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Bronchoalveolar matrix metalloproteinase 9 relates to restrictive lung function impairment in systemic sclerosis.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Pulmonary Medicine.
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2007 (English)In: Respiratory Medicine, ISSN 0954-6111, E-ISSN 1532-3064, Vol. 101, no 10, 2199-2206 p.Article in journal (Refereed) Published
Abstract [en]

Systemic sclerosis (SSc) is frequently associated with interstitial lung disease (ILD) often leading to lung fibrosis. In this study we investigated whether matrix metalloproteinase 9 (MMP-9) and its natural inhibitor; the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1), would be associated with remodelling in ILD in SSc. Levels of total MMP-9, pro-MMP-9 and TIMP-1 were measured in bronchoalveolar lavage (BAL) fluid from nine SSc patients with ILD, seven SSc patients without ILD and 16 age- and sex-matched healthy controls. Total MMP-9 and pro-MMP-9 levels were significantly elevated in SSc patients with ILD, compared to levels in SSc patients without ILD and healthy controls. In SSc patients with ILD calculated active MMP-9 levels were significantly higher than in SSc patients without ILD and tended to be higher than in healthy controls. TIMP-1 levels were elevated in both patient groups compared to healthy controls. Total-, pro- and active MMP-9 levels as well as pro-MMP-TIMP-1 and active MMP-9/TIMP-1 ratios were inversely associated with total lung capacity. The present study suggests that MMP-9 plays a pathophysiological role in the remodelling in ILD and lung fibrosis associated with SSc, and may represent a new therapeutic target in this condition.

Place, publisher, year, edition, pages
2007. Vol. 101, no 10, 2199-2206 p.
URN: urn:nbn:se:umu:diva-16971DOI: doi:10.1016/j.rmed.2007.04.019PubMedID: 17643278OAI: diva2:156644
Available from: 2007-10-25 Created: 2007-10-25 Last updated: 2010-09-15Bibliographically approved
In thesis
1. Systemic sclerosis: vascular, pulmonary and immunological aspects
Open this publication in new window or tab >>Systemic sclerosis: vascular, pulmonary and immunological aspects
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

In systemic sclerosis (SSc), interstitial lung disease (ILD) and engagement of the vascular system lead to increased morbidity and mortality.

The aim of this thesis was to elucidate, in a consecutively included cohort of SSc (limited and diffuse) patients (n = 33), the T cell cytokine profile driving the disease in ILD and to explore the role of matrix metalloproteinase 9 (MMP-9) and its inhibitor: tissue inhibitor of metalloproteinase 1 (TIMP-1) in the extracellular matrix (ECM) degrading process leading to fibrous scarring and honey combing. Moreover, to characterize the role of nitric oxide (NO) in vascular engagement.

Peripheral arterial changes cause Raynaud’s phenomenon and digital ulcers. Nitric oxide (NO) a main inducer of vasodilation is produced by endothelial nitric oxide synthase (eNOS) in response to changes in blood flow or by inflammatory cytokine inducible (i) NOS. In the vascular smooth muscle cell (VSMC) NO activates guanylate cyclase to produce cGMP, causing relaxation. We showed elevated plasma nitrate, a degradation product of NO, and increased urinary excretion of nitrate and cGMP. Plasma nitrate correlated with elevated levels of endothelial adhesion molecules: endothelial (E) selectin and vascular adhesion molecule 1, indicating that the activated endothelium is the site of NO synthesis by iNOS. Endothelial staining for E-selectin and the finding of iNOS and eNOS in SSc skin biopsies supported this notion.

In SSc increased vascular stiffness may limit the NO vasodilatory effects. We found normal endothelium-dependent (i.e. flow mediated (FMD%)) and endothelium-independent (i.e. nitroglycerin-induced (NTG%)) vasodilation in the brachial artery. Radial arterial wall stiffness measured as maximum increase in pulse pressure (dP/dtmax) was increased. FMD% and especially NTG% correlated negatively and dP/dtmax positively to measures of endothelial inflammation: plasma- nitrate and adhesion molecule levels. Thus inflammatory vascular wall changes may interfere with dilation as may the presence of nitrate tolerance.

We found elevated alveolar MMP-9 in both its pro- and active form in ILD. The levels correlated to decline in lung capacity, pointing at a causal relation. We suggest that neutrophils secrete MMP-9, which may degrade collagen IV, (the main constituent of basal membranes), collagen V, gelatins, proteoglycans and elastin. MMP-9 activity is partly regulated by the binding of pro- and active form to TIMP-1. Alveolar TIMP-1, which even stimulates fibroblast ECM synthesis, was increased independent of ILD.

The inflammatory process in ILD is orchestrated by activated T helper (h) lymphocytes. We found a mixed Th1/Th2 reaction in SSc alveolar T cells expressing messenger for interferon gamma (Th1), IL-6 and IL-10 (both Th2). No particular cytokine mRNA profile distinguished alveolar T cells in ILD.

Neutrophils invaded the bronchial epithelium, which seemed otherwise inert as levels of inflammatory cytokine sensitive transcription factors and their nuclear translocation tended to be low. The neutrophil recruitment pathway is uncertain as chemoattractants and endothelial adhesion molecules were normally expressed.

In conclusion, MMP-9 probably causes degradation of lung tissue in ILD and may represent a future therapeutic target. Alveolar T cells show a mixed Th1/Th2 cytokine profile independent of ILD. Neutrophils invade the bronchial epithelium. Activated endothelium produces increased amounts of NO and adhesion molecules and the level of activation influences brachial arterial FMD% and NTG% and radial arterial compliance. Nitrate tolerance may be present.

Place, publisher, year, edition, pages
Umeå: Reumatologi, 2008. 67 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1205
Systemic sclerosis, interstitial lung disease, MMP-9, Th1/Th2, transcription factors, NO, iNOS, E-selectin, endothelium-dependent dilation, endothelium-independent dilation.
National Category
Rheumatology and Autoimmunity
urn:nbn:se:umu:diva-1806 (URN)978-91-7264-625-4 (ISBN)
Public defence
2008-09-26, Sal D, 9tr, Tandläkarhögskolan, NUS, Umeå, 12:00 (English)
Available from: 2008-09-03 Created: 2008-09-03 Last updated: 2010-01-18Bibliographically approved

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