© 2008 American Thoracic Society
Does MMP-12 Play a Role in Human Lung Fibrosis?
University of Birmingham
Queen's University Belfast To the Editor: We read with interest the experiments of Matute-Bello and coworkers upon the potential role of MMP-12 in FasL-induced fibrosis (1). Their experiments elegantly demonstrate that in mice the activation of Fas in the lungs for 3 days results in a fibroproliferative response that is dependent on MMP-12. Based upon our own observations, however, we question whether this is likely to be true of patients with either acute lung injury (ALI) or idiopathic pulmonary fibrosis (IPF). Both conditions have previously been associated with increased bronchoalveolar lavage fluid (BALF)-immunoreactive FasL (2, 3). We believe that matrix metalloproteinases (MMP) play an important role in the pathogenesis of patients with acute lung injury and IPF. However, as to the role of MMP-12 in these conditions, there is little or no human data. We have measured MMP-12 levels in the BALF of 18 patients with IPF, 27 patients with acute lung injury, and 8 normal control subjects by luminex array (measured MMP-1, -2, -3, -7, -8, -9, -12, and –13; R&D Systems, Abingdon, UK). In contrast to what the available animal data, and the current paper by Matute-Bello and colleagues, might suggest, MMP-12 levels were only mildly elevated in patients with ALI (Day 0 median MMP-12 59 pg/ml; 95% confidence interval, 30–85) compared with normal subjects (all less than detection limit of 18 pg/ml, P = 0.02). There was no significant increase in ARDS BALF MMP-12 activity from Day 0 to Day 4 to suggest that MMP-12 up-regulation was associated with persistent disease. Similarly, in patients with IPF, MMP-12 was only detectable in BALF in 3 out of 18 patients (P = 0.7 versus normal). The MMP-12 data represent 0.006% of total MMP levels in ARDS BALF at Day 0 and 0.022% of total IPF BALF MMP levels as measured by the luminex array. It is important to recognize that the tissue levels of MMP-12 do not necessarily clearly reflect BALF levels due to the complex regulation of MMPs by local inhibitors. Nevertheless, we believe that current evidence does not support a clear role for MMP-12 in human lung fibrosis associated with ARDS or IPF. Although animal models are important in helping to define disease mechanisms, these data highlight the limitations of animal models in relation to complex human respiratory disease and reaffirm the need for clinical studies in translational research. Footnotes Conflict of Interest Statement: None of the authors has a financial relationship with a commercial entity that has an interest in the subject of this manuscript. References
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