Collagenase and gelatinase activities in bronchoalveolar lavage fluids during bleomycin-induced lung injury

Bąkowska, Julita; Adamson, I. Y. R.

doi:10.1002/(sici)1096-9896(199807)185:3<319::aid-path114>3.0.co;2-l

Cited by 40 publications

(28 citation statements)

References 23 publications

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“…In line with this, Bakowska and Adamson (1998) found that gelatinolytic activity is increased in bronchoalveolar lavage fluid of bleomycin-induced fibrosis. Swiderski et al (1998) showed that MMP-2 mRNA is also increased in homogenates of bleomycin-induced fibrotic lungs.…”

Section: Increase Of Mmp-2 and P53supporting

confidence: 54%

Role of MMP-2 in Alveolar Epithelial Cell Repair after Bleomycin Administration in Rabbits

Κunugi

Fukuda

Ishizaki

et al. 2001

Laboratory Investigation

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SUMMARY:Matrix metalloproteinases (MMPs) have been implicated in the pathological processes of interstitial lung diseases.However, underlying mechanisms, particularly for activity levels and distribution of activated MMP-2 in the disease process, are yet to be elucidated. The present study investigated the immunolocalization of MMP-2, membrane type 1-matrix metalloproteinase (MT1-MMP), tissue inhibitor of metalloproteinase (TIMP)-2, p53, and Ki-67 in a rabbit model of bleomycin-induced pulmonary fibrosis. Gelatin zymography and in situ zymography were used to examine the activity and the localization of MMP-2. Furthermore, we performed Western blot and in situ hybridization for MT1-MMP, an activator for MMP-2. The total MMP-2 level estimated by gelatin zymography increased significantly at 3, 7, and 14 days after bleomycin administration, compared with controls. In the immunohistochemical study, immunoreaction for MMP-2 was strongest in alveolar epithelial cells among the cell populations. Swollen and/or elongated type II alveolar epithelial cells showed strong immunoreactions for MMP-2, MT1-MMP, and TIMP-2. After bleomycin administration, immunoreaction for p53 was observed in bronchiolar and alveolar epithelial cells. The proportion of p53-positive cells was high in epithelial cells from 1 to 14 days as MMP-2 levels were increased, suggesting that p53 may be responsible, at least in part, for the increase of MMP-2. The ratio of activated MMP-2 to total MMP-2 estimated by gelatin zymography increased significantly at 3, 7, 14, and 28 days after bleomycin treatment. In situ zymography revealed that type II alveolar epithelial cells degraded gelatin. An increased expression of MT1-MMP protein was observed by Western blot following administration of bleomycin. In situ hybridization demonstrated that type II alveolar epithelial cells gave intense signal for MT1-MMP mRNA. These results suggest that type II alveolar epithelial cells express MT1-MMP and activate MMP-2 on their cell surfaces, which may lead to the elongation and migration of alveolar epithelial cells in the repair process of bleomycininduced pulmonary fibrosis. (Lab Invest 2001, 81:1309 -1318.

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Section: Increase Of Mmp-2 and P53supporting

confidence: 54%

Role of MMP-2 in Alveolar Epithelial Cell Repair after Bleomycin Administration in Rabbits

Κunugi

Fukuda

Ishizaki

et al. 2001

Laboratory Investigation

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“…A discrepancy was found in the low MMP-2 transcript measured 3 and 5 days after bleomycin treatment and the high protein concentration of MMP-2 detected at the protein level. It has been reported that bleomycin can induce MMP-2 expression in alveolar epithelial cells (19,20), and some shedded MMP-2 was stored in endosomal vesicles for recycling (21). Thus, it is possible that we detected not only newly produced MMP-2 but also endosomestored MMP-2 at the protein level.…”

Section: Tnfrp55-mediated Signaling In Pathogenesis Of Sclerodermamentioning

confidence: 87%

Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts

Murota¹,

Hamasaki²,

Nakashima³

et al. 2003

Arthritis & Rheumatism

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Objective. To determine the role of tumor necrosis factor receptor p55 (TNFRp55)-mediated signaling in the pathogenesis of scleroderma.Methods. A murine model of scleroderma that closely resembles systemic sclerosis in humans was used. Wild-type and TNFRp55-deficient (TNFRp55 ؊/؊ ) mice received a subcutaneous injection of bleomycin each day. The extent of skin fibrosis was determined by measurements of the dermal thickness, as well as histologic examinations. Expression levels of fibrogenic cytokines, procollagen ␣1, and matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-9 messenger RNA (mRNA) were analyzed, both in vivo and in vitro, by reverse transcriptase-polymerase chain reaction assay or Western blotting.Results. TNFRp55 ؊/؊ mice began to develop severe sclerotic changes of the dermis on day 3 of the subcutaneous injections of bleomycin, while wild-type mice did not. The expression levels of fibrogenic cytokines, procollagen ␣1, and MMP-2 and MMP-9 mRNA were unaffected in the skin of both wild-type and TNFRp55 ؊/؊ mice, with or without bleomycin treatment. Induction of MMP-1 expression was significantly inhibited in the skin from bleomycin-treated TNFRp55 ؊/؊ mice, and this phenomenon was also observed in vitro.Conclusion. These results indicated that signaling mediated by TNFRp55 plays an essential role in MMP-1 expression and a key role in the collagen degradation process in this murine model. This study might provide a basis for understanding the pathogenesis of scleroderma and formulating therapeutic intervention.

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“…The antineoplastic antibiotic bleomycin induced pulmonary Wbrosis is known to be associated with an increased activity of two gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, in bronchoalveolar lavage (BAL) and in the injured lung parenchyma (Bakowska and Adamson 1998;Betsuyaku et al 2000;Swiderski et al 1998). Matrix metalloproteinases are a family of enzymes that degrade components of the extracellular matrix.…”

Section: Introductionmentioning

confidence: 99%

Lack of evidence for caveolin-1 and CD147 interaction before and after bleomycin-induced lung injury

Barth

Bläsche

Kasper

2006

Histochem Cell Biol

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Immunohistochemical and in vitro studies indicate that caveolin-1, which occurs abundantly in alveolar epithelial type I cells and microvascular endothelial cells of the lung, is selectively downregulated in the alveolar epithelium following exposure to bleomycin. Bleomycin is also known to enhance the expression levels of metalloproteinases and of the metalloproteinase inducer CD147/EMMPRIN in lung cells. Experimental in vitro data has showed that MMP-inducing activity of CD147 is under the control of caveolin-1. We studied the effects of bleomycin on the expression of caveolin-1, CD147 and metalloproteinases using an alveolar epithelial rat cell line R3/1 with properties of both alveolar type I and type II cells and explanted rat lung slices. In parallel, retrospective samples of bleomycin-induced fibrosis in rats and mice as well as samples of wild type and caveolin-1 knockout animals were included for immunohistochemical comparison with in vitro data. Here we report that treatment with bleomycin downregulates caveolin-1 and increases CD147 and MMP-2 and -9 expression/activity in R3/1 cells using RT-PCR, Western blot analysis, MMP-2 activity assay and immunocytochemistry. Immunofluorescence double labeling revealed that caveolin-1 and CD147 were not colocalized in vitro. The in vitro findings were confirmed through immunohistochemical studies of the proteins in paraffin embedded precision-cut rat lung slices and in fibrotic rat lung tissues. The caveolin-1-negative hyperplastic ATII cells exhibited enhanced immunoreactivity for CD147 and MMP-2. Caveolin-1-negative ATI cells of fibrotic samples were mostly CD147 negative. There were no differences in the pulmonary expression of CD147 between the normal and caveolin-1 deficient animals. The results demonstrate that bleomycin-induced lung injury is associated with an increase in CD147 expression and MMP activity, particularly in alveolar epithelial cells. In addition, our data exclude any functional interaction between CD147 and alveolar epithelial caveolin-1.

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Collagenase and gelatinase activities in bronchoalveolar lavage fluids during bleomycin-induced lung injury

Cited by 40 publications

References 23 publications

Role of MMP-2 in Alveolar Epithelial Cell Repair after Bleomycin Administration in Rabbits

Role of MMP-2 in Alveolar Epithelial Cell Repair after Bleomycin Administration in Rabbits

Disruption of tumor necrosis factor receptor p55 impairs collagen turnover in experimentally induced sclerodermic skin fibroblasts

Lack of evidence for caveolin-1 and CD147 interaction before and after bleomycin-induced lung injury

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