Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c

Liu, Gang; Cooley, Marion A.; Nair, Prema M.; Donovan, Chantal; Hsu, Alan; Jarnicki, Andrew G.; Haw, Tatt Jhong; Hansbro, Philip M.; Ge, Qi; Brown, Alexandra C.; Tay, Hock L.; Foster, Paul S.; Wark, Peter; Horvat, Jay C.; Bourke, Jane E.; Grainge, Christopher; Argraves, W. Scott; Oliver, Brian G.; Knight, Darryl A.; Burgess, Janette K.

doi:10.1002/path.4979

Cited by 92 publications

(86 citation statements)

References 68 publications

(101 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Airway remodeling occurs in patients with asthma, in particular those with chronic or severe asthma (Liu et al, ). Airway remodeling is associated with the accumulation of ECM proteins, such as collagens and fibronectin (Liu et al, ). In the present study, the mRNA and protein levels of collagen type I and fibronectin were detected by qRT‐PCR and western blot, respectively.…”

Section: Resultsmentioning

confidence: 99%

“…Inhibition of mucus secretion may contribute to the treatment of asthma. Airway remodeling and inflammation in asthma are dependent on the ECM proteins, such as collagens and fibronectin (Liu et al, ). However, airway remodeling with excessive deposition of ECM is correlated with increased airway responsiveness and asthma severity (Goldstein, Lauer, Caplan, & Bonfield, ).…”

Section: Discussionmentioning

confidence: 99%

“…Asthma is a complex inflammatory disease characterized by airway inflammation, remodeling, and hyperresponsiveness (Mishra, Banga, & Silveyra, ). Asthma patients, in particular those with chronic or severe asthma, have airway remodeling that is associated with the accumulation of extracellular matrix (ECM) proteins (Liu et al, ). In addition, asthma has been proved to be associated with mucous metaplasia, production, and hypersecretion (Evans, Kim, Tuvim, & Dickey, ).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Casticin alleviates lipopolysaccharide‐induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF‐κB pathways

Wang

2018

Phytotherapy Research

View full text Add to dashboard Cite

Asthma is one of the most common chronic inflammatory diseases of childhood, characterized by airway inflammation, mucus hypersecretion, and accumulation of extracellular matrix proteins. Casticin is an active compound that possesses broad biological activities including anti-inflammatory effect. However, the effect of casticin on asthma remains unknown. The aim of the present study was to evaluate the effect and mechanism of casticin on inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells. The results showed that lipopolysaccharide induced the mRNA and protein levels of IL-6, IL-8, MUC5AC, collagen type I, and fibronectin in 16-HBE cells, whereas casticin treatment significantly inhibited the induction of lipopolysaccharide. Casticin induced Nrf2/Keap1 and inhibited nuclear factor κB pathways in 16-HBE cells. Knockdown of Nrf2 attenuated the effect of casticin on production of IL-6 and IL-8, expression of MUC5AC, collagen type I, and fibronectin in 16-HBE cells. In conclusion, the results indicated that casticin might be a novel therapeutic strategy for the treatment of asthma.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Casticin alleviates lipopolysaccharide‐induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF‐κB pathways

Wang

2018

Phytotherapy Research

View full text Add to dashboard Cite

show abstract

“…Muc7, Muc13, Muc15, and Muc19 gene and protein expression is facilitated by several cytokines, including TNF-α and IL-1β, secreted by macrophages [8,34]. In previous reported that IL-6, IL-8, and TNF-α secreted by lung lymphocytes specifically induce the secretion of Muc7, Muc13, Muc15, and Muc19 to promote destruction of lung tissue [35,36]. Muc7, Muc13, Muc15, and Muc19, IL-1β, and TNF-α expression levels in response to infection were significantly reduced in A549 cells transformed with siRNA targeting IKK-α and IKK-β.…”

Section: Discussionmentioning

confidence: 99%

Type III secretion system ofPseudomonas aeruginosaaffects mucin gene expression via NF-κB and AKT signaling in human carcinoma epithelial cells and a pneumonia mouse model

Park

Shin

et al. 2018

Preprint

View full text Add to dashboard Cite

25The type III secretion system (T3SS) in Pseudomonas aeruginosa has been linked to 26 severe disease and poor clinical outcomes in animal and human studies. Of the various T3SS 27 effector genes, ExoS and ExoT showed mutually exclusive distributions, and these two genes 28 showed varied virulence. We aimed to investigate whether the ExoS and ExoT effector proteins 29 of P. aeruginosa affect the expression of the proinflammatory mediators Muc7, Muc13, Muc15, 30 and Muc19 via the NF-κB and AKT signaling pathways. To understand the role of the T3SS, 31 we used ΔExoS, ΔExoT, and T3SS transcriptional activator ExsA mutants (ExsA::Ω), as well 32 as A549 cells stimulated with P. aeruginosa strain K (PAK). We investigated the effects of 33 ΔExoS, ΔExoT, and ExsA::Ω on the development of pneumonia in a mouse model and on 34 Muc7, Muc13, Muc15, and Muc19 production in A549 cells. ΔExoS and ΔExoT markedly 35 decreased the neutrophil count in the bronchoalveolar lavage fluid, with a reduction in Muc7, 36 Muc13, Muc15, and Muc19 expression. ΔExoS and ΔExoT reduced NF-κB and AKT 37 phosphorylation, together with Muc7, Muc13, Muc15, and Muc19 expression in PAK-infected 38 mice and A549 cells. In conclusion, P. aeruginosa infection induced the expression of Mucus, 39 and the P. aeruginosa T3SS appeared to be a key player in Muc7, Muc13, Muc15, and Muc19 40 expression, which is further controlled by NF-κB and AKT signaling. These findings might be 41 useful to devise a novel therapeutic approach for the treatment of chronic pulmonary infections 42 by targeting ExoS and ExoT.43 44 3 45 Author Summary 46Pseudomonas aeruginosa is a ubiquitous gram-negative bacterium causing serious infections. 47Many clinical isolates of P. aeruginosa have a specialized apparatus for injecting toxins into 48 eukaryotic cells, namely, the type III secretion system (T3SS). The T3SS is a syringe-like 49 apparatus on the bacterial surface, with 4 effector toxins: ExoS, ExoT, ExoY, and ExoU. We 50 investigated the effect of ExoS and ExoT of the T3SS of P. aeruginosa K strain (PAK). Mucus 51 plays a vital role in protecting the lungs from environmental factors, but conversely, in muco-52 obstructive airway disease, mucus becomes pathologic. We showed that infection with ExoS 53 and ExoT induced Muc7, Muc13, Muc15, and Muc19 expression in host cells. PAK clinical 54 strains induce proinflammatory cytokine production through the T3SS, and this involves NF-55 κB and SP1/AKT activation in pneumonia mouse models. Mucus induction in response to 56 ExoS and ExoT infection relied on NF-κB and SP1/AKT activation. Our findings highlight the 57 roles of Muc7, Muc13, Muc15, and Muc19 in inducing proinflammatory cytokine expression 58 during ExoS and ExoT exposure in PAK infections, paving the way for a novel therapeutic 59 approach for the treatment of pulmonary infections.60 4 61 62The gram-negative bacterium Pseudomonas aeruginosa uses a complex type III 63 secretion system (T3SS) to inject effector proteins into host cells [1,2]. The T3SS is a major 64 v...

show abstract

“…The area of collagen deposition (lm 2 ), airway epithelial area (lm 2 ) and cell (nuclei) number were assessed in a minimum of four small airways (basement membrane [BM] perimeter < 1000 lm) per section. Data were normalised to BM perimeter (lm) and quantified using ImageJ software (Version 1.49h; National Institutes of Health, New York City, NY, USA) 19,21,24,80 .…”

Section: Airway Remodellingmentioning

confidence: 99%

Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

et al. 2019

Self Cite

View full text Add to dashboard Cite

Objective. Chronic obstructive pulmonary disease (COPD) is a progressive disease that causes significant mortality and morbidity worldwide and is primarily caused by the inhalation of cigarette smoke (CS). Lack of effective treatments for COPD means there is an urgent need to identify new therapeutic strategies for the underlying mechanisms of pathogenesis. Tristetraprolin (TTP) encoded by the Zfp36 gene is an anti-inflammatory protein that induces mRNA decay, especially of transcripts encoding inflammatory cytokines, including those implicated in COPD.Methods. Here, we identify a novel protective role for TTP in CSinduced experimental COPD using Zfp36 aa/aa mice, a genetically modified mouse strain in which endogenous TTP cannot be phosphorylated, rendering it constitutively active as an mRNAdestabilising factor. TTP wild-type (Zfp36 +/+ ) and Zfp36 aa/aa active C57BL/6J mice were exposed to CS for four days or eight weeks, and the impact on acute inflammatory responses or chronic features of COPD, respectively, was assessed. Results. After four days of CS exposure, Zfp36 aa/aa mice had reduced numbers of airway neutrophils and lymphocytes and mRNA expression levels of cytokines compared to wild-type controls. After eight weeks, Zfp36 aa/aa mice had reduced pulmonary inflammation, airway remodelling and emphysema-like alveolar enlargement, and lung function was improved. We then used pharmacological treatments in vivo (protein phosphatase 2A activator, AAL (S) , and the proteasome inhibitor, bortezomib) to promote the activation and stabilisation of TTP and show that hallmark features of CS-induced experimental COPD were ameliorated. Conclusion. Collectively, our ª

show abstract

Airway remodelling and inflammation in asthma are dependent on the extracellular matrix protein fibulin-1c

Abstract: Asthma is a chronic inflammatory disease of the airways. It is characterized by allergic airway inflammation, airway remodelling, and airway hyperresponsiveness (AHR

Cited by 92 publications

References 68 publications

Casticin alleviates lipopolysaccharide‐induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF‐κB pathways

Casticin alleviates lipopolysaccharide‐induced inflammatory responses and expression of mucus and extracellular matrix in human airway epithelial cells through Nrf2/Keap1 and NF‐κB pathways

Type III secretion system ofPseudomonas aeruginosaaffects mucin gene expression via NF-κB and AKT signaling in human carcinoma epithelial cells and a pneumonia mouse model

Enhancing tristetraprolin activity reduces the severity of cigarette smoke‐induced experimental chronic obstructive pulmonary disease

Contact Info

Product

Resources

About