Animal Models of Chronic Obstructive Pulmonary Disease Exacerbations: A Review of the Current Status

Abstract

Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation and manifested as emphysema and chronic airway obstruction, is a major cause of morbidity and mortality worldwide, resulting in an economic and social burden that is both substantial and increasing. The natural history of COPD involves systemic manifestations, such as skeletal muscle wasting and cardiovascular impairment, and frequent exacerbations. The latter are caused by bacterial or viral infections and have major implications for patients and healthcare systems. There are no effective therapies to prevent or reverse these events. Smoking cessation remains the most effective intervention for reducing disease progression. Animal models of COPD and of COPD exacerbations have been developed to advance understanding of the pathogenesis of COPD and the role of infections in its severity. Cigarette smoke exposure, tracheal instillation of elastase, and genetic manipulation are commonly used to reproduce baseline COPD conditions, each with its advantages and disadvantages. Intratracheal instillation of lipopolysaccharide (LPS), bacteria, or viruses are the most common interventions used to exacerbate baseline COPD. This review highlights the three major animal models used for induction of emphysema and its exacerbations. Further exploration of these models should facilitate identification of new therapeutic approaches for COPD.

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

“…Nonetheless, these findings emphasize the importance of airway clearance as a means of improving health of the CF lung. We propose that the pathogenesis of CF lung disease shares mucoinflammatory components (55) with other forms of COPD, such as chronic bronchitis (31,32,56,57) and severe asthma (52,58) and thus strengthens the case for developing new therapeutics targeting these aberrant responses. n Author disclosures are available with the text of this article at www.atsjournals.org.…”

Human Umbilical Cord Mesenchymal Stem Cell-derived Extracellular Vesicles Ameliorate Airway Inflammation in a Rat Model of Chronic Obstructive Pulmonary Disease (COPD)

“…COPD is characterized by airway and parenchymal in ammation that leads to mucus overproduction and emphysema, although these characteristic may not present in all patients, as the emphysematous lung only occurs in 20% of all COPD patients (Churg, Cosio & Wright, 2008;Akram et al, 2012). Nevertheless, in the animal model, the presence of emphysema is one of the important characteristics to con rm the development of COPD (de Oliveira, 2016). On the other hand, mucus overproduction is considered di cult to reproduce in the rat model due to the low number of goblet cells in the bronchi (Churg, Cosio & Wright, 2008).…”

“…The expression of PRKCZ and NF-κβ play a vital role in in ammation and thus the pathogenesis of COPD. PRKCZ is upstream of NF-κβ, phosphorylating p65 at serine 311 to promote the acetylation of Lysine 310, thus activating the κβ transcription (Diaz-Meco & Moscat, 2012). Mice de cient of PRKCZ was found to reduce myeloperoxidase and in ux of neutrophils, and reduced pro-in ammatory cytokines such as IL-13, IL-17, IL-18, IL-1β, TNF-α, MCP-1, MIP-2, and IFN-γ, while the use of PRKCZ inhibitors blocked the activation of NF-κβ by TNF-α, thus reducing the pro-in ammatory IL-8 expression (Yao et al, 2010;Aveleira et al, 2010).…”

“…NF-κβ is also required by IL-1β and IL-17A to induce the expression of MUC5B in bronchial epithelial cells that cause goblet hyperplasia in COPD (Fujisawa et al, 2011). Besides, various studies demonstrated the upregulation of p65 and p50 expression in COPD patients (Di Stefano et al, 2002;Caramori et al, 2003;Tan et al, 2016;. Microarray study conducted by Yang et al, (2013) revealed the important role of p50 in regulating many pathways of COPD including toll-like receptor signalling pathway, cytokine-cytokine receptor interactions, chemokine signalling pathway, and apoptosis (Yang et al, 2013).…”

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“…These inflammatory cells destroy the lung connective tissues by the production of inflammatory cytokines followed by emphysematous changes and poor lung function 5 . Bacterial lipopolysaccharides or cigarette smoke 6 have been used to reproduce symptoms of exacerbations 7 as seen in computed tomography 8 .…”