Rethinking the pathogenesis of COPD

Is chronic obstructive pulmonary disease a self inflicted disease?

For 50 years, since Fletcher and Peto reported their seminal observations in young working men in London, chronic obstructive pulmonary disease (COPD) has been widely accepted as a self-inflicted condition caused by tobacco smoking.

Heavy cigarette smoking is a prerequisite or exposure to a smoke filled environment; individual susceptibility leading to damage to the bronchioles; reduction in airflow detected by a reduction in FEV1. The damage then accelerates the physiologic decline of lung function with age, and causes chronic respiratory symptoms, which are difficult to reverse and may periodically be manifested as exacerbations, eventually leading to respiratory failure.

Why do we need to rethink this?

Currently we think of COPD as irreversible hence treatment is limited to improving airflow in the lungs by the use of bronchodilators. Stopping cigarette smoking is emphasised. This does not cure the disease but may reduce the speed of degeneration of lung functions. Most people live increasingly dysfunctional life styles; may develop pulmonary hypertension which can cause cor pulmonale. Where are the discrepancies?

  • First, although tobacco smoking is the key environmental risk factor for COPD a third of affected patients worldwide are nonsmokers.
  • Other environmental pollutants, such as smoke from biomass fuel used for cooking and heating, are also major environmental risk factors for COPD in many places around the globe. 
  • Comorbid conditions are highly prevalent among patients with COPD but are largely unrelated to lung function.
  • Lung functions as measured by FEV1 have a range of trajectories in the population. This means that some people (between 4% and 12% of the general population) do not have an FEV1 peak that is in the predicted normal range for their age and sex. These persons also have a higher prevalence and an earlier incidence, by about a decade, of coexisting cardiac and metabolic disorders, as well as an increased risk of premature death. Can these people be identified as being at risk and treated early? Should we be doing FEV1 in healthy children and following up on those with reduced FEV1?
  • The diagnosis of COPD currently requires spirometric confirmation of airflow limitation. Smokers with normal spirometric findings but chronic respiratory symptoms and exacerbations or computed tomographic (CT) evidence of lung disease such as emphysema are not considered to have COPD and hence do not receive evidence-based treatment for it.

So what happens when a smoker puffs at a cigarette?

A puff of cigarette smoke contains millions of water droplets with a median aerodynamic diameter of 0.45 μm, each containing a complex mixture of toxic chemicals derived from the various types of raw tobacco plus toxic chemicals added to achieve the blend of aroma and taste that defines a particular brand of cigarette.

The larger particles, because of their momentum, collide with the mucosa of the trachea and larger bronchi and are deposited there. The intermediate particles slow as the surface area increases in the smaller bronchioles and are deposited there. The smallest particles reach the alveoli and respiratory bronchioles and are deposited there. Toxic gases diffuse into the the lung tissue throughout the duration of the puff.

How does the lung react to the smoke? The lung tissue is infiltrated by neutrophils, macrophages, and lymphocytes. In severe COPD, lymphocytes form tertiary lymphoid organs, indicating the presence of an adaptive immune response. Airway remodeling thickens the airway walls in a manner that involves the epithelium, lamina propria, smooth muscle, and adventitia of the walls of airways that are less than 2 mm in diameter. Studies using microCT have confirmed that the number of patent terminal and transitional bronchioles is reduced by 40% in mild-to-moderate COPD and by 80% in severe-to-very-severe COPD. These findings are consistent with Mead’s hypothesis that these airways represent a “quiet zone” within the lungs where damage can accumulate without being noticed.


Emphysema is a component of COPD. It is believed to be caused by an imbalance between protease and antiprotease activity due to lung infiltration by activated neutrophils, reduced antiprotease activity, or both, with the classic example being alpha1-antitrypsin deficiency. Now factors which are also considered as causing emphysema are oxidant stress, autoimmunity, maternal smoking, and malnutrition. The last two factors may cause poor alveolar development in utero.

How is the pulmonary blood flow affected in emphysema and why does cor pulmonale develop? There is a reduction in the capillary bed and there is vasoconstriction associated with hypoxia. There are inflammatory changes in the pulmonary capillaries and endothelial dysfunction. Why some patients develop pulmonary hypertension to a greater extent than airflow obstruction is not understood.

What about vaping ( inhaling vapors from electronic cigarettes)? What about exposure to biomass fumes like cooking on gas cookers, wood or coal fires, smoke from brick kilns fired by wood or coal, even cow dung or peat fumes? Their exact contribution is not known but they are one of the factors associated with COPD though severity of disease is less than that with cigarettes and the development of emphysema is slower.

What other diseases should be included as causing COPD?

The pathogenesis of chronic airflow limitation due to other diseases, such as tuberculosis, bronchiectasis, rheumatoid arthritis, and human immunodeficiency virus infection, is even less well understood, so whether these disorders should be included within the COPD syndrome requires further research.

How does healing occur in the lung after smoke related injury?

The repair process begins with activation of the coagulation system, which initiates the damage control required to stop bleeding. This is followed by the infiltration of inflammatory immune cells, primarily neutrophils and macrophages, which protect the site of injury from infection and participate in a demolition process that removes dead and damaged tissue. Subsequently, fibroblasts, myofibroblasts, and endothelial precursor cells appear and create a provisional matrix that allows the microvascular network to reconnect and supports the restoration of the epithelial surface, which under ideal circumstances can restore the tissue to a healthy state. Since smoking causes repetitive injury, it elicits a more complex form of tissue repair that combines tissue destruction with scar formation.

When the tissue insult ends resolution of inflammation (i.e., catabasis) begins. This highly regulated process requires the active participation of many different molecules, including lipid mediators (e.g., lipoxins, protectins, and resolvins) and repair factors (e.g., transforming growth factor β, vascular endothelial growth factor, hepatocyte growth factor, and peroxisome proliferator–activated receptors), as well as the elimination of apoptotic neutrophils and epithelial cells by macrophages (efferocytosis), which prevents secondary necrosis of apoptotic cells with liberation of the proinflammatory cytoplasmic content. A key macrophage efferocytosis receptor, CD44, is down-regulated in patients with COPD.

What is the role of the reaction of lung tissue to antigens? Is COPD and autoimmune disease?

There is an adaptive immune response to either self antigens or foreign antigens (bacterial, viral, or fungal) which contributes to the pathogenesis of COPD. Patients with COPD have greater numbers of T lymphocytes and B lymphocytes than healthy persons as well as B-cell infiltration (with the formation of lymphoid follicles) in the walls of terminal bronchioles and alveolar tissue, which correlates with a reduced number of alveolar attachments to the airway walls, and patients who have COPD with emphysema have a distinct B-cell transcriptomic signature.

Why do only a proportion of smokers develop COPD?

  • The best-known genetic risk factor for COPD is alpha1-antitrypsin deficiency.
  • Hobbs et al. identified 22 genetic loci associated with COPD in a large cohort 13 represented new associations with COPD. 
  • Epigenetic changes induced by smoking appear to be directly related to smoking exposure and may not resolve after cessation of smoking. These contribute to individual susceptibility to COPD.  Genomewide studies profiling DNA methylation in lung tissue from patients with COPD have revealed differences in methylation loci that are related to lung function, a diagnosis of asthma, nicotine dependence, T-cell development, and other factors. 

How does COPD progress.

So far attention has been focused on loss of airflow. What other factors need to be considered? COPD is a heterogeneous disease with components that can progress independently of one another. For instance,

  • Frequent exacerbations, each of which is associated with a decline in FEV1 and an effect on health status and prognosis, occur predominantly in a subgroup of patients. 
  • Second, multimorbid conditions can contribute to disease progression independently of lung function. 
  • Third, given that various lung-function trajectories lead to COPD in adulthood, it is possible that patients with severe disease have not had the mild and moderate stages of disease. Thus, it is possible that these stages actually result from different pathogenic mechanisms and have different natural histories. 
  • Finally, the traditional view that COPD is always a progressive disease also needs to be revised because lung function often remains stable or may even improve with time in some patients.

What role does cell senescence play in the progression of COPD?

The term “cell senescence” is often used in the discussion of lung aging in COPD and refers to a functional state of the cell characterized by irreversible replicative arrest, apoptosis resistance, and acquisition of a senescence-associated secretory phenotype (SASP) with proinflammatory and tissue-destructive effects. This occurs not only in “old cells” but also in young ones. Excessive aging can therefore also be a pathogenic mechanism of COPD, and senolytic therapies aimed at reducing the senescent-cell burden in a number of human diseases merit investigation.

Should we then regard COPD as the pulmonary component of a systemic and multimorbid syndrome?

COPD should currently be considered a clinical syndrome with many causes in addition to smoking.This does not mean that health care professionals should refrain from encouraging all their patients who smoke to quit, but it does mean that the pathogenic mechanisms in mild-to-moderate COPD may differ from those in severe-to-very-severe cases of airflow limitation. In fact, the assumption that COPD is always a progressive disease also requires careful reconsideration. The approach to COPD should be the development of specific, effective, and safe preventive and therapeutic strategies, which most likely will have to be implemented earlier in life.

Reference: Update on the Pathogenesis of Chronic Obstructive Pulmonary Disease. Alvar Agustí, M.D., Ph.D., and James C. Hogg, M.D., Ph.D. September 26, 2019
N Engl J Med 2019; 381:1248-1256
DOI: 10.1056/NEJMra1900475.

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I am a Professor of Medicine and a Nephrologist. Having served in the Army Medical College, Pakistan Army for 27 years I eventually became the Dean and Principal of the Bahria University Medical and Dental College Karachi from where I retired in 2016. My passion is teaching and mentoring young doctors. I am associated with the College of Physicians and Surgeons Pakistan as a Fellow and an examiner. I find that many young doctors make mistakes because they do not understand how they should answer questions; basically they do not understand why a question is being asked. My aim is to help them process the information they acquire as part of their education to answer questions, pass examinations and to best take care of patients without supervision of a consultant. Read my blog, interact and ask questions so that I can help you more.

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