Blocking of Akt/NF-κB Signaling by Pentoxifylline Inhibits Platelet-Derived Growth Factor–Stimulated Proliferation in Brown Norway Rat Airway Smooth Muscle Cells

Chiou, Ya‐Ling; Shieh, Jeng-Jer; Lin, Ching‐Yuang

doi:10.1203/01.pdr.0000246105.56278.98

Cited by 18 publications

(14 citation statements)

References 31 publications

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“…We observed substantially reduced Akt kinase activity in cells expressing RGS4 shRNA compared to control. Finally, to determine the requirement of RGS4 for PDGF-induced PI3K- and Akt-dependent cell cycle progression, we evaluated expression of the Akt target gene cyclin D1 by quantitative real-time PCR [19], [20], [21]. As expected, RGS4 depletion decreased PDGF-evoked cyclin D1 expression ( Figure 3H ).…”

Section: Resultsmentioning

confidence: 59%

An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma

et al. 2012

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In severe asthma, bronchodilator- and steroid-insensitive airflow obstruction develops through unknown mechanisms characterized by increased lung airway smooth muscle (ASM) mass and stiffness. We explored the role of a Regulator of G-protein Signaling protein (RGS4) in the ASM hyperplasia and reduced contractile capacity characteristic of advanced asthma. Using immunocytochemical staining, ASM expression of RGS4 was determined in endobronchial biopsies from healthy subjects and those from subjects with mild, moderate and severe asthma. Cell proliferation assays, agonist-induced calcium mobilization and bronchoconstriction were determined in cultured human ASM cells and in human precision cut lung slices. Using gain- and loss-of-function approaches, the precise role of RGS proteins was determined in stimulating human ASM proliferation and inhibiting bronchoconstriction. RGS4 expression was restricted to a subpopulation of ASM and was specifically upregulated by mitogens, which induced a hyperproliferative and hypocontractile ASM phenotype similar to that observed in recalcitrant asthma. RGS4 expression was markedly increased in bronchial smooth muscle of patients with severe asthma, and expression correlated significantly with reduced pulmonary function. Whereas RGS4 inhibited G protein-coupled receptor (GPCR)-mediated bronchoconstriction, unexpectedly RGS4 was required for PDGF-induced proliferation and sustained activation of PI3K, a mitogenic signaling molecule that regulates ASM proliferation. These studies indicate that increased RGS4 expression promotes a phenotypic switch of ASM, evoking irreversible airway obstruction in subjects with severe asthma.

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Section: Resultsmentioning

confidence: 59%

An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma

et al. 2012

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“…Furthermore, PDGF-BB stimulated the secretion of IL-6 and IL-8 from human lung cells as well as it activated NF-B in animal lung cell (3,10,37,47). Interestingly, the activation of NF-B by PDGF-BB might be cell type specific, as it was induced in animal airway smooth muscle cells (10), fibroblasts (37), and human skin fibroblasts (40), but not in human vascular smooth muscle cells and fibroblasts (39). In pulmonary artery-derived smooth muscle cells, PDGF-BBinduced NF-B activation occurred only after 24 h (36).…”

Section: Discussionmentioning

confidence: 97%

“…It further stimulated ASMC to secrete components of the extracellular matrix, thus increasing tissue remodeling (25,44). Furthermore, PDGF-BB stimulated the secretion of IL-6 and IL-8 from human lung cells as well as it activated NF-B in animal lung cell (3,10,37,47). Interestingly, the activation of NF-B by PDGF-BB might be cell type specific, as it was induced in animal airway smooth muscle cells (10), fibroblasts (37), and human skin fibroblasts (40), but not in human vascular smooth muscle cells and fibroblasts (39).…”

Section: Discussionmentioning

confidence: 99%

Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

Seidel

Merfort²,

Hughes³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…In contrast, zileuton does not influence the OA-induced phosphorylation of ERK1/2. Cyclin D1 is an important protein regulator of the early G1 phase of the cell cycle [25]. Results imply that OA can activate PI3K and p-Akt to increase cyclin D1 expression and induce ASM cell hyperplasia.…”

Section: Discussionmentioning

confidence: 99%

“…Target protein bands were normalized against β-actin. Data were presented as the fold change between the experimental and control groups [25]. …”

Section: Methodsmentioning

confidence: 99%

Effects of Zileuton on Airway Smooth Muscle Remodeling after Repeated Allergen Challenge in Brown Norway Rats

et al. 2013

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Background: Chronic asthma is characterized by airway inflammation and remodeling. Objective: This study aimed to evaluate the effects of zileuton on bronchial hyperresponsiveness, airway inflammation and airway smooth muscle (ASM) remodeling. Methods: Two experimental groups of brown Norway rats sensitized and repeatedly challenged with aerosolized ovalbumin (OA) were given oral zileuton (OA-zileuton group) and oral saline only (OA-saline group). A third, control group was sensitized and challenged by saline. The rats were anesthetized and paralyzed. Pulmonary function tests were performed at baseline and after varying doses of acetylcholine. Bronchoalveolar lavage fluid and lung tissues were examined. Results: Zileuton had beneficial effects on pulmonary function, airway inflammation and ASM remodeling in the OA-zileuton group compared to the OA-saline group. Zileuton inhibited an OA-stimulated increase in ASM by inhibiting hypertrophy, hyperplasia and increased extracellular matrix via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway, thereby reducing cyclin D1 expression and attenuating bronchial hyperresponsiveness. Conclusion: OA increases airway inflammation and ASM mass. Zileuton effectively prevents bronchial hyperresponsiveness, airway inflammation and ASM remodeling in sensitized rats through the PI3K/Akt pathway, which reduces cyclin D1 expression.

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Blocking of Akt/NF-κB Signaling by Pentoxifylline Inhibits Platelet-Derived Growth Factor–Stimulated Proliferation in Brown Norway Rat Airway Smooth Muscle Cells

Cited by 18 publications

References 31 publications

An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma

An RGS4-Mediated Phenotypic Switch of Bronchial Smooth Muscle Cells Promotes Fixed Airway Obstruction in Asthma

Dimethylfumarate inhibits NF-κB function at multiple levels to limit airway smooth muscle cell cytokine secretion

Effects of Zileuton on Airway Smooth Muscle Remodeling after Repeated Allergen Challenge in Brown Norway Rats

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