Small airway fibrosis in COPD

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterised by an accelerated decline in airway function with age compared to age-matched non-smokers. There is increasing evidence that this is due to small airway disease rather than from emphysema, especially in the early stages of the disease. Small airways (<2 mm internal diameter) are narrowed in COPD with thickening and distortion of the airway wall and peribronchiolar fibrosis. In addition, loss of elasticity in alveolar attachments and mucus hypersecretion contribute to the airway narrowing and closure, leading to air trapping. The mechanisms of peribronchiolar fibrosis are poorly understood and small airway fibroblasts have not been characterised. In small airways of COPD patients the fibroblasts are profibrotic, pro-inflammatory and senescent. There is a reduction in the anti-ageing molecules sirtuin-1 and -6, which are regulated by specific microRNAs that are increased in COPD cells. It is plausible that extracellular vesicles from senescent airway epithelium transmit senescent signals to airway fibroblasts to stimulate fibrosis and inflammation. Small airways fibrosis is a target for new drug development that inhibit growth factor receptors, new antioxidants and particularly those that are targeted to mitochondria and inhibitors of cellular senescence or senolytic therapies.

Introduction

Professor Geoff Laurent, previous editor of this journal, was an outstanding respiratory scientist, who provided important new insights into chronic lung diseases, and particularly those that involve fibrosis of the lungs (Laurent et al., 2007). His research laid the foundations for current understanding of fibrosing lung diseases, particularly idiopathic pulmonary fibrosis (IPF), which has now become a major focus for research (Maher et al., 2007). Chronic obstructive pulmonary disease (COPD) is not usually regarded as a fibrotic lung disease and the main abnormality in the lung parenchyma is destruction of alveoli (emphysema) rather than fibrosis, although is some patients emphysema and lung fibrosis may occur together –the rare combined pulmonary fibrosis emphysema (CPFE) patients (Alsumrain et al., 2019). However, fibrosis appears to be a major mechanism for the narrowing of small airways, which is now recognised as probably the earliest and most important mechanism for COPD progression (Hogg et al., 2017). For this reason, I have focussed on what is known about small airway fibrosis in COPD, although this area of research has been surprisingly neglected, so there are no relevant animal models and little is understood about the mechanisms of small airway fibrosis.

COPD has now become a global epidemic and affects over 300 million people worldwide. It is now the third most prevalent cause of death globally, a leading cause of hospital admission and the fifth ranked cause of disability (Barnes et al., 2015; Global Burden of Disease Collaborators, 2017). COPD is increasing even in high income countries as populations age and mortality from other common causes of death decrease. The increasing prevalence of COPD in low-to-middle income countries is even greater as smoking is increasing, especially in women, and a large proportion of the population is exposed to household air pollution and traffic pollution (Salvi and Barnes, 2009; Sood et al., 2018). COPD is difficult to manage as long-acting bronchodilators, which are the mainstay of current management, do not treat the underlying progressive disease process and corticosteroids, which are highly effective anti-inflammatory treatments in asthma, provide little clinical benefit for most patients. It has proved difficult to develop effective and safe anti-inflammatory or disease-modifying treatments as underlying disease mechanisms are not well understood and the heterogeneity of the disease makes it difficult to select the right patient population (Barnes, 2013). More research is needed on underlying disease mechanisms and a molecular and cellular level in order to identify new therapeutic targets for future drug development.

Section snippets

Pathophysiology of COPD

There are three major pathological mechanisms in the lungs of COPD patients, although their relative proportions may vary between patients (Hogg and Timens, 2009). Chronic bronchitis involves goblet cell hyperplasia with increased mucus secretion which may predispose to bacterial colonisation and acute exacerbations (Boucher, 2019). Emphysema is due to destruction of alveolar walls, resulting in reduced gas diffusion and appears to be a late feature of the disease in most patients. Although

Small airway obstruction in COPD

Small airways of less than 2 mm internal diameter offer less than 10% of airway resistance in normal lungs due their very high number, but become a major site of airway obstruction in COPD patients. This has been confirmed by measurement of airway resistance by direct measurements of intrabronchial pressure (Yanai et al., 1992). Several ways of measuring small airway obstruction in COPD patients have now been developed (Ostridge et al., 2019). The forced oscillation technique (FOT) using

Small airway fibrosis in COPD

The mechanisms of small airway fibrosis in COPD are poorly understood. Cigarette smoke extract induces oxidative stress and apoptosis of human lung fibroblasts (Carnevali et al., 2003). COPD lung fibroblasts show defective repair functions and contraction of collagen gels (Togo et al., 2008). Very little is known about the function of fibroblasts in small airways or whether these differ from interstitial lung fibroblasts which have been extensively investigated. There is increasing evidence for

Mechanisms of small airway fibrosis

Oxidative stress is increased in the lungs of COPD patients and persists on smoking cessation due to the production of reactive oxygen species by inflammatory cells. It drives many of the inflammatory mechanisms in COPD and is a stimulus for the release of profibrotic mediators, such as TGF-β from airway epithelial cells (Fig. 2) (Kirkham and Barnes, 2013). Airway epithelial cells may release several profibrotic mediators. Increased expression of TGF-β has been reported in small airway

Cellular senescence in COPD

There is increasing evidence that COPD represents accelerated ageing of the lung, with the accumulation of senescent cells (Barnes, 2017; Barnes et al., 2019). Small airway epithelial cells from COPD patients show increased senescence with reduced cellular growth and increased expression of senescence markers such as the cyclin-dependent kinase inhibitors p16INK4a and p21CIP/WAF with a reduction in the anti-ageing molecules sirtuin-1 and sirtuin-6 (Baker et al., 2019, 2016). These senescent

Therapeutic implications

In view of the key role of small airway fibrosis in disease progression, particularly in the early stages in COPD, it is surprising that there have been so few studies in COPD patients. The mechanisms of peribronchiolar fibrosis remain to be elucidated, but it now seems likely that SAFs may play a key role through the release of profibrotic mediators, inflammatory proteins and MMPs (Kadota et al., 2018). It is possible that small airway epithelial cells that are exposed to an oxidative stress

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