Mast cell–derived plasminogen activator inhibitor type 1 promotes airway inflammation and remodeling in a murine model of asthma

Jo, Ara; Lee, Sun H.; Kim, Dong Young; Hong, Seung‐Jae; Teng, Michael N.; Kolliputi, Narasaiah; Lockey, Richard F.; Schleimer, Robert P.

doi:10.1016/j.jaci.2018.01.040

Cited by 9 publications

(4 citation statements)

References 8 publications

(18 reference statements)

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“…Previous studies report that elevated SERPINE1 levels are correlated with cellular senescence and the aging process ( Yamamoto et al, 2005 ; Kortlever et al, 2006 ; Eren et al, 2014 ). We have been studying the role of PAI-1 in the airway remodeling of asthma ( Cho et al, 2001 ; Jo et al, 2018 ; Cho et al, 2019 ). However, it has not been known about the role of PAI-1 in NP, especially in age-related roles.…”

Section: Discussionmentioning

confidence: 99%

Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps

Choi

Han

et al. 2022

Front. Pharmacol.

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Objective: Our previous studies showed an age-related increased prevalence of nasal polyps (NP) and reduced production of S100A8/9 in elderly patients with chronic rhinosinusitis with NP (CRSwNP). In this study, we investigated an unbiased age-related gene expression profile in CRSwNP subjects and healthy controls, and further identified the differences in their tissue remodeling.Methods: Microarrays using NP and uncinate tissues from health controls (elderly, age ≥65 vs. non-elderly, age 18–49) were performed, and differentially regulated genes were analyzed. Quantitative real-time PCR (qPCR), Immunostaining, Periodic acid-Schiff (PAS), trichrome staining, Western blot, and ELISA were performed for further investigation.Results: Microarrays identified differentially expressed genes according to disease and age; 278 in NP vs. controls, 75 in non-elderly NP vs. non-elderly controls, and 32 in elderly NP vs. elderly controls. qPCR confirmed that the PLAT gene was downregulated and the SERPINB2 gene upregulated in NP vs. controls. The serous glandular cell-derived antimicrobial protein/peptide-related genes such as BPIFB3, BPIFB2, LPO, and MUC7 were remarkably reduced in NP, regardless of age. SERPINE1 gene (plasminogen activator inhibitor-1, PAI-1) expression was significantly increased in elderly NP versus elderly controls. IHC and western blot confirmed significantly decreased production of MUC7 and LPO in NP versus controls. There was a trend of age-related reduction of submucosal gland cells in normal controls. Trichrome and immunofluorescence staining demonstrated an age-related increase of collagen and fibrin deposition in NP, consistent with increased PAI-1 production.Conclusion: This study demonstrated age-related differential glandular remodeling patterns and fibrosis in NP and normal controls. PAI-1 expression was significantly increased in elderly NP versus elderly controls, suggesting PAI-1 as a potential treatment target in elderly NP.

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Section: Discussionmentioning

confidence: 99%

Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps

Choi

Han

et al. 2022

Front. Pharmacol.

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“…We postulated that nasal application of CD40 siRNA was more powerful than intravenous. Tissue remodelling is a common feature of allergic inflammation in the lower airway and can lead to irreversible airflow obstruction [40]. Rhinovirus infection can promote airway remodelling to trigger asthma [41].…”

Section: Mediators Of Inflammationmentioning

confidence: 99%

The Role of CD40 in Allergic Rhinitis and Airway Remodelling

Cheng

Zhou

Liu

et al. 2021

Mediators of Inflammation

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Background. Allergic rhinitis (AR) affects millions of people and is lack of effective treatment. CD40 is an important costimulatory molecule in immunity. However, few studies have focused on the role of CD40 in AR. Methods. In this study, we built mouse model of chronic AR. The mice were divided into the AR, control, intravenous CD40 siRNA, and nasal CD40 siRNA groups ( n = 6 each). We detected OVA-sIgE, IL-4, IL-5, IL-13, IL-10, IFN-γ, and TGF-β levels in serum and supernatant by ELISA, CD40+ splenic DCs, and Foxp3+ Tregs by flow cytometry and CD40 mRNA by RT2-PCR. We also used PAS and MT stains to assess tissue remodelling. Results. (1) The OVA-sIgE, IL-4, IL-5, and IL-13 levels in the serum or supernatant of nasal septal membrane of AR mice were significantly higher than control. After treated with CD40 siRNA, those indicators were significantly decreased. The IFN-γ, IL-10, and TGF-β levels in AR mice were significantly lower than that in control and were increased by administration of CD40 siRNA. (2) AR mice had significantly fewer Foxp3+ Tregs in the spleen than control mice. After treated with CD40 siRNA, AR mice had significantly more Foxp3+ Tregs. (3) AR mice exhibited a significantly higher CD40 mRNA levels than control. Administration of CD40 siRNA significantly reduced the CD40 mRNA level. (4) The AR mice showed significantly greater collagen deposition than the control in MT staining. Applications of CD40 siRNA significantly reduced the collagen deposition in AR mice. Conclusion. CD40 siRNA therapy shows promise for chronic AR as it significantly attenuated allergic symptoms and Th2-related inflammation and upregulated Foxp3+ Tregs. CD40 plays a role in tissue remodelling in AR, which can be inhibited by CD40 siRNA application.

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“…The pathophysiological process of asthma involves several types of cells and cellular components, among which airway remodeling is a well-known characteristic caused by recurrent injury and repair processes initiated by chronic inflammation ( 2 ). As a chronic inflammatory disorder of the respiratory air passages, asthma may initially be reversible but progresses into an irreversible state due to airway remodeling ( 3 ). Moreover, the prevalence of asthma has been increasing worldwide with a yearly rate of 1.8%, and 300 million people affected are in mainland China, causing a substantial economic burden ( 4 , 5 ); therefore, understanding the precise pathophysiology of asthma is paramount to achieve optimal management.…”

Section: Introductionmentioning

confidence: 99%

Glycyrrhizic acid restrains airway inflammation and remodeling in asthma via the TGF‑β1/Smad signaling pathway

Yao

2021

Exp Ther Med

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The anti-inflammatory effects of glycyrrhizic acid (GA) against asthma have previously been reported; however, the underlying molecular mechanism of GA in asthma has not yet been elucidated. Thus, the present study aimed to determine the function and potential molecular mechanism of GA for modulating the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway in asthma-associated airway inflammation and remodeling. In order to study the mechanism of GA on airway inflammation and airway remodeling in asthmatic mice, a mouse model of chronic asthma was constructed. A total of 50 female mice were randomly assigned into five groups (10 mice/group), as follows: Blank group, asthma group, GA group, dexamethasone group and GA + TGF-β1 group. Hematoxylin and eosin, and Masson staining were performed to assess the airway inflammation and remodeling in mice with ovalbumin (OVA)-induced asthma. The serum levels of interleukin (IL)-4, IL-5, IL-13 and IL-17 in mice were assessed via the enzyme-linked immunosorbent assay. Reverse transcription-quantitative PCR and western blot analyses were performed to detect the levels of TGF-β1 and Smads in lung tissues of each group of mice. The results demonstrated that GA and dexamethasone treatment mitigated airway inflammation, inflammatory cell infiltration and airway remolding, with a concomitant decrease in the expression levels of IL-4, IL-5, IL-13 and IL-17, in mice with OVA-induced asthma. In addition, the levels of TGF-β1 and Smad2 notably decreased, while Smad7 expression increased in the GA and dexamethasone groups compared with the asthma group. Furthermore, histopathological morphometry exhibited significantly elevated inflammatory cell infiltration, airway wall and smooth muscle, collagen secretion and inflammatory cytokines in the serum of mice in the GA + TGF-β1 group compared with the GA group. Taken together, the results of the present study suggest that GA ameliorates airway inflammation and remodeling via the TGF-β1/Smad signaling pathway in mice with asthma.

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Mast cell–derived plasminogen activator inhibitor type 1 promotes airway inflammation and remodeling in a murine model of asthma

Cited by 9 publications

References 8 publications

Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps

Age-Related Increase of Collagen/Fibrin Deposition and High PAI-1 Production in Human Nasal Polyps

The Role of CD40 in Allergic Rhinitis and Airway Remodelling

Glycyrrhizic acid restrains airway inflammation and remodeling in asthma via the TGF‑β1/Smad signaling pathway

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