Abstract:Extracellular matrix remodeling and tissue rupture contribute to the progression of emphysema. Lung tissue elasticity is governed by the tensile stiffness of fibers and the compressive stiffness of proteoglycans. It is not known how proteoglycan remodeling affects tissue stability and destruction in emphysema. The objective of this study was to characterize the role of remodeled proteoglycans in alveolar stability and tissue destruction in emphysema. At 30 days after treatment with porcine pancreatic elastase,… Show more
“…The PGs normally contribute to the mechanical stability of the collagen-elastin network and prevent collapse of alveolar structures caused by electrostatic interactions from the negatively charged GAGs (81). Structural remodeling of the lung resulting from abnormal expression of PG-GAG complexes and structural changes to the GAG side chains can contribute to the development of pulmonary diseases (45,(83)(84)(85)(86)(87)(88).…”
Section: Proteoglycansmentioning
confidence: 99%
“…Other studies have shown that low molecular weight HA fragments create a proinflammatory state by stimulating macrophages to release chemokines and MMPs (specifically, MMP-12), resulting in chronic inflammation, destruction of the lung parenchyma, and airway wall remodeling in emphysema (101,102). In a recent study using a mouse model of porcine pancreatic elastase-induced emphysema, the loss of the structural role of PGs related to the change in charge density on the GAGs reduced alveolar stability and led to a more progressive disease phenotype (85). In that study, the changes in mouse lung tissue stiffness and the alveolar shape distortion under the influence of varying tonicity conditions were increased in experimental emphysema, thus suggesting that the loss of PGs affects lung tissue stability and the progression of emphysema.…”
Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-b1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.
“…The PGs normally contribute to the mechanical stability of the collagen-elastin network and prevent collapse of alveolar structures caused by electrostatic interactions from the negatively charged GAGs (81). Structural remodeling of the lung resulting from abnormal expression of PG-GAG complexes and structural changes to the GAG side chains can contribute to the development of pulmonary diseases (45,(83)(84)(85)(86)(87)(88).…”
Section: Proteoglycansmentioning
confidence: 99%
“…Other studies have shown that low molecular weight HA fragments create a proinflammatory state by stimulating macrophages to release chemokines and MMPs (specifically, MMP-12), resulting in chronic inflammation, destruction of the lung parenchyma, and airway wall remodeling in emphysema (101,102). In a recent study using a mouse model of porcine pancreatic elastase-induced emphysema, the loss of the structural role of PGs related to the change in charge density on the GAGs reduced alveolar stability and led to a more progressive disease phenotype (85). In that study, the changes in mouse lung tissue stiffness and the alveolar shape distortion under the influence of varying tonicity conditions were increased in experimental emphysema, thus suggesting that the loss of PGs affects lung tissue stability and the progression of emphysema.…”
Pulmonary fibrosis and emphysema are chronic lung diseases characterized by a progressive decline in lung function, resulting in significant morbidity and mortality. A hallmark of these diseases is recurrent or persistent alveolar epithelial injury, typically caused by common environmental exposures such as cigarette smoke. We propose that critical determinants of the outcome of the injury-repair processes that result in fibrosis versus emphysema are mesenchymal cell fate and associated extracellular matrix dynamics. In this review, we explore the concept that regulation of mesenchymal cells under the influence of soluble factors, in particular transforming growth factor-b1, and the extracellular matrix determine the divergent tissue remodeling responses seen in pulmonary fibrosis and emphysema.
“…Because of their highly sulfated and negatively charged carbohydrate groups, GAGs have the capacity to hold large quantities of water. Only a few studies have investigated the mechanics of PGs in the lung [1,27,59,145]. Perhaps the most important role the PGs play in mechanics is that they hinder the alignment of fibers in the ECM during stretch [27].…”
Section: Aging Of the Proteoglycansmentioning
confidence: 99%
“…Note, the reduction of GAG density and chain length in the adult aggrecan. Based on morphometric and biochemical analyses complemented with computational modeling, a loss of PGs has been predicted to promote the progression of heterogeneous airspace enlargement in emphysema [145]. It remains to be shown whether the loss of GAGs during aging contribute to the characteristic homogeneous airspace enlargement ( Fig.…”
Aging is a process that affects cells, the extracellular matrix (ECM), tissues, and organs. The lung is the entry of oxygen into the body and any deterioration in its ability to take up and distribute oxygen uniformly in the parenchyma compromises the cardiovascular system and hence contributes to the aging of the organism. In this chapter, we provide an overview of the biochemical, structural, and biomechanical properties of the aging lung parenchyma. We also discuss several measurement techniques that are suitable to assess the biomechanical properties of the lung. Following a review of general constitutive relations used in lung biomechanics, we derive a specific multiscale constitutive equation for the lung tissue strip that allows us to partition the contributions of collagen, elastin, their volume fraction, and their interaction with the proteoglycan matrix. This model provides a better understanding of how airspace enlargement, local stiffening of ECM fibers and macroscopic lung compliance are related to each other. These constitutive relations have important implications for lung function during aging. Specifically, there is an increase in ECM stiffness due to cross-linking of collagen which influences cellular behavior at the microscale. Despite ECM stiffening, at the scale of thousands of alveoli, parenchymal stiffness may be near normal and lung compliance may even increase in the elderly due to the enlargement alveoli enabling relatively normal gas exchange in the absence of exercise. Finally, we discuss possible new research directions that may help better understand and reduce the risk of pulmonary diseases of old age.
“…A wide variety of studies have highlighted the proteolytic activity of elastase in causing structural changes, such as higher mean linear intercept and alveolar enlargement both in mice [71][72][73][74][75] and in rats [76][77][78][79] (Table 2). Furthermore, several studies reported changes in ECM composition after elastase administration, such as disorganized elastin [80,81], degradation of proteoglycans [82], and abnormal collagen remodeling [83][84][85][86][87][88]. However, as in CS models, these effects are dependent on several factors, including strain; enzyme dose at each instillation; and number of elastase challenges (Figure 2).…”
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.
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