Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema

DʼArmiento, Jeanine; Dalal, Seema S.; Okada, Yasunori; Berg, Richard A.; Chada, Kiran

doi:10.1016/0092-8674(92)90391-o

Cited by 350 publications

(270 citation statements)

References 35 publications

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“…Our previous studies identified a causal relationship between MMP-1 production and emphysema (9,10). The present findings suggest that emphysema patients may represent a subset of persons predisposed to long-term ERK signaling in the lung, which may render them susceptible to increased collagen destruction by MMP-1.…”

Section: Discussionsupporting

confidence: 54%

“…It has been shown that mitogen-activated protein kinase activation alters mucin production and inflammation in the lung (36). The present study links this same kinase pathway to increased MMP-1 expression seen in emphysema and alveolar destruction (10). The MAP kinase pathway is also implicated in apoptosis (37-39), a cell death mechanism associated with emphysema (14,40,41).…”

Section: Discussionsupporting

confidence: 53%

“…Studies in mice reveal that knocking out metalloelastase (MMP-12) 1 confers resistance to cigarette smokeinduced emphysema (3), although levels of the enzyme are not elevated in human disease (9). Evidence from human tissue and animal models support a role for collagenolytic enzymes in emphysema pathogenesis (9,10,13). Elevated MMP-1 levels and decreased pulmonary collagen content are measured in guinea pigs after cigarette smoke exposure (12,14).…”

mentioning

confidence: 99%

“…Elevated MMP-1 levels and decreased pulmonary collagen content are measured in guinea pigs after cigarette smoke exposure (12,14). Transgenic mice expressing human collagenase (MMP-1) develop emphysematous changes in their lungs (10) caused by months of proteolytic damage to the lung parenchyma (15). Human studies reveal increased collagenolytic activity in bronchoalveolar lavage fluid and lung tissue from patients with chronic obstructive pulmonary disease (8,16,17).…”

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confidence: 99%

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Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

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158

172

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The interstitial collagenase matrix metalloproteinase-1 (MMP-1) is up-regulated in the lung during pulmonary emphysema. The mechanisms underlying this aberrant expression are poorly understood. Although cigarette smoking is the predominant cause of emphysema, only 15-20% of smokers develop the disease. To define the signaling pathways activated by smoke and to identify molecules responsible for emphysema-associated MMP-1 expression, we performed several in vitro and in vivo experiments. In this study, we showed that cigarette smoke directly induced MMP-1 mRNA and protein expression and increased the collagenolytic activity of human airway cells. Treatment with various chemical kinase inhibitors revealed that this response was dependent on the extracellular regulated kinase-1/2 (ERK) mitogen activated protein kinase pathway. Cigarette smoke increased phosphorylation of residues Thr-202 and Tyr-204 of ERK in airway lining cells and alveolar macrophages in mice at 10 days and 6 months of exposure. Moreover, analysis of lung tissues from emphysema patients revealed significantly increased ERK activity compared with lungs of control subjects. This ERK activity was evident in airway lining and alveolar cells. The identification of active ERK in the lungs of emphysema patients and the finding that induction of MMP-1 by cigarette smoke in pulmonary epithelial cells is ERKdependent reveal a molecular mechanism and potential therapeutic target for excessive matrix remodeling in smokers who develop emphysema.

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Section: Discussionsupporting

confidence: 54%

Section: Discussionsupporting

confidence: 53%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Mercer

Kolesnikova

Sonett

et al. 2004

Journal of Biological Chemistry

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158

172

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“…Abnormal production of MMPs is implicated in the induction of emphysema. Thus, transgenic mice expressing human MMP-1 develop emphysema through destruction of collagen fibrils (24). Furthermore, MMP-2, MMP-9, and MMP-12 lead to emphysema by degradation of elastin fibers (25,26).…”

Section: Enhanced Expression Levels Of Mmps In Fut8 ؊/؊ Lungs and Futmentioning

confidence: 99%

Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice

Wang

Inoué

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

405

347

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The core fucosylation (␣1,6-fucosylation) of glycoproteins is widely distributed in mammalian tissues, and is altered under pathological conditions. To investigate physiological functions of the core fucose, we generated ␣1,6-fucosyltransferase (Fut8)-null mice and found that disruption of Fut8 induces severe growth retardation and death during postnatal development. Histopathological analysis revealed that Fut8 ؊/؊ mice showed emphysema-like changes in the lung, verified by a physiological compliance analysis. Biochemical studies indicated that lungs from Fut8 ؊/؊ mice exhibit a marked overexpression of matrix metalloproteinases (MMPs), such as MMP-12 and MMP-13, highly associated with lung-destructive phenotypes, and a down-regulation of extracellular matrix (ECM) proteins such as elastin, as well as retarded alveolar epithelia cell differentiation. These changes should be consistent with a deficiency in TGF-␤1 signaling, a pleiotropic factor that controls ECM homeostasis by down-regulating MMP expression and inducing ECM protein components. In fact, Fut8 ؊/؊ mice have a marked dysregulation of TGF-␤1 receptor activation and signaling, as assessed by TGF-␤1 binding assays and Smad2 phosphorylation analysis. We also show that these TGF-␤1 receptor defects found in Fut8 ؊/؊ cells can be rescued by reintroducing Fut8 into Fut8 ؊/؊ cells. Furthermore, exogenous TGF-␤1 potentially rescued emphysema-like phenotype and concomitantly reduced MMP expression in Fut8 ؊/؊ lung. We propose that the lack of core fucosylation of TGF-␤1 receptors is crucial for a developmental and progressive͞ destructive emphysema, suggesting that perturbation of this function could underlie certain cases of human emphysema.fucosylation ͉ glycobiology ͉ matrix metalloproteinase

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Temporal and spatial regulation of gene expression mediated by the promoter for the human tissue inhibitor of metalloproteinases-3 (TIMP-3)-encoding gene

Zeng

Rosborough

et al. 1998

Dev. Dyn.

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A complex interplay between enzymes involved in extracellular matrix formation and their inhibitors is thought to control organogenesis during mammalian development. Disturbance of this balance may result in a wide range of diseases, including macular degeneration, arthritis, and tumor metastases. In order to define elements which may be involved in regulating human tissue inhibitor of metalloproteinase 3 (TIMP3) expression, we isolated and sequenced a clone containing 1315 bp of the 5′‐upstream region of the human TIMP‐3‐encoding gene. A 1.2 kb fragment of this clone, which contains multiple motifs which are binding sites for known transcription factors, was used to drive expression of the lacZ reporter gene in multiple lines of transgenic mice. TIMP3 promoter activity, detected through β‐galactosidase histochemical assay, was observed at high levels in selected tissues, the identity of which varied according to developmental stage. TIMP3 promoter activity was detected at embryonic and early postnatal stages in tissues undergoing extensive remodeling, such as developing somites, bones and joints, choroid plexus, webs between the digits, and the spongiotrophoblastic portion of the placenta. In adulthood, TIMP3 promoter activity was restricted to a few tissues which exhibit high metabolic activity or rapid turnover. These include the retinal pigment epithelium (RPE), cells of the kidney cortex, hair follicles, gingiva, ovarian follicles, and testis. The results suggest that TIMP3 expression plays an active role in developmental patterning and in the maintenance of specific differentiated tissues. Dev. Dyn. 1998;211:228‐237. © 1998 Wiley‐Liss, Inc.

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Collagenase expression in the lungs of transgenic mice causes pulmonary emphysema

Cited by 350 publications

References 35 publications

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Extracellular Regulated Kinase/Mitogen Activated Protein Kinase Is Up-regulated in Pulmonary Emphysema and Mediates Matrix Metalloproteinase-1 Induction by Cigarette Smoke

Dysregulation of TGF-β1 receptor activation leads to abnormal lung development and emphysema-like phenotype in core fucose-deficient mice

Temporal and spatial regulation of gene expression mediated by the promoter for the human tissue inhibitor of metalloproteinases-3 (TIMP-3)-encoding gene

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