, macrolides, and oxygen therapy.