Interfering with extracellular matrix degradation to blunt inflammation

O’Reilly, Philip; Gaggar, Amit; Blalock, J. Edwin

doi:10.1016/j.coph.2008.02.003

Cited by 26 publications

(21 citation statements)

References 47 publications

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“…Although these enzymes primarily function intracellularly (10), a subset are transported extracellularly, where they have been largely described in regulating ECM remodeling (11). Extracellular proteases have also recently been shown to exhibit unique roles in controlling cellular homeostasis through a variety of mechanisms, including regulation of immune responses, disruption of cell-to-cell contacts, modulation of cell surface receptors for signal transduction, and modulation of cell-ECM interactions (12)(13)(14)(15).…”

mentioning

confidence: 99%

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

Szul

Bratcher

Fraser³

et al. 2016

Am J Respir Cell Mol Biol

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Proteases are important regulators of pulmonary remodeling and airway inflammation. Recently, we have characterized the enzyme prolyl endopeptidase (PE), a serine peptidase, as a critical protease in the generation of the neutrophil chemoattractant tripeptide Pro-Gly-Pro (PGP) from collagen. However, PE has been characterized as a cytosolic enzyme, and the mechanism mediating PE release extracellularly remains unknown. We examined the role of exosomes derived from airway epithelia as a mechanism for PE release and the potential extracellular signals that regulate the release of these exosomes. We demonstrate a specific regulatory pathway of exosome release from airway epithelia and identify PE as novel exosome cargo. LPS stimulation of airway epithelial cells induces release of PEcontaining exosomes, which is significantly attenuated by small interfering RNA depletion of Toll-like receptor 4 (TLR4). These differences were recapitulated upon intratracheal LPS administration in mice competent versus deficient for TLR4 signaling. Finally, sputum samples from subjects with cystic fibrosis colonized with Pseudomonas aeruginosa demonstrate elevated exosome content and increased PE levels. This TLR4-based mechanism highlights the first report of nonstochastic release of exosomes in the lung and couples TLR4 activation with matrikine generation. The increased quantity of these proteolytic exosomes in the airways of subjects with chronic lung disease highlights a new mechanism of injury and inflammation in the pathogenesis of pulmonary disorders.Keywords: protease; Toll-like receptor 4; exosome; cystic fibrosis; pulmonary Cell-to-cell communication via secreted soluble mediators is critical to the maintenance of cellular homeostasis in complex metazoans. Much of this intercellular communication is regulated through the classical secretory mechanism, in which proteins containing an endoplasmic reticulum (ER)-signaling sequence are actively released via the ER-toGolgi pathway (1). Despite the broad range of proteins entering this pathway, a number of actively secreted proteins lack a signal sequence for release and are released via alternative mechanisms, including exosomes (2).

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confidence: 99%

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

Szul

Bratcher

Fraser³

et al. 2016

Am J Respir Cell Mol Biol

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“…The pathogens also release endopeptidases that can disintegrate the ECM and release ECM protein fragments with pro-inflammatory properties (Morwood and Nicholson, 2006). In many pulmonary diseases, including ARDS and bacterial pneumonias, abnormal remodeling or destruction of ECM has been reported (Elkington and Friedland, 2006;O'Reilly et al, 2008;Okamoto et al, 2004). Not only do the pro-inflammatory and apoptotic mediators such as TNF-a, IL-1-b and FAS regulate the expression and activation of MMPs and TIMPs, but the MMPs and TIMPs can also regulate the expression of pro-inflammatory and apoptotic mediators as well as the recruitment of inflammatory cells to the inflammation site.…”

Section: Alcohol Modulates Immune Response During Bacterial and Viralmentioning

confidence: 99%

Alcohol, Signaling, and ECM Turnover

Seth

El-Guindy

Apte

et al. 2009

Alcoholism Clin & Exp Res

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Alcohol is recognized as a direct hepatotoxin, but the precise molecular pathways that are important for the initiation and progression of alcohol-induced tissue injury are not completely understood. The current understanding of alcohol toxicity to organs suggests that alcohol initiates injury by generation of oxidative and nonoxidative ethanol metabolites and via translocation of gut-derived endotoxin. These processes lead to cellular injury and stimulation of the inflammatory responses mediated through a variety of molecules. With continuing alcohol abuse, the injury progresses through impairment of tissue regeneration and extracellular matrix (ECM) turnover, leading to fibrogenesis and cirrhosis. Several cell types are involved in this process, the predominant being stellate cells, macrophages, and parenchymal cells. In response to alcohol, growth factors and cytokines activate many signaling cascades that regulate fibrogenesis. This mini-review brings together research focusing on the underlying mechanisms of alcohol-mediated injury in a number of organs. It highlights the various processes and molecules that are likely involved in inflammation, immune modulation, susceptibility to infection, ECM turnover and fibrogenesis in the liver, pancreas, and lung triggered by alcohol abuse.

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“…No presente estudo demonstrou-se que os níveis de MPM-2 e MPM-9 nas amostras de saliva foram significativamente maiores nos pacientes com DPOC em relação aos sujeitos saudáveis, tendose observado também correlação negativa entre os níveis de expressão da MPM-2 e os parâmetros de obstrução aérea VEF 1 e VEF 1 /CVF nos pacientes com DPOC. Como as MPM são extremamente representativas na DPOC [8][9][10][11][12][13] , a correlação entre os níveis de expressão da MPM-2 na saliva e os parâmetros de avaliação da capacidade pulmonar funcional indicam fortes perspectivas para a caracterização de biomarcadores, proteicos ou peptídicos específicos, utilizando estratégias experimentais da área de proteômica, como a espectrometria de massas. Já foi relatado que, em comparação com indivíduos saudáveis, os pacientes com DPOC apresentam aumento dos níveis de MPM-1 e MPM-9 no lavado broncoalveolar 17 , acentuado aumento na expressão e atividade de MPM-2 e MPM-9 no parênquima pulmonar e no escarro 18 .…”

Section: Discussão E Conclusãounclassified

“…As MPM catalisam componentes proteicos da matriz extracelular produzindo moléculas peptídicas biologicamente ativas, que participam do processo inflamatório envolvido na DPOC [8][9][10] . A MPM-2 e a MPM-9 pertencem ao grupo das gelatinases, que podem hidrolisar múltiplas moléculas da matriz extracelular, tais como colágeno tipos I, II, III e IV, elastina e proteoglicanos 11 .…”

Section: Introductionunclassified

Expressão das metaloproteinases da matriz 2 e 9 na saliva de pacientes com doença pulmonar obstrutiva crônica

Santos

Malaguti

Corso³

et al. 2009

Fisioter. Pesqui.

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RESUMO: O aumento da expressão das metaloproteinases da matriz extracelular (MPM) é considerado um importante fator no desenvolvimento da doença pulmonar obstrutiva crônica (DPOC). O presente estudo teve como objetivo avaliar os níveis de expressão da MPM-2 e MPM-9 na saliva de pacientes com DPOC em comparação com indivíduos saudáveis, verificando a viabilidade de usar a saliva para a caracterização de biomarcadores específicos em DPOC. Foram selecionados pacientes com DPOC (n=16) e controles saudáveis (n=9). Em ambos os grupos foram realizados teste espirométrico e obtidas amostras de saliva de cada indivíduo. Os níveis de MPM-2 e MPM-9 na saliva foram determinados pela técnica Western blot. A MPM-2 e a MPM-9 foram significativamente maiores em pacientes com DPOC do que no grupo de indivíduos saudáveis. Foi encontrada moderada correlação negativa entre a concentração de MPM-2 e o volume expiratório forçado no primeiro segundo (r= -0,582, p=0,014) em pacientes com DPOC. Estes resultados abrem novas perspectivas para o estudo específico de biomarcadores na saliva para predizer e monitorar a obstrução ao fluxo aéreo em pacientes com DPOC. DESCRITORES: Doença pulmonar obstrutiva crônica; Metaloproteinase 2 da matriz; Metaloproteinase 9 da matriz; Saliva ABSTRACT: The increased expression of matrix metalloproteinases (MMP) is considered a key factor in the development of chronic obstructive pulmonary disease (COPD). This study aimed at assessing expression levels of MMP-2 and MMP-9 in saliva from patients with COPD, comparing them to those of healthy subjects, thus assessing the feasibility of characterizing specific biomarkers for COPD. Patients with COPD (n=16) and healthy controls (n=9) were selected; both groups submitted to spirometry and to collection of saliva samples. Saliva levels of MMP-2 and MMP-9 were determined by Western blot. MMP-2 and MMP-9 levels were significantly higher in COPD patients than in control subjects. In COPD patients, a moderate, negative correlation was found between MMP-2 concentration and forced expiatory volume at the first second (r= -0.582; p=0.014). These findings open new perspectives to study specific biomarkers in saliva to predict and monitor airway obstruction in COPD patients. KEY WORDS: Matrix metalloproteinase 2; Matrix metalloproteinase 9; Pulmonary disease, chronic obstructive; Saliva Fisioterapia e Pesquisa, São Paulo, v.16, n.4, p.299-305, out./dez. 2009

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Interfering with extracellular matrix degradation to blunt inflammation

Cited by 26 publications

References 47 publications

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

Toll-Like Receptor 4 Engagement Mediates Prolyl Endopeptidase Release from Airway Epithelia via Exosomes

Alcohol, Signaling, and ECM Turnover

Expressão das metaloproteinases da matriz 2 e 9 na saliva de pacientes com doença pulmonar obstrutiva crônica

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