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Does MMP-12 Play a Role in Human Lung Fibrosis?

University of Washington School of Medicine
Seattle, Washington

From the Authors:

We have read the letter by Dr. David Thickett and coworkers, regarding our recent article "Essential role of MMP-12 in Fas-induced lung fibrosis" (1), and we would like to submit the following response.

We agree with the comments of Dr. Thickett and colleagues regarding the need to translate laboratory findings to the bedside. The low concentrations of MMP-12 in bronchoalveolar lavage (BAL) fluid of patients with acute lung injury or pulmonary fibrosis do not necessarily absolve MMP-12 from a role in the pathogenesis of these diseases. First, the bronchoalveolar lavage procedure used in most centers dilutes alveolar fluid from 50- to 100-fold, which can make detecting low abundance proteins difficult. Second, MMP-12 is released in relatively small concentrations by human alveolar macrophages and may not be detected in undiluted samples. A better indicator of MMP-12 up-regulation would be MMP-12 expression in alveolar macrophages, measured by PCR, or possibly immunocytochemistry (2). Third, MMP-12 is likely to act at a local level by inducing proteolytic activation of target proteins. Because proteolytic activation can act as an amplification process, the target proteins are the ones that are likely to be changed in BAL fluid, rather than MMP-12 itself. Finally, issues related to timing of BAL sampling can also make detection of MMP-12 in the lungs difficult. Our results predict that MMP-12 activity would begin to increase at Day 4 after onset of ARDS, and peak on Day 7 (1); however, Thickett's measurements were performed earlier, between Days 0 and 4. We continue to believe that MMP-12 may have a role in the response to lung injury in humans, but further studies are warranted to confirm this point.

Footnotes

Conflict of Interest Statement: G.M.-B. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

References

1. Matute-Bello G, Wurfel MM, Lee JS, Park DR, Frevert CW, Madtes DK, Shapiro SD, Martin TR. Essential role of MMP-12 in Fas-induced lung fibrosis. Am J Respir Cell Mol Biol 2007;37:210–221.[Abstract/Free Full Text]
2. Molet S, Belleguic C, Lena H, Germain N, Bertrand CP, Shapiro SD, Planquois JM, Delaval P, Lagente V. Increase in macrophage elastase (MMP-12) in lungs from patients with chronic obstructive pulmonary disease. Inflamm Res 2005;54:31–36.[CrossRef][Medline]

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