Role of matrix metalloproteases in pulmonary fibrosis

Pardo, Annie; Selman, Moisés

doi:10.1007/978-3-7643-8585-9_3

Cited by 5 publications

(1 citation statement)

References 68 publications

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“…ALI also reduces fibrosis owing to the fact it decreases levels of MMPs (metalloproteinases), which are proteases involved in the physiopathology of fibrosis and abnormal remodeling of the extracellular matrix (ECM) (Abuelezzy et al, 2016;Kunugi, Fukuda, Ishizaki, & Yamanaka, 2001;Pardo & Selman, 2012).…”

Section: Introductionmentioning

confidence: 99%

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review

Marin

Bertassoli²,

Carvalho

et al. 2019

Drug Development Research

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Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty‐three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

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Section: Introductionmentioning

confidence: 99%

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review

Marin

Bertassoli²,

Carvalho

et al. 2019

Drug Development Research

View full text Add to dashboard Cite

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Resolution of Lung Injury after a Single Event of Aspiration

Araos

Ayala

Meneses

et al. 2015

The American Journal of Pathology

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Gastric aspiration is a high-risk condition for lung injury. Consequences range from subclinical pneumonitis to respiratory failure, with fibrosis development in some patients. Little is known about how the lung repairs aspiration-induced injury. By using a rat model of single orotracheal instillation of whole gastric contents, we studied the time course of morphological and biochemical changes during injury and resolution, and evaluated whether repair involved long-term fibrosis. Anesthetized rats received one gastric fluid instillation. At 4, 12, and 24 hours and 4 and 7 days, we performed lung histological studies and biochemical measurements in bronchoalveolar lavage fluid and lung tissue. Physiological measurements were performed at 12 to 24 hours. Long-term outcome was studied histologically at day 60. During the first 24 hours, severe peribronchiolar injury involving edema, intra-alveolar proteinaceous debris, hemorrhage, increased neutrophils and cytokines, and physiological dysfunction were observed. At days 4 and 7, an organizing pneumonia (OP) pattern developed, with foreign-body giant cells and granulomas. Lung matrix metalloproteinase 9 and 2 activities increased, with metalloproteinase-9 linked to early inflammation and metalloproteinase-2 to OP. At day 60, lung architecture was normal. In conclusion, a continuum of alterations starting with severe injury, evolving toward OP and later resolving, characterizes the rat single aspiration event. In addition to identifying markers of staging and severity, this model reveals that OP participates in the repair of aspiration-induced injury.

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A common tag nucleotide variant inMMP7promoter increases risk for hypertension via enhanced interactions with CREB transcription factor

Subramanian

Maghajothi

Singh

et al. 2019

Preprint

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MMP7 (Matrilysin), a potent extracellular matrix degrading enzyme with wide substrate specificity, is emerging as a new regulator of cardiovascular diseases including coronary artery disease and atherosclerosis. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we first probed for the association of a tag single nucleotide polymorphism (SNP) in the MMP7 gene promoter (-181A/G; rs11568818) with hypertension in an urban south Indian population (n=1517).The heterozygous A/G genotype showed a strong association with hypertension as compared to the A/A wild-type genotype (OR=1.641, 95% CI=1.276-2.109; p=1x10 -4 ); AG genotype carriers also displayed significantly higher diastolic blood pressure and mean arterial pressure than AA genotype subjects. The study was replicated in a north Indian population (n=977) as well (OR=1.520, 95% CI =1.106-2.090; p=0.01). Transient transfection experiments using MMP7 promoter-luciferase reporter constructs revealed that the variant -181G allele conferred greater promoter activity than the -181A allele.Computational prediction and structure-based conformational and molecular dynamics simulation studies suggested higher binding affinity for the transcription factor CREB to the -181G promoter. In corroboration, over-expression/down-regulation of CREB and chromatin immunoprecipitation experiments provided convincing evidence for stronger binding of CREB with the -181G promoter. Further, the -181G promoter also displayed an enhanced response to hypoxia and epinephrine-treatment. The higher promoter activity of -181G allele also translated to increased MMP7 protein levels. Indeed, MMP7-181A/G heterozygous individuals displayed elevated plasma MMP7 levels which positively correlated with blood pressure. In conclusion, the MMP7 A-181G promoter SNP increased expression of MMP7 under pathophysiological (such as hypoxic stress and catecholamine excess) conditions via increased interactions with the transcription factor CREB and enhanced the risk for hypertension in its carriers.Keywords: MMP7, hypertension, single nucleotide polymorphism, association study, transcriptional regulation, CREB, epinephrine, hypoxia.informed written consent and the study was approved by the institutional ethics Committee at Indian Institute of Technology Madras. Demographic, physiological and biochemical parameters of both the study populations are listed in the Tables S1 and S2. Genotyping of MMP7 -181A/G polymorphismGenomic DNA was isolated from heparin/EDTA-anticoagulated blood samples using Flexigene DNA kit. The promoter region of MMP7 comprising of -302 bp to -153 bp (NCBI accession number: NM_002423.4) was PCR-amplified using specific primers, purified and digested with EcoRI to detect the genotypes at the -181 bp position (Fig. S1). Estimation of biochemical parametersCommon biochemical parameters such as glucose, lipid profile, urea, creatinine, hemoglobin, sodium and potassium levels in plasma were estimated by standard assays. Blood pressure was m...

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Role of matrix metalloproteases in pulmonary fibrosis

Cited by 5 publications

References 68 publications

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review

Resolution of Lung Injury after a Single Event of Aspiration

A common tag nucleotide variant inMMP7promoter increases risk for hypertension via enhanced interactions with CREB transcription factor

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