Early and Late Changes of MMP-2 and MMP-9 in Bleomycin-Induced Pulmonary Fibrosis

Kim, Ji Young; Choeng, Hyun Cheol; Ahn, Cheolmin; Cho, Sang-Ho

doi:10.3349/ymj.2009.50.1.68

Cited by 72 publications

(71 citation statements)

References 43 publications

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“…Bleomycin-induced fibrosis is associated with a Th1/Th17 response at early time points (25); this finding supports our data, which show the presence of miR-326 during the onset of the disease. Our fibrosis array data also suggest a significant down-regulation in MMP-2 expression in miR-326 transfected cells, which has been previously implicated in the pathogenesis of pulmonary fibrosis (34). TGFb1 transcripts could be present with two distinct 39UTR lengths (543 and 144 bases), although multiple human cell lines predominantly express transcripts with the shorter 39UTR (20).…”

Section: Discussionmentioning

confidence: 54%

MicroRNA-326 Regulates Profibrotic Functions of Transforming Growth Factor-β in Pulmonary Fibrosis

Das

Kumar

Negi

et al. 2014

Am J Respir Cell Mol Biol

148

122

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Idiopathic pulmonary fibrosis (IPF) is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor (TGF)-b has a wellestablished role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-b has been disappointing, and strategies to directly suppress TGF-b1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-b1 regulation and to validate the role of miR-326 in pulmonary fibrosis.We show that hsa-miR-326 regulates TGF-b1 expression and that hsa-miR-326 levels are inversely correlated to TGF-b1 protein levels in multiple human cell lines. The increase in TGF-b1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-b1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-b signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-b1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis.

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Section: Discussionmentioning

confidence: 54%

MicroRNA-326 Regulates Profibrotic Functions of Transforming Growth Factor-β in Pulmonary Fibrosis

Das

Kumar

Negi

et al. 2014

Am J Respir Cell Mol Biol

148

122

View full text Add to dashboard Cite

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“…Macrophages are the most important inflammatory effector cells and accumulate at sites of inflammation (13). MMP-9 and TiMP-1 play an important role in the regulation, turnover and remodeling of the ecM (5), and are therefore considered to play a crucial role in the pathophysiology of pulmonary inflammation and fibrosis (8,(14)(15)(16), in particular the overexpression of alveolar macrophage MMP-9 (16). in the present study, radiation had a dramatic effect on the up-regulation of MMP-9 protein, but did not affect TiMP-1 protein levels in the RWA264.7 cells.…”

Section: Discussionmentioning

confidence: 99%

Modulation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in RAW264.7 cells by irradiation

Zhou

Lin

et al. 2010

Mol Med Rep

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Abstract. radiation-induced pulmonary injury is a severe complication affecting the quality of life of patients. although the pathophysiology of the process is not fully understood, we hypothesized that it is potentially related to macrophages and their secretion of matrix metalloproteinase-9 (MMP-9). Macrophages are a type of inflammatory cell that synthesize hundreds of bioactive substances and enzymes. MMP-9 is closely involved in the maintenance of the basilar membrane, and leads to increased extracellular matrix deposition within the lung, which is a characteristic feature of radiation-induced lung fibrosis. We examined the role of ionizing radiation in modulating the production of MMP-9 in a macrophage cell line. RAW264.7 cells were irradiated with various doses of γ-rays, and then MMP-9 and tissue inhibitor of metalloproteinase-1 (TiMP-1) levels were determined at several time points. rT-Pcr revealed a marked increase in the levels of MMP-9 mRNA, which peaked at 24 h post-irradiation and had begun to decline by 48 h. By contrast, TIMP-1 mRNA experienced only a slight increase at 24 h post-irradiation, reaching significance at 48 h post-irradiation. Western blot analysis demonstrated an increased expression of MMP-9 protein in the irradiated cells, while TiMP-1 protein levels were not notably changed. dexamethasone inhibited the increased expression of MMP-9 protein induced by ionizing radiation. These results indicate that MMP-9 expression by RAW264.7 cells, and an imbalance between MMP-9 and TiMP-1, may be involved in radiation-induced lung injury.

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“…Histology and BAL analysis demonstrated an acute injury pattern on day 4 following intratracheal instillation of 1.5 units?kg -1 bleomycin. Neutrophils were the dominant source of MMP-9 detected in BAL and macrophages were the main source of MMP-2 [23].…”

Section: In Vivo Modelsmentioning

confidence: 99%

“…Bleomycin injury in rats has also been used to investigate the profile of MMP-2 and -9 in early and late phases of lung injury [23]. Histology and BAL analysis demonstrated an acute injury pattern on day 4 following intratracheal instillation of 1.5 units?kg -1 bleomycin.…”

Section: In Vivo Modelsmentioning

confidence: 99%

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

Davey¹,

McAuley

O'Kane

2011

European Respiratory Journal

206

156

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Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) comprise a spectrum of acute inflammatory pulmonary oedema resulting in refractory hypoxaemia in the absence of an underlying cardiogenic cause. There are multiple pulmonary and extrapulmonary causes and ALI/ARDS patients are a clinically heterogeneous group with associated high morbidity and mortality.Inflammatory injury to the alveolar epithelial and endothelial capillary membrane is a central event in the pathogenesis of ALI/ARDS, and involves degradation of the basement membrane. Matrix metalloproteinases (MMPs) have been implicated in a wide variety of pulmonary pathologies and are capable of degrading all components of the extracellular matrix including the basement membrane and key non-matrix mediators of lung injury such as chemokines and cell surface receptors.While many studies implicate MMPs in the injurious process, there are significant gaps in our knowledge of the role of specific proteases at different phases of injury and repair. This article examines the role of MMPs in injury and repair of the alveolar epithelial-endothelial capillary barrier and discusses the potential for MMP modulation in the prevention and treatment of ALI. The need for further mechanistic and in vivo studies to inform appropriate subsequent clinical trials of MMP modulation will be highlighted. KEYWORDS: Acute lung injury, acute respiratory distress syndrome, extracellular matrix, inflammation, matrix metalloproteinases, repair A cute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are part of a disease spectrum associated with high mortality and considerable morbidity. The most recent diagnostic criteria for ALI/ARDS, developed by the 1994 American-European Consensus Conference Committee [1], are based on the gross clinico-radiological findings; acute onset, bilateral infiltrates on chest radiography, absence of left ventricular failure and the ratio of arterial oxygen tension (Pa,O 2 , expressed in mmHg) to inspired oxygen fraction (FI,O 2 ) measuring ,200 (ARDS) or ,300 (ALI) [2][3][4]. However, ALI/ARDS patients are clinically heterogeneous and this definition does not take into account the underlying aetiology or severity of illness reflected by failure of other organ systems [2]. Irrespective of aetiology, the pathogenesis of ALI/ARDS consists of an excessive and inappropriate inflammatory response to a range of pulmonary or extrapulmonary insults, resulting in damage to the alveolar epithelial-endothelial capillary barrier [3,4]. Clinically, this manifests as refractory hypoxaemia and decreased pulmonary compliance. Pathologically, three phases are recognised: an initial acute inflammatory or exudative phase characterised by

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Early and Late Changes of MMP-2 and MMP-9 in Bleomycin-Induced Pulmonary Fibrosis

Cited by 72 publications

References 43 publications

MicroRNA-326 Regulates Profibrotic Functions of Transforming Growth Factor-β in Pulmonary Fibrosis

MicroRNA-326 Regulates Profibrotic Functions of Transforming Growth Factor-β in Pulmonary Fibrosis

Modulation of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in RAW264.7 cells by irradiation

Matrix metalloproteinases in acute lung injury: mediators of injury and drivers of repair

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