Bronchoalveolar matrix metalloproteinase 9 relates to restrictive lung function impairment in systemic sclerosis

Abstract

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.

Pathogenesis of Pulmonary Fibrosis in Systemic Sclerosis: Lessons from Interstitial Lung Disease

“…It is likely that abnormalities of the fibrotic lung will be reflected in the composition of the BALF, and numerous investigators have examined the cellular and soluble components of BALF in both SSc-associated and idiopathic ILDs. In keeping with prior reports that MMP-9 is elevated in the idiopathic forms of UIP and NSIP [17], Anderson et al [18] demonstrated increased total and pro-matrix metalloproteinase-9 (MMP-9) levels in the BAL fluid of individuals with SSc-ILD versus individuals with SSc and no evidence of ILD and normal controls. BALF levels of TIMP-1, however, were elevated in all individuals with SSc, regardless of the presence of ILD [18].…”

“…In keeping with prior reports that MMP-9 is elevated in the idiopathic forms of UIP and NSIP [17], Anderson et al [18] demonstrated increased total and pro-matrix metalloproteinase-9 (MMP-9) levels in the BAL fluid of individuals with SSc-ILD versus individuals with SSc and no evidence of ILD and normal controls. BALF levels of TIMP-1, however, were elevated in all individuals with SSc, regardless of the presence of ILD [18]. It is possible that the balance between key MMPs and TIMPs in the alveolar compartment may serve as a stronger predictor of the presence or severity of ILD, and further study is warranted.…”

Monitoring of Lung Involvement in Rheumatologic Disease

“…Biomarkers of various kinds have an important theoretical role in this regard, both in initial evaluation and in monitoring. However, candidate serum, bronchoalveolar lavage and imaging biomarkers in CTD-ILD have mostly been studied only at a single point in time [34], including surfactant protein A and B (SP-A, SP-B) [35,36,37], Krebs von den Lungen (KL)-6 [35,38,39,40,41], other lung epithelium-derived proteins, as well as chemokines, cytokines, matrix metalloproteinases and interleukins [34,42,43,44,45,46,47,48]. Serial biomarker trends have the potential to refine prognostic evaluation with exciting possibilities with the introduction of a therapy, and short-term biomarker changes might provide invaluable information on longer-term efficacy.…”

Circulating Biomarkers of Interstitial Lung Disease in Systemic Sclerosis

“…MMP-9 (gelatinase B), associated with chronic inflammatory autoimmune diseases and conditions characterised by excessive fibrosis, was significantly increased in serum of SSc patients compared to healthy controls [81] and in bronchoalveolar lavage of SSc-ILD patients [82]. Interestingly, circulating levels of MMP-12 have been reported to be tightly inversely correlated with FVC ( r = −0.82), and MMP-12 staining to be significantly increased in SSc-ILD lungs compared to normal controls [83].…”