The human lung differs substantially from its mouse counterpart, resulting in a distinct distal airway architecture affected by disease pathology in chronic obstructive pulmonary disease. In humans, the distal branches of the airway interweave with the alveolar gas-exchange niche, forming an anatomical structure known as the respiratory bronchioles. Owing to the lack of a counterpart in mouse, the cellular and molecular mechanisms that govern respiratory bronchioles in the human lung remain uncharacterized. Here we show that human respiratory bronchioles contain a unique secretory cell population that is distinct from cells in larger proximal airways. Organoid modelling reveals that these respiratory airway secretory (RAS) cells act as unidirectional progenitors for alveolar type 2 cells, which are essential for maintaining and regenerating the alveolar niche. RAS cell lineage differentiation into alveolar type 2 cells is regulated by Notch and Wnt signalling. In chronic obstructive pulmonary disease, RAS cells are altered transcriptionally, corresponding to abnormal alveolar type 2 cell states, which are associated with smoking exposure in both humans and ferrets. These data identify a distinct progenitor in a region of the human lung that is not found in mouse that has a critical role in maintaining the gas-exchange compartment and is altered in chronic lung disease. Human respiratory bronchioles contain a unique population of secretory cells called respiratory airway secretory cells that are distinct from the cells in the larger proximal airways, and act as unidirectional progenitors for alveolar type 2 cells. 

Human distal airways contain a multipotent secretory cell that can regenerate alveoli

Smoking is relevant to infectious diseases resulting in increased prevalence and mortality. In this article, we aim to provide an overview of the effects of smoking in various infections and to explain the potential mechanisms. We searched PubMed and other relevant databases for scientific studies that explored the relationship between smoking and infection. The mechanisms of susceptibility to infection in smokers may include alteration of the structural, functional and immunologic host defences. Smoking is one of the main risk factors for infections in the respiratory tract, digestive tract, reproductive tract, and other systems in humans, increasing the prevalence of HIV, tuberculosis, SARS-CoV, and the current SARS-CoV-2. Smoking cessation can reduce the risk of infection. Smoking increases the incidence of infections and aggravates the progress and prognosis of infectious diseases in a dose-dependent manner. Smoking cessation promotion and education are the most practical and economical preventive measures to reduce aggravation of disease infection owing to tobacco use.

http://www.tobaccoinduceddiseases.org/pdf-123845-53073?filename=Smoking increases the.pdf

Smoking increases the risk of infectious diseases: A narrative review.

Although it is well accepted that air pollution exposure exacerbates preexisting airway disease, it has not been firmly established that long-term pollution exposure increases the risk of new-onset asthma or chronic obstruction pulmonary disease (COPD). This Workshop brought together experts on mechanistic, epidemiological, and clinical aspects of airway disease to review current knowledge regarding whether air pollution is a causal factor in the development of asthma and/or COPD. Speakers presented recent evidence in their respective areas of expertise related to air pollution and new airway disease incidence, followed by interactive discussions. A writing committee summarized their collective findings. The Epidemiology Group found that long-term exposure to air pollution, especially metrics of traffic-related air pollution such as nitrogen dioxide and black carbon, is associated with onset of childhood asthma. However, the evidence for a causal role in adult-onset asthma or COPD remains insufficient. The Mechanistic Group concluded that air pollution exposure can cause airway remodeling, which can lead to asthma or COPD, as well as asthma-like phenotypes that worsen with long-term exposure to air pollution, especially fine particulate matter and ozone. The Clinical Group concluded that air pollution is a plausible contributor to the onset of both asthma and COPD. Available evidence indicates that long-term exposure to air pollution is a cause of childhood asthma, but the evidence for a similar determination for adult asthma or COPD remains insufficient. Further research is needed to elucidate the exact biological mechanism underlying incident childhood asthma, and the specific air pollutant that causes it.

Outdoor Air Pollution and New-Onset Airway Disease. An Official American Thoracic Society Workshop Report.

Regenerative Metaplastic Clones in COPD Lung Drive Inflammation and Fibrosis.

Experimental models are critical for the understanding of lung health and disease and are indispensable for drug development. However, the pathogenetic and clinical relevance of the models is often unclear. Further, the use of animals in biomedical research is controversial from an ethical perspective.The objective of this task force was to issue a statement with research recommendations about lung disease models by facilitating in-depth discussions between respiratory scientists, and to provide an overview of the literature on the available models. Focus was put on their specific benefits and limitations. This will result in more efficient use of resources and greater reduction in the numbers of animals employed, thereby enhancing the ethical standards and translational capacity of experimental research.The task force statement addresses general issues of experimental research (ethics, species, sex, age, ex vivo and in vitro models, gene editing). The statement also includes research recommendations on modelling asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, lung infections, acute lung injury and pulmonary hypertension.The task force stressed the importance of using multiple models to strengthen validity of results, the need to increase the availability of human tissues and the importance of standard operating procedures and data quality.

https://erj.ersjournals.com/content/erj/51/5/1702133.full.pdf

Optimising experimental research in respiratory diseases: an ERS statement.

Structural changes to airway morphology, such as increased bronchial wall thickness (BWT) and airway wall area, are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a ...

https://journals.physiology.org/doi/pdf/10.1152/ajplung.00328.2019

Airway Remodeling in Ferrets with Cigarette Smoke Induced COPD using µCT Imaging.

Intact CFTR (cystic fibrosis transmembrane conductance regulator) function is crucial for proper airway, pancreatic, and reproductive tract functions by regulating chloride and bicarbonate transport at the epithelial surface (1). Cystic fibrosis, an autosomal-recessive genetic disorder, is a consequence of dysfunctional CFTR function and results in defective respiratory host defense, including abnormal mucus, diminished mucociliary clearance, and a propensity for bacterial infections, ultimately leading to bronchiectasis (1). Even in the absence of genetic CFTR mutations, individuals with smoking-related illnesses such as chronic obstructive pulmonary disease can develop acquired CFTR dysfunction, which is associated with chronic bronchitis, disease severity, and bronchiectasis (2). Compelling data indicate that acquired CFTR dysfunction is demonstrable in the nasal epithelium (3), lungs (4), and even sweat glands (5) of smokers with and without chronic obstructive pulmonary disease compared with healthy control subjects, and can partially (but not completely) reverse with smoking cessation (6). Elevated sweat chloride levels underscore the fact that cigarette smoking causes systemic CFTR dysfunction beyond the respiratory tract. Moreover, in vitro evidence demonstrates that plasma from smokers can transmit CFTR dysfunction to healthy human bronchial epithelial cells (5), indicating that reactive constituents such as acrolein (5), cadmium (7), and other oxidants (1) have the potential to reduce CFTR function. Maternal smoking confers a risk of infection to the infant, including otitis media, upper respiratory infections, and pneumonia; however, the mechanistic basis of this heightened risk is not well established (8). The consequences of smoking for the respiratory health of infants have been postulated to be partially induced in utero through transplacental exposure to circulating cigarette smoke toxins during the key stages of neonatal development (8, 9). However, to our knowledge, there have been no studies investigating the effects of smoking on the epithelial function of the infant or fetus. We hypothesized that cigarette smoking by pregnant mothers could induce acquired CFTR dysfunction and transmit this to the fetus, ultimately inducing a risk of respiratory infection. A portion of this work has been presented in the form of an abstract (10).

/pdf/maternal-smoking-induces-acquired-cftr-dysfunction-in-2xa5y9h0tx.pdf

Maternal Smoking Induces Acquired CFTR Dysfunction in Neonatal Rats

The Gycopolymer PAAG Improves MCT in Trachea Derived From a Ferret Model of COPD and Bronchitis

Alpha-1 Antitrypsin Deficiency Accelerates Progression of Smoke Induced Emphysema in a Ferret Model

Comparative Transcriptomics Analysis of Ferret, Mouse and Human COPD Models Reveals Genes Dysregulated in human COPD Uniquely Common to Ferret COPD Model

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