Profibrotic Activities for Matrix Metalloproteinase-8 during Bleomycin-Mediated Lung Injury

Craig, Vanessa J.; Quintero, Pablo; Fyfe, Susanne E.; Patel, Avignat S.; Knolle, Martin; Kobzik, Lester; Owen, Caroline A.

doi:10.4049/jimmunol.1201043

Cited by 67 publications

(51 citation statements)

References 93 publications

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“…MMP8 promotes wound healing in murine skin by activated TGF-β signaling [30]. Also, MMP8 contributes to fibrotic responses in mice [31,32]. Wild-type mice exhibited an increase in the levels of interleukin-10, an antiinflammatory cytokine that can suppress TGF-β synthesis, while the absence of MMP8 results in increased inflammation, but also increased levels of interleukin-10, in mice lungs [31].…”

Section: Discussionmentioning

confidence: 96%

The Copper Chelator Tetrathiomolybdate Regressed Bleomycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions

Ovet

Öztay

2014

Biol Trace Elem Res

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Pulmonary fibrosis (PF) is characterized by an increase in the number of fibroblasts and an accumulation of collagen fibers in the extracellular matrix (ECM). The members of the copper-dependent lysyl oxidase (LOX) enzyme family regulate the collagen accumulation in the ECM. Tetrathiomolybdate (TM) is a copper chelator. The present study reported the effect of TM on the expression of LOX proteins (LOX, LOXL1, and LOXL2), collagen digestion enzymes (MMP2 and MMP8), and TIMP1 (a collagenase inhibitor) in PF. The PF in mice was induced by intratracheal bleomycin instillation. Adult mice were divided into four groups: mice dissected after 21 days of the first bleomycin (0.08 mg/kg, single dose) treatment (I) and their controls (II), and mice treated with TM for 1 week (1.2 mg/day/mice for the first 4 days and 0.9 mg/day/mice for the last 3 days) after 14 days of the first bleomycin instillation and dissected in the 21st day of the experiment (III) and their controls (IV). Mice in groups III and IV were fed a low-copper (2 mg/kg) diet during the last 7 days of the experiment. The fibrosis score in the lung was determined under a microscope. The expressions of collagen-I, LOX, MMP, and TIMP1 proteins were analyzed by Western blotting in the lung. Mice lungs with fibrosis were characterized by an overexpression of collagen-I, LOX, MMP, and TIMP1 proteins in addition to an accumulation of collagen fibers. TM treatments significantly regressed the overexpression of these proteins in the fibrotic mice lung. In conclusion, TM treatments can be used for the regression of PF, by decreasing collagen-I protein expression and accumulation.

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Section: Discussionmentioning

confidence: 96%

The Copper Chelator Tetrathiomolybdate Regressed Bleomycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions

Ovet

Öztay

2014

Biol Trace Elem Res

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“…MMPs have been found to be required for the establishment of chemoattractant gradients (36) and for enabling cells including fibroblasts to migrate through matrix in response to these gradients (37). In the context of these and other functions, individual deficiencies in several MMPs have been found to decrease rather than increase lung matrix protein deposition in models of pulmonary fibrosis, including MMP-3, -7, and -8 (36,38,39). We observed that the expression of multiple MMPs, including MMP-2, -7 and -9, by PSFBs was significantly reduced in LPA 1 KO mice, possibly reducing their ability to migrate through matrix during the formation of alveolar septa.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization

Funke

Knudsen

Lagares³

et al. 2016

Am J Respir Cell Mol Biol

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Lysophosphatidic acid (LPA) signaling through one of its receptors, LPA 1 , contributes to both the development and the pathological remodeling after injury of many organs. Because we found previously that LPA-LPA 1 signaling contributes to pulmonary fibrosis, here we investigated whether this pathway is also involved in lung development. Quantitative assessment of lung architecture of LPA 1 -deficient knockout (KO) and wild-type (WT) mice at 3, 12, and 24 weeks of age using design-based stereology suggested the presence of an alveolarization defect in LPA 1 KO mice at 3 weeks, which persisted as alveolar numbers increased in WT mice into adulthood. Across the ages examined, the lungs of LPA 1 KO mice exhibited decreased alveolar numbers, septal tissue volumes, and surface areas, and increased volumes of the distal airspaces. Elastic fibers, critical to the development of alveolar septa, appeared less organized and condensed and more discontinuous in KO alveoli starting at P4. Tropoelastin messenger RNA expression was decreased in KO lungs, whereas expression of matrix metalloproteinases degrading elastic fibers was either decreased or unchanged. These results are consistent with the abnormal lung phenotype of LPA 1 KO mice, being attributable to reduced alveolar septal formation during development, rather than to increased septal destruction as occurs in the emphysema of chronic obstructive pulmonary disease. Peripheral septal fibroblasts and myofibroblasts, which direct septation in late alveolarization, demonstrated reduced production of tropoelastin and matrix metalloproteinases, and diminished LPA-induced migration, when isolated from LPA 1 KO mice. Taken together, our data suggest that LPA-LPA 1 signaling is critically required for septation during alveolarization.

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“…Pulmonary fibrosis is a common disease with high mortality because of damage to the lung parenchyma by inflammatory factors that ultimately lead to fibrosis (1)(2)(3). Chemotherapy with BLM and therapy with amiodarone as an anti-arrhythmic agent often result in lung injury with fibrosis (4,5).…”

Section: Introductionmentioning

confidence: 99%

The Preventive Role of Gemfibrozil on Bleomycin-Induced Lung Injury and Fibrosis in Rats

Mohammadi

Khodayar

Hemmati

et al. 2017

Jundishapur J Nat Pharm Prod

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Background: Pulmonary fibrosis could be a threat for the health society. Oxidative stress, inflammatory, and fibrotic factors have an important role in the pathology of pulmonary fibrosis. The inhibition of these factors is a central mechanism for lung fibrosis prevention and therapy. Objectives: According to Gemfibrozil (GEM) effects, such as antioxidative and anti-inflammatory effects, this study was designed to evaluate the effect of GEM in an animal model of pulmonary injury and fibrosis induced by Bleomycin (BLM). Methods: Experiments were done at 2 different time periods, 1 and 3 weeks in duration after BLM. In each time period, thirty rats were divided to 5 groups: 1, vehicle orally + saline Intratracheally (IT); 2, vehicle orally + BLM (IT) and 3 -5, GEM at the doses of 25, 50, and 100 mg/kg, orally + BLM (IT), respectively. Gem was administered 3 day before BLM and continued for one or three weeks. Results: At the end of both phases, 7th day and 21th day lung index and tissue collagen level were determined. Furthermore, macroscopic appearance and histopathological were analyzed. The results showed that gemfibrozil had beneficial effects in a dosedependent manner and best results were found in animals treated by 100 mg/kg of GEM. Conclusions: Finally, the current study concluded that GEM could be considered as a candidate in lung injury and fibrosis and could be used for improvement of lung damage and fibrosis in humans.

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Profibrotic Activities for Matrix Metalloproteinase-8 during Bleomycin-Mediated Lung Injury

Cited by 67 publications

References 93 publications

The Copper Chelator Tetrathiomolybdate Regressed Bleomycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions

The Copper Chelator Tetrathiomolybdate Regressed Bleomycin-Induced Pulmonary Fibrosis in Mice, by Reducing Lysyl Oxidase Expressions

Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization

The Preventive Role of Gemfibrozil on Bleomycin-Induced Lung Injury and Fibrosis in Rats

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