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Project

A study on the loss of small airways and epithelial cell changes in chronic lung diseases

The main function of the lung is to ensure optimal gas exchange of oxygen uptake and removal of carbon dioxide during breathing. Air entering the nose and mouth is travelling through a well-organized airway tree consisting of branches like in trees. This starts at the trachea (termed generation 0), splitting at the first bifurcation (generation 1) into two branches, each dividing many times along the tree into smaller airways and ending up in terminal bronchioles (generation 5-16). The bifurcations are not symmetrical dichotomous but most often asymmetrical with major and minor bifurcations (1). The diameter and length of the airways are decreasing with increasing generation in a well-balanced and orderly fashion. The fractal geometry system of the airways and the distribution of flow and pressure along this system is highly relevant to understand lung pathologies but are often neglected. There are currently no comprehensive studies which have explored this aspect on (healthy) human lungs or lungs from patients with respiratory diseases as, up to now techniques allowing analyzing human airway organization were lacking. This will be the first issue addressed in this project.

The structure of the airways is adapted to their functions and differs between the conducting zone and the respiratory zone. In the conducting zone (up to generation 16), convection occurs while in the respiratory zone (generation 17-23), gas exchange is taking place by diffusion. While large airways have a thick wall of fibrous connective tissue and cartilage rings, which confers them robustness, small airway (diameter <2mm) wall consists only in a thin layer of smooth muscle (suitable for diffusion) which is supported by alveolar attachment to maintain small airways open. This structure makes them more vulnerable as they are not well equipped to face excessive pressure and flow disturbance, they are more prone to collapse, and they do not possess a niche of progenitor cells such that repeated damage is thought to result in disappearance of small airways due to defect in repair process. We therefore believe that the small airways represent the Achilles heel of the lung.

The airway epithelium, which is essential to maintain airway homeostasis, consists in a pseudostratified epithelium whose composition differs along the airway tree. The most abundant cells are the ciliated cells accounting for 50-80% of the lung epithelial cells. These ensure that dust and mucous are removed. Goblet cells (20-25%) mainly produce mucous and are replaced by club cells with increasing airway generations. Together with ciliated cells, they are the main players for mucociliary clearance (2) and for preventing alveolar collapse. Basal cells are considered the main progenitor cells in the airways and they are able to proliferate and differentiate into virtually all the cell types of the airway epithelium. They are present in various proportion (6-30%) throughout the airways with their amount decreasing as the airways are getting smaller. In addition, other cells like secretory club cells can also act as progenitor cells for ciliated and goblet cells while in alveolar epithelium, the type II cells are able to proliferate and differentiate into type I and type II cells. Any disruption in maintenance and repair processes of epithelium integrity can lead to epithelium abnormalities ranging from hypoplasia (failure to differentiate) to basal- and goblet-cell hyperplasia, squamous- and goblet-cell metaplasia, dysplasia and malignant transformation. These abnormalities are commonly seen in respiratory diseases. It has been suggested that airway basal cells might contribute to respiratory disease susceptibility and progression. Indeed, basal cell exhaustion caused by continuous activation of the repair process following repeated injuries to the epithelium would promote abnormal airway remodeling and contribute to the development of chronic diseases in addition to the loss of small airways. How disturbance in cellular profile and cell behavior affects the disappearance of the terminal bronchioles remains unknown. Is it like in trees where leave fall in autumn is under the control of a separation process taking place in the abscission zone of specific cells? To better understand this process, we will analyze the cellular profile (issue 2) and the cellular behavior (issue 3) of the epithelial cells in the small airways and determine how they impact on airway morphology. We will focus on the “abscission zone” which is the zone where airways tend to disappear and where the bifurcation occurs.

This project will focus on 2 major respiratory diseases namely chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) as they are characterized by impaired ability to properly protect, regenerate and repair the (small) airway epithelium. COPD is expected to become the third leading cause of mortality by 2030 (3) while IPF affects approximately 3 million people worldwide. Both diseases share similar risk factors such as cigarette smoke, air pollution, genetic predisposition…). COPD is associated with airflow limitation by mucous hypersecretion and thickened airway walls (chronic bronchitis) and tissue destruction (emphysema). Altered airway epithelium in COPD is characterized by a basal and mucous cell hyperplasia with loss of cilia associated with ciliary dysfunction, it contains fewer basal cells (exhaustion) and the remaining cells even start to lose their progenitor function. In advanced COPD, it is shown that only 10% of the terminal bronchioles remain intact (4). IPF is a chronic, progressive disease which belongs to the interstitial lung diseases. With the accumulation of fibroblasts and fibrous connective tissue in the alveolar interstitium, the alveolar wall is thickening and consequently reduced gas exchange and elastic recoil prevent the alveoli and thus the lung to open during inhalation (5). This implies that small airways may collapse at inhalation, as alveolar attachments are dysfunctional and result in a restrictive lung function impairment. This implies that small airways may collapse. Some data indicating morphological and physiological abnormalities of the small airways in IPF patients suggest that small airways might play a potential role in IPF (6). This has been confirmed in our lab showing that only 20% of the small airways remain normal in end-stage IPF (accepted for publication, Lancet Resp. Med.).

Several evidences are now pointing out the weaknesses of the small airways suggesting that they may represent the Achille heel of the lungs being the first to fail. We hypothesize that their alterations would represent the initial step driving lung disease onset with the basal (progenitor) cells playing an important role in the disappearance of the small airways. The goal of this project is to gain more insight into the morphological and epithelial cell changes of the airway epithelium between healthy and diseased lungs in COPD and IPF and to determine how epithelium changes affect the morphology of the lung. This will be addressed in explant lungs from healthy donors, COPD and IPF patients obtained from lung transplantation. The morphological changes of the airways, with a specific focus on the small airways will be assessed by µCT on whole lung and small lung cores. Changes in epithelial cell composition in small airways and at abscission zones will be visualized on lung core sections by immunostaining. Behavior of epithelial cells will be followed in vitro in an air liquid interface cell culture system in. For that purpose, primary bronchial epithelial cells will be isolated from fresh explant lungs. The majority of the techniques used to address these issues are already established in our laboratory.

Date:15 Oct 2019 →  Today
Keywords:small airways, chronic lung diseases
Disciplines:Respiratory medicine
Project type:PhD project