Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

Tanner, Lloyd; Single, Andrew

doi:10.1159/000502489

Cited by 75 publications

(77 citation statements)

References 325 publications

(318 reference statements)

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“…Many studies found elevated MMPs concentration and increased elastin degradation in chronic obstructive pulmonary diseases [21][22][23]. Neutrophil elastase or matrix metalloproteinases (MMPs) were held culprit [24]. But it appears that the protease secreted by various bacteria had never been taken into account.…”

Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosainduced acute emphysema through bacterial secretion in mice

Zhu

Pan

2020

Preprint

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Pulmonary emphysema is the major pathological feature of chronic obstructive pulmonary disease (COPD). It is a slowly progressive pathological condition and acute lung infection is not considered to play a role in emphysema initiation. Recently, we found that the secretion from Pseudomonas aeruginosa could cause severe lung emphysema in mice rapidly. Since this bacterium is ubiquitous and secrets proteases, we hypothesized that direct P. aeruginosa airway infection would have a similar effect. To address this issue, we applied a unilateral lung injury model. P. aeruginosa secretion was extracted and instilled intratracheally into the left lung of C57BL/6 and C3H/HeJ mice, while the right lung was saved as self-control. Alveolar diameter and lung compliance were measured. Later, we tested the effect of P. aeruginosa inoculation in C57BL/6 mice, immunosuppressed C57BL/6 mice, and C3H/HeJ (TLR4 deficient) mice. P. aeruginosa secretion extract caused acute panacinar emphysema and decreased dynamic lung compliance. Different types of emphysema are transformable. However, the P. aeruginosa infection could only elicit emphysema in C3H/HeJ mice and immunosuppressed C57BL/6 mice, indicating normal immunity is essential to protect the hosts from emphysema. P. aeruginosa could be an important pathogen in COPD initiation. Our finding filled a major gap in COPD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Pseudomonas aeruginosainduced acute emphysema through bacterial secretion in mice

Zhu

Pan

2020

Preprint

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“…In this study, we used a 21-day intratracheally bleomycin-challenged murine model to confirm TH5487 efficacy in vivo. This model reproduces several phenotypic features of human IPF, including peripheral alveolar septal thickening and acute cytokine production resolving in fibrosis (19,20).…”

Section: Introductionmentioning

confidence: 89%

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Tanner

Single

Bonghir

et al. 2021

Preprint

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Interstitial lung diseases such as idiopathic pulmonary fibrosis (IPF) are caused by persistent micro-injuries to alveolar epithelial tissues together with aberrant repair processes. Despite substantial advancement in our understanding of IPF progression, numerous questions remain concerning disease pathology. IPF is currently treated with pirfenidone and nintedanib, compounds which slow the rate of disease progression but fail to treat underlying causes of disease. The DNA repair enzyme 8-oxoguanine DNA glycosylase-1 (OGG1) is upregulated following TGF-β exposure in several fibrosis-associated cell types. Currently, no pharmaceutical solutions targeting OGG1 have been utilized in the treatment of IPF. In this study, a novel small molecule OGG1 inhibitor, TH5487, decreased myofibroblast transition and associated pro-fibrotic markers in fibroblast cells. In addition, TH5487 decreased pro-inflammatory cytokine production, inflammatory cell infiltration, and lung remodeling in a murine model of bleomycin-induced pulmonary fibrosis. Taken together, these data strongly suggest that TH5487 is a potent, specific, and clinically-relevant treatment for IPF.

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“…Subsequent analysis of functions may use epithelial cell models such as the air-liquid interface, in vitro airway epithelial model that has been adapted to studying viral infection and the changes it induced in the airway (Yan et al, 2016;Boda et al, 2018;Tan et al, 2018a). Animal-based diseased models have also been developed to identify systemic mechanisms of acute exacerbation (Shin, 2016;Gubernatorova et al, 2019;Tanner and Single, 2019). Furthermore, the humanized mouse model that possess human immune cells may also serves to unravel the immune profile of a viral infection in healthy and diseased condition (Ito et al, 2019;Li and Di Santo, 2019).…”

Section: Clinical Significance Of Identifying Additional Mechanisms Omentioning

confidence: 99%

Respiratory Viral Infections in Exacerbation of Chronic Airway Inflammatory Diseases: Novel Mechanisms and Insights From the Upper Airway Epithelium

Tan

Lim

Liu

et al. 2020

Front. Cell Dev. Biol.

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Respiratory virus infection is one of the major sources of exacerbation of chronic airway inflammatory diseases. These exacerbations are associated with high morbidity and even mortality worldwide. The current understanding on viral-induced exacerbations is that viral infection increases airway inflammation which aggravates disease symptoms. Recent advances in in vitro air-liquid interface 3D cultures, organoid cultures and the use of novel human and animal challenge models have evoked new understandings as to the mechanisms of viral exacerbations. In this review, we will focus on recent novel findings that elucidate how respiratory viral infections alter the epithelial barrier in the airways, the upper airway microbial environment, epigenetic modifications including miRNA modulation, and other changes in immune responses throughout the upper and lower airways. First, we reviewed the prevalence of different respiratory viral infections in causing exacerbations in chronic airway inflammatory diseases. Subsequently we also summarized how recent models have expanded our appreciation of the mechanisms of viral-induced exacerbations. Further we highlighted the importance of the virome within the airway microbiome environment and its impact on subsequent bacterial infection. This review consolidates the understanding of viral induced exacerbation in chronic airway inflammatory diseases and indicates pathways that may be targeted for more effective management of chronic inflammatory diseases.

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Animal Models Reflecting Chronic Obstructive Pulmonary Disease and Related Respiratory Disorders: Translating Pre-Clinical Data into Clinical Relevance

Cited by 75 publications

References 325 publications

Pseudomonas aeruginosainduced acute emphysema through bacterial secretion in mice

Pseudomonas aeruginosainduced acute emphysema through bacterial secretion in mice

Small-molecule-mediated OGG1 inhibition attenuates pulmonary inflammation and lung fibrosis

Respiratory Viral Infections in Exacerbation of Chronic Airway Inflammatory Diseases: Novel Mechanisms and Insights From the Upper Airway Epithelium

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