In contrast to lung fibroblasts – no signs of senescence in skin fibroblasts of patients with emphysema

Müller, Kai-Christian; Paasch, K; Feindt, B; Welker, Lutz; Watz, Henrik; Weise, Michael; Schmid, Ralph A.; Nakashima, Masaki; Branscheid, D.; Magnussen, H; Jörres, Rudolf A.; Holz, Olaf

doi:10.1016/j.exger.2007.12.011

Cited by 9 publications

(9 citation statements)

References 33 publications

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“…Sulforaphane decreases intracellular ROS, restores the viability of A549 cells, and attenuates G1 block of the cell cycle in cigarette smoke-exposed A549 cells [ 227 ]. Primary lung fibroblasts harvested from patients with emphysema are senescent, which express higher levels of IGFBP-3 mRNA and protein than those from controls [ 228 , 229 ]. The possible prosenescence effect of IGFBP-3 in fibroblasts is supposed to be mediated by IGFBP-3/IGF-2 interactions, not by IGF-1 [ 230 ].…”

Section: Igf-1 Signaling In Copdmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

Wang

Guo

et al. 2018

BioMed Research International

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Insulin-like growth factor-1 (IGF-1) was firstly identified as a hormone that mediates the biological effects of growth hormone. Accumulating data have indicated the role of IGF-1 signaling pathway in lung development and diseases such as congenital disorders, cancers, inflammation, and fibrosis. IGF-1 signaling modulates the development and differentiation of many types of lung cells, including airway basal cells, club cells, alveolar epithelial cells, and fibroblasts. IGF-1 signaling deficiency results in alveolar hyperplasia in humans and disrupted lung architecture in animal models. The components of IGF-1 signaling pathways are potentiated as biomarkers as they are dysregulated locally or systemically in lung diseases, whereas data may be inconsistent or even paradoxical among different studies. The usage of IGF-1-based therapeutic agents urges for more researches in developmental disorders and inflammatory lung diseases, as the majority of current data are collected from limited number of animal experiments and are generally less exuberant than those in lung cancer. Elucidation of these questions by further bench-to-bedside researches may provide us with rational clinical diagnostic approaches and agents concerning IGF-1 signaling in lung diseases.

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Section: Igf-1 Signaling In Copdmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

Wang

Guo

et al. 2018

BioMed Research International

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“…Comparable mechanical cues to the emphysematous lung, such as reduced stretch and stiffness, have been observed to reduce fibroblast differentiation, proliferation and gene expression of structural proteins [ 32 , 35 , 36 , 37 , 38 ]. Notably, the changes shown in primary human emphysematous fibroblasts demonstrate changes in cellular behaviour that correlate with the changes to fibroblasts experiencing reduced mechanical cues, such as decreased substrate stiffness and stretch forces [ 31 , 32 , 74 , 114 ]. Although these changes are likely influenced by the other aspects of the emphysematous lung environment, this correlation indicates that altered mechanical cues are likely a key driving force for the changes that occur within emphysematous fibroblasts.…”

Section: Discussionmentioning

confidence: 99%

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research

et al. 2021

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The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.

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“…Differences between normal and COPD fibroblasts have been observed for a variety of fibroblast repair functions, including decreased proliferation (11), decreased migration (25), decreased contraction of 3D collagen gels (25), increased senescence (26,27), and increased sensitivity to the toxic effects of cigarette smoke extract (28). Decreased development of PGE2 resistance would render COPD fibroblasts more sensitive to PGE2 inhibition of repair and could further potentiate these functional differences in vivo.…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Inhibitory Prostaglandin E2 Signaling in Human Lung Fibroblasts Is Mediated by Phosphodiesterase 4

Michalski¹,

Kanaji

Liu³

et al. 2012

Am J Respir Cell Mol Biol

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The etiology of chronic obstructive pulmonary disease (COPD) is complex and involves an aberrant inflammatory response. Prostaglandin (PG)E2 is elevated in COPD, is a key modulator of lung fibroblast functions, and may influence COPD progression. Most studies evaluating the effects of PGE2 on lung fibroblasts have used acute exposures. The current study evaluated whether longer-term exposure would induce attenuation of PGE2 signaling as part of an autoregulatory pathway. Human fetal lung fibroblasts were pretreated with PGE2 for 24 hours, and migration and cAMP accumulation in response to acute stimulation with PGE2 were assessed. Fibroblasts from adults with and without COPD were pretreated, and migration was assessed. PGE2 pretreatment attenuated subsequent PGE2-mediated inhibition of chemotaxis and cAMP stimulation. This attenuation was predominantly due to an increase in phosphodiesterase (PDE)4-mediated degradation of cAMP rather than to decreased activation of PGE2 receptors (receptor desensitization). Albuterol-and iloprost-mediated signaling were also attenuated after PGE2 pretreatment, suggesting that activation of PDE4 was able to broadly modulate multiple cAMP-coupled pathways. Lung fibroblasts from adult control subjects pretreated with PGE2 also developed attenuation of PGE2-mediated inhibition of chemotaxis. In contrast, fibroblasts obtained from patients with COPD maintained inhibitory PGE2 signaling after PGE2 pretreatment. These data identify a PDE4-mediated attenuation of PGE2 inhibitory signaling in normal fibroblasts that appears to be altered in COPD fibroblasts. These alterations may contribute to COPD pathogenesis and could provide novel therapeutic targets.

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In contrast to lung fibroblasts – no signs of senescence in skin fibroblasts of patients with emphysema

Cited by 9 publications

References 33 publications

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

Insulin-Like Growth Factor-1 Signaling in Lung Development and Inflammatory Lung Diseases

How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research

Attenuation of Inhibitory Prostaglandin E2 Signaling in Human Lung Fibroblasts Is Mediated by Phosphodiesterase 4

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