COPD corner seriesMurine models of 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).
References (111)
- et al.
Alternative projections of mortality and disability by cause 1990–2020: Global burden of disease study
Lancet
(1997) Modeling asthma and COPD in animals: a pointless exercise?
Curr Opin Pharmacol
(2003)- et al.
Morphological and biochemical features of elastase-induced emphysema in strain A/J mice
Toxicol Appl Pharmacol
(1983) - et al.
Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema
Cell
(1992) - et al.
Neutrophil elastase contributes to cigarette smoke-induced emphysema in mice
Am J Pathol
(2003) - et al.
Spontaneous emphysema in surfactant protein D gene-targeted mice
Chest
(2000) - et al.
Ultrastructure of lung elastin and collagen in mouse models of spontaneous emphysema
Matrix Biol
(1999) - et al.
Cigarettes are a rich source of bacterial endotoxin
Chest
(1996) - et al.
Bacterial endotoxin is an active component of cigarette smoke
Chest
(1999) - et al.
Grain dust and endotoxin inhalation challenges produce similar inflammatory responses in normal subjects
Chest
(1996)
Oxidative stress and lung inflammation in airways disease
Eur J Pharmacol
Role of oxidants/antioxidants in smoking-induced lung diseases
Free Radic Biol Med
damage in mouse heart, liver, and lung tissue due to acute side-stream tobacco smoke exposure
Arch Biochem Biophys
Few smokers develop COPD. Why?
Respir Med
Contributions of retinoids to the generation and repair of the pulmonary alveolus
Chest
Bone marrow-derived cells contribute to lung regeneration after elastase-induced pulmonary emphysema
FEBS Lett
All-trans retinoic acid modulates the balance of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in patients with emphysema
Chest
Burden and clinical features of chronic obstructive pulmonary disease (COPD)
The Lancet
Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary
Am J Respir Crit Care Med
The natural history of chronic airflow obstruction
Br Med J
The electrophoretic alpha-1 globulin pattern of serum in alpha-1 antitrypsin deficiency
Scand J Clin Lab Invest
Initial sequencing and comparative analysis of the mouse genome
Nature
A miracle enough: the power of mice
Nat Med
Animal models of emphysema and their relevance to studies of particle-induced disease
Inhal Toxicol
Animal models of emphysema
Am Rev Respir Dis
Animal models of emphysema
Am Rev Respir Dis
The development of emphysema in cigarette smoke-exposed mice is strain dependent
Am J Respir Crit Care Med
Different lung responses to cigarette smoke in two strains of mice sensitive to oxidants
Eur Respir J
Animal models for chronic obstructive pulmonary disease. Age of Klotho and marlboro mice
Am J Respir Cell Mol Biol
Chronic obstructive pulmonary disease * 3: Experimental animal models of pulmonary emphysema
Thorax
Acute effects of cigarette smoke on inflammation and oxidative stress: a review
Thorax
Mediators of chronic obstructive pulmonary disease
Pharmacol Rev
Measurement of pulmonary emphysema
Am Rev Respir Dis
Experimental emphysema: its production with papain in normal and silicotic rats
Arch Environ Health
Prevention of leucocyte elastase-induced emphysema in mice by heparin fragments
Eur Respir J
Emphysematous changes are caused by degradation of type III collagen in transgenic mice expressing MMP-1
Exp Lung Res
Progressive adult-onset emphysema in transgenic mice expressing human MMP-1 in the lung
Am J Physiol Lung Cell Mol Physiol
Inducible targeting of IL-13 to the adult lung causes matrix metalloproteinase- and cathepsin-dependent emphysema
J Clin Invest
Interferon gamma induction of pulmonary emphysema in the adult murine lung
J Exp Med
Requirement for macrophage elastase for cigarette smoke-induced emphysema in mice
Science
Chemotactic activity of elastin-derived peptides
J Clin Invest
Elastin fragments attract macrophage precursors to diseased sites in pulmonary emphysema
Science
Elastolytic metalloproteinases produced by human mononuclear phagocytes. Potential roles in destructive lung disease
Am J Respir Crit Care Med
Macrophage metalloelastase mediates acute cigarette smoke-induced inflammation via tumor necrosis factor-{alpha} release
Am J Respir Crit Care Med
Tumor necrosis factor-alpha is central to acute cigarette smoke-induced inflammation and connective tissue breakdown
Am J Respir Crit Care Med
Tumor necrosis factor-{alpha} drives 70% of cigarette smoke-induced emphysema in the mouse
Am J Respir Crit Care Med
Spontaneous air space enlargement in the lungs of mice lacking tissue inhibitor of metalloproteinases-3 (TIMP-3)
J Clin Invest
Increased metalloproteinase activity, oxidant production, and emphysema in surfactant protein D gene-inactivated mice
Proc Natl Acad Sci USA
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Prof Dr Romain A. Pauwels deceased on 3/01/2005.