Matrix Metalloproteinases Promote Inflammation and Fibrosis in Asbestos-Induced Lung Injury in Mice

Tan, Roderick J.; Fattman, Cheryl L.; Niehouse, Laura M.; Tobolewski, Jacob M.; Hanford, Lana E.; Li, Qinglang; Monzon, Federico A.; Parks, William C.; Oury, Tim D.

doi:10.1165/rcmb.2005-0471oc

Cited by 101 publications

(74 citation statements)

References 37 publications

(65 reference statements)

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“…MMPs are known to play an essential role in each of these responses, either by direct matrix molecule cleavage or by generating bioactive mediators and other biologic regulators. In accord with this complexity, circulating fibrocytes that have recently been implicated in the pathogenesis of pulmonary fibrosis are known to make MMPs (58) and interventions that block MMP-12 (and possibly other MMPs) also diminish asbestos-induced pulmonary fibrotic responses (59). As would be expected from studies cited above, our studies demonstrate that TGF-␤ 1 inhibits MMP-9 while stimulating TIMP-1 during the generation of pulmonary fibrosis.…”

Section: Discussionsupporting

confidence: 77%

Transforming Growth Factor (TGF)-β1 Stimulates Pulmonary Fibrosis and Inflammation via a Bax-dependent, Bid-activated Pathway That Involves Matrix Metalloproteinase-12

Kang

Cho

Lee

et al. 2007

Journal of Biological Chemistry

160

118

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Fibrosis, apoptosis, and the exaggerated production of transforming growth factor (TGF)-␤ 1 are juxtaposed in a variety of pulmonary diseases including the interstitial lung diseases and asthma. In these disorders, the relationships between these responses are not well defined. In addition, the apoptosis pathways that contribute to these responses and the mechanism(s) of their contribution have not been described. We hypothesized that BH3 domain-only protein-induced apoptosis plays an important role in the pathogenesis of TGF-␤ 1 -induced pulmonary responses. To test this hypothesis, we characterized the effects of transgenic TGF-␤ 1 in mice with wild type (WT) and null Bax loci. To investigate the mechanisms of Bax activation and its effector functions, we also compared the effects of TGF-␤ 1 in mice with WT and null Bid and matrix metalloproteinase (MMP)-12 loci, respectively. These studies demonstrate that TGF-␤ 1 is a potent stimulator of Bax, Bid, and MMP-12. The studies also demonstrate that Bax and Bid play key roles in the pathogenesis of TGF-␤ 1 -induced inflammation, fibrosis, and apoptosis; that TGF-␤ 1 stimulates MMP-12, TIMP-1, and cathepsins and inhibits MMP-9 and p21 via Bax-and Bid-dependent mechanisms; and that TGF-␤ 1 -stimulated pulmonary fibrosis is ameliorated in MMP-12-deficient animals. Finally, they demonstrate that Bax, Bid, and MMP-12 play similar roles in bleomycin-induced fibrosis, thereby highlighting the importance of this Bid-activated, Baxmediated pathway and downstream MMP-12 in a variety of fibrogenic settings.Fibrosis is an important cause of morbidity and mortality in the lung and other organs. This can be seen in the interstitial lung diseases (ILD) including idiopathic pulmonary fibrosis (IPF), scleroderma, radiation-induced pulmonary fibrosis, and bleomycin lung where matrix molecule deposition, enhanced collagen accumulation, and alveolar septal rupture with honeycombing are seen and can lead to fatal consequences (1-4). It is also seen in asthma, which is characterized by chronic inflammation and subepithelial airway fibrosis (5, 6). Pathologic examinations have highlighted the frequent juxtaposition of fibrosis, structural cell (usually epithelial cell) apoptosis, and the exaggerated production of transforming growth factor (TGF) 2 -␤ 1 in these diseases and models of these disorders (1,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Studies have also demonstrated that TGF-␤ 1 plays an essential role in wound healing and matrix molecule deposition, and induces fibrotic and alveolar remodeling responses in vivo (14, 16, 17, 20 -23). They also demonstrated that TGF-␤ 1 is a potent stimulator of epithelial apoptosis (22, 24 -27) and that interventions that block apoptosis can ameliorate fibrotic and alveolar remodeling responses in a variety of experimental systems (7, 22). As a result of these studies, TGF-␤ 1 is believed to be a critical mediator of pathologic, fibrotic, and remodeling responses in the lung and other organs, and these responses are believe...

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Section: Discussionsupporting

confidence: 77%

Transforming Growth Factor (TGF)-β1 Stimulates Pulmonary Fibrosis and Inflammation via a Bax-dependent, Bid-activated Pathway That Involves Matrix Metalloproteinase-12

Kang

Cho

Lee

et al. 2007

Journal of Biological Chemistry

160

118

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“…Use of a general MMP inhibitor, GM6001, attenuated both the inflammation and the degree of fibrotic reaction [49]. MMP-13 knockout mice also have reduced acute inflammation and fibrosis when exposed to radiation [50].…”

Section: Mmp-13mentioning

confidence: 99%

Metalloproteinases in idiopathic pulmonary fibrosis

2011

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In this article, we outline the current state of knowledge about the balance between collagen production and degradation in idiopathic pulmonary fibrosis (IPF). The dysregulated action of metalloproteinases implicated in IPF may play a central role in IPF pathogenesis. Inhibiting metalloproteinases in IPF may, therefore, have therapeutic potential, but our knowledge of their pathophysiological role is held back by limited animal models and the lack of specific inhibitors.

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“…Asbestos delivery to the lung has been used in the mouse to cause lung fibrosis (23). As with bleomycin, numerous routes of administration include aerosolization (23,35,119,125,136) and intratracheal administration (143). In the investigation of asbestos-induced fibrosis in mice, various cytokines and mediators of inflammation and cell signaling have been implicated, including the MAP kinase pathway (125) and ERK1/2 (35), protein kinase C (136), MMPs (143), TNF-α (90), and oxidative stress (69,103).…”

Section: Inhaled Irritants: Silicosis Asbestosis and Cigarette Smokingmentioning

confidence: 99%

The Role of Inflammation in the Pathogenesis of Idiopathic Pulmonary Fibrosis

Bringardner

Baran

Eubank

et al. 2008

Antioxidants & Redox Signaling

253

190

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The role of inflammation in idiopathic pulmonary fibrosis (IPF) is controversial. If inflammation were critical to the disease process, lung pathology would demonstrate an influx of inflammatory cells, and that the disease would respond to immunosuppression. Neither is true. The classic pathology does not display substantial inflammation, and no modulation of the immune system is effective as treatment. Recent data suggest that the pathophysiology of the disease is more a product of fibroblast dysfunction than of dysregulated inflammation. The role of inflammation in disease pathogenesis comes from pathology from atypical patients, biologic samples procured during exacerbations of the disease, and careful examination of biologic specimens from patients with stable disease. We suggest that inflammation is indeed a critical factor in IPF and propose five potential nontraditional mechanisms for the role of inflammation in the pathogenesis of IPF: the direct inflammatory hypothesis, the matrix hypothesis, the growth factor-receptor hypothesis, the plasticity hypothesis, and the vascular hypothesis. To address these, we review the literature exploring the differences in pathology, prognosis, and clinical course, as well as the role of cytokines, growth factors, and other mediators of inflammation, and last, the role of matrix and vascular supply in patients with IPF.

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Matrix Metalloproteinases Promote Inflammation and Fibrosis in Asbestos-Induced Lung Injury in Mice

Cited by 101 publications

References 37 publications

Transforming Growth Factor (TGF)-β1 Stimulates Pulmonary Fibrosis and Inflammation via a Bax-dependent, Bid-activated Pathway That Involves Matrix Metalloproteinase-12

Transforming Growth Factor (TGF)-β1 Stimulates Pulmonary Fibrosis and Inflammation via a Bax-dependent, Bid-activated Pathway That Involves Matrix Metalloproteinase-12

Metalloproteinases in idiopathic pulmonary fibrosis

The Role of Inflammation in the Pathogenesis of Idiopathic Pulmonary Fibrosis

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