COPD corner series
Murine models of COPD

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Abstract

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, that is not fully reversible, and that is associated with an abnormal inflammatory response of the airways and lungs to noxious particles and gases. The airflow limitation is caused by increased resistance of the small conducting airways and by decreased elastic recoil forces of the lung due to emphysematous destruction of the lung parenchyma. In vivo animal models can help to unravel the molecular and cellular mechanisms underlying the pathogenesis of COPD. Mice represent the most favored animal species with regard to the study of (both innate and adaptive) immune mechanisms, since they offer the opportunity to manipulate gene expression. Several experimental approaches are applied in order to mimic the different traits of COPD in these murine models. Firstly, the tracheal instillation of tissue-degrading enzymes induces emphysema-like lesions in the lung parenchyma, adding further proof to the protease-antiprotease imbalance hypothesis. Secondly, the inhalation of noxious stimuli, including tobacco smoke, sulfur dioxide, nitrogen dioxide, or oxidants such as ozone, may also lead to COPD-like lesions in mice, depending on concentration, duration of exposure and strainspecific genetic susceptibility. Thirdly, in transgenic mice, a specific gene is either overexpressed (non-specific or organ-specific) or selectively depleted (constitutively or conditionally). The study of these transgenic mice, either per se or in combination with the above mentioned experimental approaches (e.g. the inhalation of tobacco smoke), can offer valuable information on both the physiological function of the gene of interest as well as the pathophysiological mechanisms of diseases with complex traits such as COPD.

Section snippets

Why do we need murine models of COPD/pulmonary emphysema?

Chronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world [1]. Since COPD is currently listed as the fifth leading cause of death in the world, and is also an important cause of chronic disability and permanent impairment, COPD represents a major economic and social burden worldwide [2]. COPD is defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as ‘a disease state characterized by airflow limitation that is

Different experimental models of COPD/pulmonary emphysema in mice: introduction

Several experimental models of COPD and emphysema exist in mice, based upon different approaches [9], [10]. Firstly, the tracheal instillation of tissue-degrading enzymes has been used since a long time to study the development of emphysematous lung lesions [11], [12]. Secondly, inhalation of tobacco smoke and other noxious stimuli in mice induces lung tissue destruction, although the development of emphysema-like lesions appears to be strain-dependent [13], [14]. Thirdly, several mouse strains

COPD/pulmonary emphysema and the protease/antiprotease imbalance

An imbalance between proteases and their inhibitors is believed to play an essential role in the development of pulmonary emphysema. This imbalance may occur either by an excessive release of proteases by inflammatory cells and lung resident cells, or by a reduced synthesis or increased breakdown of antiproteases. The protease/antiprotease hypothesis of emphysema was first proposed 40 years ago, based on the observations that smokers with a deficiency of α1-antitrypsin were at increased risk

Innate immunity and murine models of COPD/pulmonary emphysema

Lipopolysaccharide (LPS or endotoxin) is a strong proinflammatory compound present in the cell wall of Gram-negative bacteria. LPS contains two parts: a polysaccharide part, that is characteristic and unique for each bacterial strain and a lipid part (lipid A), which is the least variable portion of the molecule and is responsible for the endotoxic activity [53].

Bacterial endotoxin was demonstrated to be present in high concentrations in tobacco (approximately 20 μg/cigarette) and bioactive LPS

COPD/pulmonary emphysema and the oxidant/antioxidant imbalance

Cigarette smoke contains high concentrations of reactive oxygen species (ROS) [61], [62]. Increased levels of ROS in airways and lungs upon cigarette smoking originate not only directly from the oxidants in cigarette smoke, but also indirectly from the release of ROS by infiltrating macrophages and neutrophils [61], [63]. This excess of ROS disturbs the balance between oxidants and antioxidants, resulting in oxidative stress [64]. Oxidative stress may be important in different aspects of the

Pulmonary repair processes and airway remodeling in COPD/pulmonary emphysema

Long-term exposure to toxic gases and particles, mostly cigarette smoke, is the primary cause of COPD. Host defenses against these stimuli include innate immune responses (mucociliary clearance, epithelial repair and the acute inflammatory response) and adaptive immune responses (humoral and cellular components). Both types of response are associated with a repair process that remodels damaged tissue by restoring the epithelium and microvasculature and by adding connective-tissue matrix in an

Apoptosis of lung structural cells: development of pulmonary emphysema without inflammation

Retamales et al. [97] showed that smokers who developed severe emphysema had a severalfold increase in the numbers of macrophages, T-lymphocytes, neutrophils and eosinophils in their lungs, compared with persons who smoked similar amounts of cigarettes, but maintained normal lung function. This suggests that people who develop emphysema have an amplified inflammatory response to cigarette smoke, as explicitly mentioned in the definition of COPD by GOLD [4]. Also in murine models of chronic

Limitations of murine models of human COPD/pulmonary emphysema

In vivo murine models can offer valuable information on several aspects of the pathogenesis and treatment of COPD and emphysema. However, as for other animal species, murine models of COPD/emphysema also have several limitations. Firstly, no model mimics the entire COPD phenotype, since many models specifically mimic only one trait of the disease, eg the enlargement of the pulmonary alveoli due to injury to the lung parenchyma (i.e. pulmonary emphysema). However, the pathogenesis of the

Acknowledgements

This work was funded by the Fund for Scientific Research Flanders (FWO / Project Grant Number 3G001103), the Institute for the Promotion of Innovation by Science and Technology in Flanders (IWT) and the Concerted Research Initiative of the Ghent University (BOF/ GOA Project Number 01251504).

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    Prof Dr Romain A. Pauwels deceased on 3/01/2005.

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