Sukhwinder S. Sohal, PhD, on the Pathogenesis of COPD

A better understanding of the pathogenesis of chronic obstructive pulmonary disease (COPD) will help create more-effective, and even preventive, therapies for patients. A research team from Australia, led by Sukhwinder S. Sohal, PhD, MSc, MS, BSc, recently authored an update on the pathogenesis of COPD.

Dr Sohal is board director of the Thoracic Society of Australia and New Zealand; head of the Respiratory Translational Research Group; chair for Histology North Tasmania; senior lecturer in Histopathology, Discipline of Laboratory Medicine; and director of the Tasmanian Respiratory Tissue Bank.

Pulmonology Consultant reached out to Dr Sohal with questions about this update.

PULM CON: Can you give us an update on the pathogenesis of COPD? What have we learned about it in recent years that may help treat the disease?

Sukhwinder Sohal: The prime pathology in COPD pertains to small airway fibrosis that leads to disrupted airway function. Small airway destruction occurs quite early in the disease and also often correlates with emphysema. The other closely associated pathology of COPD is the development of airway epithelial cancer, predominantly in large airways (ie, squamous cell carcinomas), though adenocarcinomas are also seen. One mechanism that seems to be central to these pathologies is the process of epithelial to mesenchymal transition (EMT).

EMT is a biological process by which epithelial cells lose cell-cell adhesion, gain mesenchymal traits of migration and invasion, and produce components of extracellular matrix. EMT is a manifestation of airway basal cell reprogramming in smokers and people with COPD. EMT does not need to be a binary process, rather cells can display a spectrum of phenotypes, ranging from fully epithelial to fully mesenchymal. Hallmarks of EMT have been observed in the airways of people with COPD and smokers, and lung cancer cells can attain either partial EMT (ie, a hybrid epithelial/mesenchymal phenotype) or a complete EMT phenotype.

My laboratory has previously published and was the first to report that EMT is an active process in both small and large airways of smokers and patients with COPD with consequential effects on lung physiological parameters in these patients.2 In the large airways, we observed that EMT-related changes were associated with increased hypervascularity of the underlying reticular basement membrane (Rbm), representing a typical active type-3 EMT process, considered as a precursor to malignant conditions and metastasis. It is important to note that it is large airways where most of the squamous cell carcinomas occur, and type-3 EMT could be central to this. The other key pathology associated with COPD is peribronchiolar fibrosis and obliteration, which is attributed to active type-2 EMT at this site, but fibrosis in general is also associated with malignancy. 

In a first-ever randomized controlled trial of its kind, we hypothesized that EMT might be the process through which the effect of inhaled corticosteroids (ICS) occurs.3 The results of this study showed that inhaled fluticasone propionate delivered in high doses over 6 months suppressed airway epithelial activation and EMT-related changes in large airways of COPD patients. In the same population, we also investigated effects of ICS on vascular remodeling in COPD.3 ICS did not change Rbm vascularity but improved lamina propria vascularity in COPD past smokers. Physiological indices of air trapping showed negative correlations with increased vessel numbers (ie, more vessels, less air trapping). Perhaps for Rbm hypervascularity, longer duration with ICS or intravenous doses are required to attenuate vascular components of EMT.

More recently, in lung resections from cancer patients, we reported4 active EMT as the leading edge of invasive non-small-cell lung cancer, both squamous carcinomas and adenocarcinomas, with tumor aggressiveness strongly related to EMT activity. Further, EMT markers within the tumors closely related to EMT activity from nontumor-affected airway wall epithelium. This work suggests that the level of EMT activity in the airway wall, even in large airways that are acquiescent to bronchoscopy, could potentially be used as a marker for smokers most likely to develop both COPD and lung cancer. 

Airway inflammation has also been suggested as a contributor of COPD and lung cancer development in patients with COPD, but careful interpretation is required. Our data from a comprehensive cross-sectional study5 demonstrated hypocellularity in the lamina propria of both large and small airway walls of patients with COPD compared with never-smokers. There was also no change in the proportions of key immune cell populations such as neutrophils, macrophages (CD68+), and CD8+ and CD4+ cells. The only increase was observed for CD8+ cells in the small airways. We further identified differential macrophage switching in the small airway wall, lumen, and alveolar spaces. We observed that the airway wall in never-smokers was predominantly M2 (CD163+), which switched to a more M1 phenotype in patients with COPD. In the lumen and alveolar spaces, however, we found an increase in M2 macrophages over M1s in both current smokers and patients with COPD compared with never smokers. Bronchioalveolar lavage cytokine profile also matched these findings, which skewed toward a more M2 profile. Interestingly, M2 are also the predominant phenotype observed in lung cancer and are known to promote tumorigenicity. ICS may play a role in suppressing these specific phenotypic changes, thus restricting COPD progression to cancer, but this requires further probing.

Acute exacerbations of COPD (AECOPD) are associated with accelerated loss of lung function, increased mortality, and decreased health-related quality of life and cause substantial economic burden to society. Bacterial pathogens constitute a significant portion of AECOPD, with non-typeable Haemophilus influenzae (NTHi) being the most common bacterium followed by Streptococcus pneumoniae and Moraxella catarrhalis. Microbial infections frequently cause severe pneumonia in susceptible patients with COPD. These infectious pathogenicities are often observed to be further aggravated by an increase of viral coinfections. Although a robust pulmonary immune defense system exists, involving highly evolved mechanisms of both innate and adaptive immunity, under pathological conditions, microbes often manage to defend or evade host immune response, increasing the bacterial load and colonization in the tissue. One possible evasive mechanism employed by microbes is increased adherence to airway epithelial cells through receptors such as platelet-activating factor receptor (PAFr) and intracellular adhesion molecule-1 (ICAM-1).

The prerequisite step is the adherence of pathogens to the respiratory mucosa. The interaction between the epithelial and bacterial surface occurs through the phosphorylcholine (ChoP)—a molecular mimic of platelet-activating factor (PAF) present on the bacterial surface—while PAFr is expressed on the airway epithelium. Both airway pathogens, Pneumococcus and Haemophilus influenzae can attach to airway epithelial PAFr through ChoP and remain protected from the body’s innate immune responses. We have previously reported that PAFr expression increases in the airways of smokers and patients with COPD.6 We also observed increases in PAFr expression in the small airway, inflammatory cells, and alveolar epithelium of patients with COPD.6

The pan airway presence of PAFr in patients with COPD is likely to provide necessary adhesion sites throughout the lung tissue, hence increasing the risk of bacterial colonization at multiple regions. Similarly, in patients with COPD, we observed an epithelial increase in another such adhesion molecule, ICAM-1, suggesting involvement of more than one receptor that facilitates such mechanisms. In an in-vitro study7 using BEAS-2B lung epithelial cells, we further demonstrated that antagonizing PAFr by using specific chemical blockers leads to a significant decrease in adherence and engulfment of both non-typeable H influenzae (NTHI) and S pneumoniae in a dose-dependent manner. This also suggests PAFr is a potential therapeutic target for COPD to block chronic microbial colonization and reduce acute exacerbations.

PULM CON: What do we still not know about COPD? What knowledge gaps still exist?

SS: COPD is a common and devastating disease with huge impacts on people and health services throughout the world. It is mainly due to cigarette smoking, though environmental pollution may play a part. There are no current treatments that affect the overall course of COPD; current drugs focus on symptomatic relief and, to some extent, reducing exacerbation rates. There is urgent need for in-depth studies of the fundamental pathogenic mechanisms underpinning COPD. This is vital, given that nearly 50% of small airways in patients with COPD are obliterated, and major increases in susceptibility to lung cancer occur well before the first measurable changes in lung function are noticed.

Current COPD research mostly revolves around late disease and/or innate immune activation within the airway lumen, but the actual damage to the airway wall has early onset. What we see in COPD today is an end result of complex mechanisms, triggered in response to epithelial activation. To change the disease course, it is very important to understand mechanisms in the epithelium that get switched on early in smokers. Understanding the dynamic nature of COPD will open new windows for therapy. We need to know the key mechanisms contributing to early COPD so that we can change the disease trajectory in the early days of the disease process. Another question is how early is early? Where should we draw the line?

PULM CON: What is your key take-home message about the pathogenesis of COPD?

SS: I believe there is a need for debate and further in-depth studies of what are the fundamental issues with this disease, we have made some progress but need more answers. Even major published overviews of COPD largely ignore important aspects of the disease such as the realization that 50% of small airways have been obliterated by fibrosis before the FEV1 even changes and the lethal association between even early/mild COPD and lung cancer.

It is biologically plausible that the link between cancer and COPD, which is an independent risk apart from smoking, may be related to parameters that could be more widely measured, such as markers of EMT and epithelial hypervascularity. EMT may represent a fundamental important aspect of COPD pathology and a “novel therapeutic target” for prevention of both epithelial malignancy and small airway fibrosis. Indeed, ICS treatment does attenuate these changes. Inflammation forms a crucial factor in COPD and is known to variably affect patients based on their disease stage and age. However, more recently, the effectiveness of immune cell function has been called into question, with several studies indicating both dysfunctionality and dysregulation in immune cells.

Furthermore, cellular profiles in airway tissue have been somewhat paradoxical; although literature evidence demonstrates a consistent increase in airway inflammatory cells in the lumen, the overall picture in the airway wall has been variable across laboratories for several years. Our recent observation suggested a decrease in both total cellularity and key inflammatory cells in the airway wall of patients with mild to moderate COPD compared with smokers and healthy controls, which indicates possible immune suppression and thus increased susceptibility to infections at least early in the disease. Microbial adhesion molecules are important epithelial attachment sites for both viruses and bacteria. This complex pathology is further exaggerated due to increasingly immunocompromised situations in patients with COPD. Our findings in COPD might well be applicable to other chronic lung diseases such as asthma and interstitial lung diseases. Translational research in this area of microbial-epithelial interactions is still in its infancy but has huge potential to provide novel insights into COPD for the prevention of acute exacerbations.

We may now be getting into a position that allows an integrated understanding of this airway disease, with the potential to be translated into a new paradigm for earlier or even preventive therapy. It is vital to understand fundamental disease mechanisms for early interventions. We should promote novel descriptive human tissue studies that provide new insights and paradigms. There is an essential need to rethink COPD airway pathology for the identification of new therapeutic targets.

For additional references related to the pathogenesis of COPD, click here.

References:

1. Eapen MS, Sohal S. Update on the pathogenesis of COPD. N Engl J Med. 2019;381(25):2483-2484. https://doi.org/10.1056/nejmc1914437.
2. Sohal SS, Reid D, Soltani A, et al. Reticular basement membrane fragmentation and potential epithelial mesenchymal transition is exaggerated in the airways of smokers with chronic obstructive pulmonary disease. Respirology. 2010;15(6):930-938. https://doi.org/10.1111/j.1440-1843.2010.01808.x.
3. Sohal SS, Soltani A, Reid D, et al. A randomized controlled trial of inhaled corticosteroids (ICS) on markers of epithelial-mesenchymal transition (EMT) in large airway samples in COPD: an exploratory proof of concept study. Int J Chron Obstruc Pulmon Dis. 2014;9:533-542. https://doi.org/10.2147/copd.s63911.
4. Mahmood MQ, Ward C, Muller HK, Sohal SS, Walters EH. Epithelial mesenchymal transition (EMT) and non-small cell lung cancer (NSCLC): a mutual association with airway disease. Med Oncol. 2017;34(3):45. https://doi.org/10.1007/s12032-017-0900-y.
5. Eapen MS, McAlinden K, Tan D, et al. Profiling cellular and inflammatory changes in the airway wall of mild to moderate COPD. Respirology. 2017;22(6):1125-1132. https://doi.org/10.1111/resp.13021.
6. Shukla SD, Muller HK, Latham R, Sohal SS, Walters EW. Platelet-activating factor receptor (PAFr) is upregulated in small airways and alveoli of smokers and COPD patients. Respirology. 2016;21(3):504-510. https://doi.org/10.1111/resp.12709.
7. Shukla SD, Fairbairn RL, Gell DA, et al. An antagonist of the platelet-activating factor receptor inhibits adherence of both nontypeable Haemophilus influenzae and Streptococcus pneumoniae to cultured human bronchial epithelial cells exposed to cigarette smoke. Int J Chron Obstruct Pulmon Dis. 2016;11:1647-1655. https://doi.org/10.2147/copd.s108698.