1,721,013 research outputs found
Testing of Compounds in Models of Pulmonary Emphysema
No full textThere is a pressing need for the development of new therapies for emphysema, particularly as no existing treatment has been shown to reduce disease progression. Compounds with a potential activity against the pathological mechanisms postulated to play a role in the development and progression of emphysema should be tested in vivo in animal models of this disease. The choice of the model is of capital importance. While models of elastase-induced emphysema are relatively easy to execute, require low personnel capacity and provide fast results, they also have a limited clinical relevance. On the other hand, models of chronic smoke exposure are time-consuming, expensive and require high personnel capacity but have a high clinical relevance. Presently, mainly two pharmacological approaches are being considered and investigated in experimental studies. The first approach consists of pharmacological interventions designed to slow down the rate at which alveolar wall is lost in emphysema. In this approach we find anti-inflammatory agents, protease inhibitors and antioxidants. The attempt to reduce lung inflammatory cell infiltration is most appealing since such an effect would also reduce the lung burden of both proteases and oxidants. The second approach is an attempt to reverse the process of alveolar loss by inducing alveolar growth. To our knowledge here only the effects of retinoids and/or retinoid receptor agonists have been investigated. This report presents a selected review of the literature of animal studies using these pharmacological approaches
Models of Genetic Emphysema: The C57Bl/6J Mice and Their Mutans: Tight-Skin, Pallid and Beige
No full textThe dual role of neutrophil elastase in lung destruction and repair
No full textThe purpose of this review was to modify the prevailing view that neutrophil elastase (NE) is mainly a matrix-degrading enzyme. Recent observations indicate that the role of NE in inflammation is more complex than the simple degradation of extra-cellular matrix components. Several lines of evidence suggest that NE aims specifically at a variety of regulatory functions in local inflammatory processes. This enzyme can modulate many biological functions by promoting chemokine and cytokine activation and degradation, cytokine receptor shedding, proteolysis of cytokine binding proteins and the activation of different specific cell surface receptors. However, the current knowledge of regulatory mechanisms by which NE potentially regulates inflammatory processes is primarily derived from in vitro studies. The extent of these NE-dependent pathways and their relevance under various pathophysiological conditions remains poorly understood and a matter for further investigation. Recent studies suggest that NE not only plays a key role in lung destruction (emphysema) but can also modulate proliferative changes (fibrosis) in inflammatory processes. Thus, NE could be considered to have potential multiple roles in the pathogenesis of both emphysema and lung fibrosis
Models for COPD involving cigarette smoke
No full textChronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality throughout the world. Its impact has resulted in dynamic research into the mechanisms involved in the development of this disease and the search for new drugs. In vitro and ex-vivo models of COPD involving cigarette smoke can provide a quick answer to hypotheses and are economical, whereas in vivo models can investigate the pathogenesis of COPD and test potential novel therapeutical approaches. This short review is an attempt to present the advantages and the limitations of the in vitro, ex vivo and some in vivo models of COPD. Every model is valid and has its value when used in the appropriate context
A 16-month study of the development of genetic emphysema in tight-skin mice
No full textThe tight-skin (tsk) mouse has been recently proposed as a model of genetically determined emphysema. In the present study, the development of this lung lesion was investigated morphometrically in both male and female tsk mice from 4 days to 16 months of age. "Pallid" (pa) mice with a closely related genetic background served as controls. Despite small differences in the mean linear intercept seen at 1 and at 16 months, both male and female tsk mice were found to be similarly susceptible to the development of the emphysematous lesion. Three main phases were observed in the evolution of the emphysema. The first phase, from 4 days to 2 months after birth, included enlargement of the peripheral lung units, already evident at 4 and at 15 days, and destruction of the lung parenchyma, which occurred between 15 days and 1 month and rapidly progressed for as long as 2 months. A second phase of stabilization or of mild progression of the emphysematous lesion occurred between 2 and 8 months of age. A third phase, in the advanced age between 8 and 16 months, included a further exacerbation of the parenchymal destruction. At 16 months of age, the lungs of the pa mice also showed some patchy areas of air-space enlargement with destruction of the alveolar septa
Small animal models of emphysema
No full textThe present chapter takes a different approach in an attempt to selectively and critically review small animal models of chronic obstructive pulmonary disease (COPD) induced by cigarette smoke exposure. Because cigarette smoke has been identified as the most important risk factor for the development of COPD10, these models may provide the basis for the understanding of the complex pathogenetic cellular and molecular mechanisms involved in the development of the disease. In addition pharmacological studies of cigarette smoke-induced models of COPD are also considered here since the results could be of interest for future potential therapeutical approaches in man
Animal Models
No full textThe main purpose of studying animal models of human disease is to gain insight into the underlying mechanisms of the disease. The recognition that chronic obstructive pulmonary disease (COPD) is a global health problem with no effective treatment has resulted in recent years in an explosion of new animal models of emphysema, a major component of COPD.
The present work is a review of some selected animal models developed in recent years that in the eyes of the authors, may provide new insight into the pathogenesis of emphysema and COPD
Tsk mice with genetic emphysema. Right ventricular hypertrophy occurs without hypertrophy of muscular pulmonary arteries or muscularization of arterioles
No full textThe causes for the development of right ventricular hypertrophy (RVH) in emphysema are not fully understood. In the 1960s, studies of RVH in association with emphysema found no correlation between the extent of tissue damage in the lung and the RV weight. This was thought to disprove the theory that the RVH was due to an increase in pulmonary vascular resistance secondary to capillary destruction. In the present study, the development of RVH was investigated in tight-skin (tsk) mice with genetic emphysema. RVH started to develop in mature to senescent animals between 8 and 16 months of age and progressed thereafter. At 24 months of age, RV weight and the ratios RV/body weight and RV/LV + S weight were, respectively, 52, 96, and 60% greater than in control (pa) mice. At this time blood gas analysis revealed hypoxemia in tsk but not in pa mice. The mean linear intercept of tsk mice was 83% larger and the surface area of the walls of distal air spaces per unit lung volume was 40% smaller than in pa mice. There was a strong correlation between the severity of emphysema, assessed by both techniques, and the RV/LV + S ratio (p less than 0.001 for both). No muscularized arterioles were seen in the tsk mice, and the medial thickness of muscular arteries was almost identical in the two groups. This demonstrates that in emphysema, RVH can develop in the absence of pulmonary vascular changes and is probably due to tissue (and thus capillary) destruction
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