Upregulated P-Rex1 exacerbates human airway smooth muscle hyperplasia in asthma

Huang, Yapei; Xie, Yan; Jiang, Haihong; Abel, Peter W.; Panettieri, Reynold A.; Casale, Thomas B.; Tu, Yaping

doi:10.1016/j.jaci.2018.09.020

Cited by 3 publications

(4 citation statements)

References 12 publications

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“…Recently, P-Rex1, a Rac1 exchange factor, has been shown to be aberrantly upregulated in lung tissue from patients with asthma and to potentiate growth factor-induced human aSMC proliferation. 34 Therefore, it can be hypothesised that the activation of aSMC Rac1 observed in severe asthma patients could be related, at least in part, to this aberrant upregulation of The increase in aSMC mass in asthma patients was associated with airflow obstruction. 9 10 Indeed, aSMC are not only responsible for AHR through their contractile activity, but also contribute to the inflammatory process by modifying the extracellular matrix and producing mediators that act on inflammatory cells.…”

Section: Discussionmentioning

confidence: 99%

Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling

Dilasser

Rose

Hassoun

et al. 2021

Thorax

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BackgroundSevere asthma is a chronic lung disease characterised by inflammation, airway hyperresponsiveness (AHR) and airway remodelling. The molecular mechanisms underlying uncontrolled airway smooth muscle cell (aSMC) proliferation involved in pulmonary remodelling are still largely unknown. Small G proteins of the Rho family (RhoA, Rac1 and Cdc42) are key regulators of smooth muscle functions and we recently demonstrated that Rac1 is activated in aSMC from allergic mice. The objective of this study was to assess the role of Rac1 in severe asthma-associated airway remodelling.Methods and resultsImmunofluorescence analysis in human bronchial biopsies revealed an increased Rac1 activity in aSMC from patients with severe asthma compared with control subjects. Inhibition of Rac1 by EHT1864 showed that Rac1 signalling controlled human aSMC proliferation induced by mitogenic stimuli through the signal transducer and activator of transcription 3 (STAT3) signalling pathway. In vivo, specific deletion of Rac1 in SMC or pharmacological inhibition of Rac1 by nebulisation of NSC23766 prevented AHR and aSMC hyperplasia in a mouse model of severe asthma. Moreover, the Rac1 inhibitor prevented goblet cell hyperplasia and epithelial cell hypertrophy whereas treatment with corticosteroids had less effect. Nebulisation of NSC23766 also decreased eosinophil accumulation in the bronchoalveolar lavage of asthmatic mice.ConclusionThis study demonstrates that Rac1 is overactive in the airways of patients with severe asthma and is essential for aSMC proliferation. It also provides evidence that Rac1 is causally involved in AHR and airway remodelling. Rac1 may represent as an interesting target for treating both AHR and airway remodelling of patients with severe asthma.

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Section: Discussionmentioning

confidence: 99%

Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling

Dilasser

Rose

Hassoun

et al. 2021

Thorax

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“…16,17 The PREX1 gene region is frequently deleted or amplified in cancer, suggesting the role of PREX1 as a putative oncogene in human cancers. [18][19][20] In addition to the P-Rex1 pathway's extensive involvement in the inflammatory response, neurite differentiation, 21 lung endothelial permeability, 22,23 and pulmonary fibrosis, 24 its involvement in cancer has only recently been studied. 17,25,26 However, the role of P-Rex1 in liver cancer remains elusive.…”

Section: Introductionmentioning

confidence: 99%

<p>Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway</p>

Qiu¹,

Chang²,

Liu³

et al. 2020

OTT

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Background: Rho-GTPases and their activators, guanine nucleotide exchange factors (GEFs), are increasingly being recognized as essential mediators of oncogenic signaling. Although it is known that P-Rex1, a member of the Dbl family of GEFs for the Rac small GTPase, contributes to the migration of cancer cells, its exact role in liver cancer and the underlying mechanisms remain unclear. Materials and Methods: Public datasets from the Gene Expression Omnibus database (GEO) and clinical liver cancer samples were analyzed to explore the expression of P-Rex1. P-Rex1 knockdown and overexpression cell lines were established using a recombinant lentiviral transfection system. BrdU and colony formation assays were performed to determine cell viability. Migratory capacity was analyzed using a transwell migration assay and an in vitro wound-healing assay. Nude mice bearing subcutaneous xenograft tumors were established to determine the effects of P-Rex1 on tumorigenesis in vivo. The role of P-Rex1 in hepatocarcinogenesis was determined through Western blot and coimmunoprecipitation. Results: Induced expression of endogenous P-Rex1 was identified in liver cancer tumors when compared with adjacent nonmalignant tissues from clinical data. In response to HGF treatment, P-Rex1-knockdown cells displayed reduced proliferation and migration in vitro as well as reduced xenograft tumor growth in vivo. Overexpression of P-Rex1 promoted liver cancer cell proliferation and migration. P-Rex1 primarily acts as a downstream effector of GPCR signaling. This study demonstrated that downregulation of P-Rex1 led to a significant decrease in the phosphorylation of Akt and Erk1/2 by reducing the phosphorylation of the tyrosine kinase receptor c-Met. Furthermore, a physical association between P-Rex1 and c-Met was observed after HGF treatment, suggesting that P-Rex1 may be involved in the HGF/c-Met signaling pathway. Conclusion: These results support the role of P-Rex1 as a novel player in liver cancer, which suggest that targeting P-Rex1 may provide a potential strategy for liver cancer treatment.

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“…Three human ASM cell lines were used. These cell lines were established by Panettieri's laboratory using human lung tissue samples obtained from nonasthmatic donors during open-lung resection at the time of death (48). Cells were cultured at 37°C with 5% CO 2 in smooth muscle cell growth medium from Genlantis containing antibiotics and antimycotic.…”

Section: Reagents and Cellsmentioning

confidence: 99%

“…Protein samples were loaded on 10% SDS polyacrylamide gels, electrophoresed, and transferred onto polyvinylidene difluoride membranes. Protein bands recognized by primary antibodies were visualized by using secondary antibodies for the Odyssey IR imaging system (LI-COR Bioscience), and densitometry analysis was performed with Image Studio software as described (48). The signal for phosphorylated MLC2 or VASP was normalized to the signal for total MLC2 or VASP protein, respectively.…”

Section: Western Blotmentioning

confidence: 99%

Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma

et al. 2020

Self Cite

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Overuse of β2-adrenoceptor agonist bronchodilators evokes receptor desensitization, decreased efficacy, and an increased risk of death in asthma patients. Bronchodilators that do not target β2-adrenoceptors represent a critical unmet need for asthma management. Here, we characterize the utility of osthole, a coumarin derived from a traditional Chinese medicine, in preclinical models of asthma. In mouse precision-cut lung slices, osthole relaxed preconstricted airways, irrespective of β2-adrenoceptor desensitization. Osthole administered in murine asthma models attenuated airway hyperresponsiveness, a hallmark of asthma. Osthole inhibited phosphodiesterase 4D (PDE4D) activity to amplify autocrine prostaglandin E2 signaling in airway smooth muscle cells that eventually triggered cAMP/PKA-dependent relaxation of airways. The crystal structure of the PDE4D complexed with osthole revealed that osthole bound to the catalytic site to prevent cAMP binding and hydrolysis. Together, our studies elucidate a specific molecular target and mechanism by which osthole induces airway relaxation. Identification of osthole binding sites on PDE4D will guide further development of bronchodilators that are not subject to tachyphylaxis and would thus avoid β2-adrenoceptor agonist resistance.

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Upregulated P-Rex1 exacerbates human airway smooth muscle hyperplasia in asthma

Cited by 3 publications

References 12 publications

Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling

Essential role of smooth muscle Rac1 in severe asthma-associated airway remodelling

<p>Identification of P-Rex1 in the Regulation of Liver Cancer Cell Proliferation and Migration via HGF/c-Met/Akt Pathway</p>

Airway relaxation mechanisms and structural basis of osthole for improving lung function in asthma

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