The Development of Bleomycin-Induced Pulmonary Fibrosis in Mice Deficient for Components of the Fibrinolytic System

Swaisgood, Carmen M.; French, Esther; Noga, Chris; Simon, Richard H.; Ploplis, Victoria A.

doi:10.1016/s0002-9440(10)64529-4

Cited by 158 publications

(116 citation statements)

References 38 publications

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“…As stated previously, Swaisgood and colleagues 23 found similar effects in the lungs of uPAdeficient mice after bleomycin treatment. Histologically, the lungs appeared fibrotic with major structural changes in the alveoli and abundant inflammatory cell infiltrate, but HPLC analysis of the hydroxyproline content in these tissues showed that collagen levels remained unchanged compared with their wild-type counterparts.…”

Section: Discussionsupporting

confidence: 70%

“…An association between reduced fibrinolysis and the development of fibrosis has been highlighted in other pathological experimental model systems in studies similar to ours using mice with overexpression or underexpression of various components of the fibrinolytic system. 22,23,34,35 Eitzman and colleagues 22 found that overexpression of PAI-1, resulted in enhanced deposition of collagen in the lungs of bleomycin-treated mice, whereas PAI-1-deficient mice produced levels of collagen comparable to wildtype controls. Of particular interest, a study by Swaisgood and colleagues 23 also using PA-deficient mice, showed that bleomycin-instillation resulted in approximately a twofold increase in the amount of collagen in the lungs of tPA-deficient mice compared with uPA-deficient and wild-type mice directly correlating with findings in the present study.…”

Section: Discussionmentioning

confidence: 99%

“…After bleomycin-induced lung injury, mice deficient in plasminogen, uPA, or tPA, or those that overexpress PAI-1, show extensive fibrin deposition, collagen accumulation, and accelerated pulmonary fibrosis when compared with control mice. 22,23 These studies concluded that reduced fibrinolysis results in fibrin accumulation at the site of injury and subsequent fibrosis ensues. However, despite evidence in other systems, an association between the persistence of fibrin and increased collagen accumulation in the skin has not been shown.…”

mentioning

confidence: 99%

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Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Giorgio-Miller

Bottoms

Laurent

et al. 2005

The American Journal of Pathology

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The deposition of fibrin is an integral part of the tissue repair process, but its persistence is also associated with a number of fibrotic conditions. This study addressed the hypothesis that reduced fibrinolysis and fibrin persistence are associated with an enhanced accumulation of collagen and the development of skin fibrosis. Decreased fibrinolysis was confirmed in fibrin gel cultures that contained human dermal fibroblasts plus the specific plasmin inhibitor ␣ 2 -antiplasmin or dermal fibroblasts isolated from plasminogen activator (PA)-deficient mice. Collagen accumulation was significantly increased in the presence of inhibitor and in tPA-deficient, but not uPAdeficient, fibroblasts compared with controls. These findings were also confirmed using a skin fibrosis model in which multiple injections of fibrin were given subcutaneously to PA-deficient mice. Injection sites from tPA-deficient mice displayed significantly increased collagen levels compared with uPA-deficient mice and wild-type controls. Up-regulation of fibroblast procollagen gene expression and reduced activation of pro-MMP-1 appeared to mediate the increase in collagen by human dermal fibroblasts in the presence of ␣2-antiplasmin. These findings suggest that persistent fibrin is associated with enhanced collagen accumulation that may result in the development of fibrotic skin disorders in which reduced fibrinolysis is a feature.

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Section: Discussionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Giorgio-Miller

Bottoms

Laurent

et al. 2005

The American Journal of Pathology

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“…The fibrinolytic activity that is normally present in bronchoalveolar lavage (BAL) fluid is depressed in patients with many types of lung injury due to increased levels of plasminogen activator inhibitors, particularly plasminogen activator inhibitor (PAI)-1 (3-7). The importance of this perturbation has been demonstrated in animal models where suppression of plasminogen activator activity worsens fibrosis, whereas enhanced plasminogen activator activity limits scarring (8)(9)(10)(11)). An obvious explanation for the link between suppressed fibrinolysis and fibrosis is that successful repair requires the timely removal of the fibrin-rich provision matrix that accumulates after tissue injury.…”

mentioning

confidence: 99%

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

Matsuoka

Sisson

Nishiuma

et al. 2006

Am J Respir Cell Mol Biol

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Interventions that enhance plasminogen activation within the lung consistently limit the fibrosis that follows alveolar injury. However, this protective effect cannot be attributed solely to accelerated clearance of fibrin that forms as a provisional matrix after lung injury. To explore other mechanisms, we considered interactions between the plasminogen activation system and hepatocyte growth factor (HGF). HGF is known to have antifibrotic activity, but to do so, it must be both released from its sites of sequestration within extracellular matrix (ECM) and activated by proteolytic cleavage. A recent study using bleomycin-exposed mice showed that manipulations of the plasminogen activation system influenced the amount of free HGF within bronchoalveolar lavage fluid without affecting total lung HGF mRNA or protein. To elucidate the mechanisms, we studied the role of plasminogen activation in fibroblastmediated HGF release and activation. We found that NIH3T3 and mouse lung fibroblasts release ECM-bound HGF in a plasminogendependent fashion. The plasminogen effect was lost when lung fibroblasts from urokinase-type plasminogen activator (uPA)-deficient mice were used, and was increased by fibroblasts from plasminogen activator inhibitor (PAI)-1-deficient mice. Plasminogen addition to NIH3T3 or mouse lung fibroblasts increased conversion of pro-HGF to its active form. The plasminogen effect on activation was lost when uPA-deficient fibroblasts were used and accentuated by PAI-1-deficient fibroblasts. In conjunction with the previous in vivo study, these results suggest that plasminogen activation can protect the lung against fibrosis by increasing the availability of active HGF.

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“…Bleomycin sulphate (0.015 U/ 30 μL/mouse, Sigma, Poole, UK) was administered as previously described [19].…”

Section: Bleomycin-induced Model Of Ipfmentioning

confidence: 99%

An Assessment of Epithelial and Mesenchymal Phenotypes in Experimental and Clinical Pulmonary Fibrosis

et al. 2012

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Epithelial injury has been implicated as a driving factor for the pathogenesis of idiopathic pulmonary fibrosis (IPF). In this study we investigated changes in epithelial and mesenchymal markers in experimental models of fibrosis and associated this with IPF. TGFβ 1 induced an epithelial to mesenchymal transition (EMT) phenotype in A549 cells and normal human bronchial epithelial cells, with A549 cells exhibiting a more profound transition to a mesenchymal phenotype. TGFβ 1 overexpression in the lungs of mice resulted in an early increase in mesenchymal cell markers and apoptotic genes that preceded collagen deposition, suggesting an early epithelial injury triggers the downstream fibrotic response. In contrast, bleomycin had a gradual increase in mesenchymal cell marker and a decrease in E-cadherin expression that correlated with collagen protein deposition. Finally, we compared normal healthy lung tissue with surgical lung biopsies from IPF patients and observed alterations in epithelial and mesenchymal cell markers, as well as an increase in the apoptotic marker GSK3β. Interestingly, the mesenchymal changes were more profound in rapidly progressive patients in comparison to IPF patients with slowing progressing disease. In summary, this study provides evidence of alterations in epithelial and mesenchymal markers in experimental models of lung fibrosis and how these findings are relevant to clinical disease.

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The Development of Bleomycin-Induced Pulmonary Fibrosis in Mice Deficient for Components of the Fibrinolytic System

Cited by 158 publications

References 38 publications

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Fibrin-Induced Skin Fibrosis in Mice Deficient in Tissue Plasminogen Activator

Plasminogen-Mediated Activation and Release of Hepatocyte Growth Factor from Extracellular Matrix

An Assessment of Epithelial and Mesenchymal Phenotypes in Experimental and Clinical Pulmonary Fibrosis

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