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(Chest. 2002;121:25S-26S.)
© 2002 American College of Chest Physicians

Overexpression of Matrix Metalloproteinase-7 in Pulmonary Fibrosis*

Gregory P. Cosgrove, MD; Marvin I. Schwarz, MD, FCCP; Mark W. Geraci, MD; Kevin K. Brown, MD, FCCP and G. Scott Worthen, MD

* From the Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, and the Department of Medicine, National Jewish Medical and Research Center, Denver, CO.

Correspondence to: Gregory P. Cosgrove, MD, 1400 Jackson St, D403, Denver, CO 80206; e-mail: cosgroveg{at}njc.org

Key Words: genomics • idiopathic pulmonary fibrosis • matrix metalloproteinase • matrix metalloproteinase-7 • nonspecific interstitial pneumonitis • oligonucleotide microarray • pulmonary fibrosis

Matrix metalloproteinases (MMPs) are inducible zinc-dependent proteinases involved in a variety of normal biological processes, including connective tissue degradation, uterine involution, and wound repair.1 MMP-2, MMP-7, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1 have been demonstrated in pulmonary epithelium in patients with asthma, ARDS, and cystic fibrosis.2 3 4 5 Prior studies have implicated MMP-2, MMP-9, and TIMP-1 in the pathogenesis of pulmonary fibrosis.6 We hypothesize that MMP-7 may also be involved in the aberrant reparative processes in fibrotic lung diseases.

Frozen lung samples from patients with idiopathic pulmonary fibrosis (IPF; n = 2), nonspecific interstitial pneumonitis (NSIP; n = 1), and normal subjects (n = 5) were obtained from the National Jewish Medical and Research Center tissue bank. Total RNA was isolated, reverse-transcribed to complementary DNA, and then amplified to labeled, complementary RNA using an RNeasy Mini kit (QIAGEN, Valencia, CA). Amplified complementary RNA was fragmented, hybridized to GeneChip HuGeneFL Array (Affymetrix; Santa Clara, CA), and analyzed using Affymetrix Microarray Suite 3.3 (Affymetrix). A significant difference in expression was considered to be a > 1.8-fold change between the diseased and normal lung with a concordant expression pattern.

Microarray gene analysis demonstrated significantly increased expression of MMP-7 in patients with IPF (fourfold) and NSIP (33-fold) compared to normal lung in which low levels of MMP-7 were observed. Interestingly, other metalloproteinases, such as MMP-2, MMP-9, and TIMP-1, were not differentially expressed between normal and diseased lungs. Subsequent immunohistochemical analysis has demonstrated overexpression of MMP-7 in the alveolar pneumocytes and within the interstitium in specimens from patients with NSIP and IPF. Additionally, intense staining for MMP-7 also was seen in areas considered to be sites of active fibrosis, termed fibroblastic foci, in patients with IPF. While additional confirmation is necessary, these results support the hypothesis that metalloproteinases, especially MMP-7, may have an important role in fibrosing lung disorders.


   Footnotes
 
Abbreviations: IPF = idiopathic pulmonary fibrosis; MMP = matrix metalloproteinase; NSIP = nonspecific interstitial pneumonitis; TIMP = tissue inhibitor of metalloproteinase

This study was supported by the National Heart, Lung, and Blood Institute/National Institutes of Health grant 5 T32 HL07085–26.


   References
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  2. Betsuyaku, T, Fukuda, Y, Parks, WC, et al (2000) Gelatinase B is required for alveolar bronchiolization after intratracheal bleomycin. Am J Pathol 157,525-535[Abstract/Free Full Text]
  3. Cataldo, D, Munaut, C, Noel, A, et al (2000) MMP-2- and MMP-9-linked gelatinolytic activity in the sputum from patients with asthma and chronic obstructive pulmonary disease. Int Arch Allergy Immunol 123,259-267[CrossRef][ISI][Medline]
  4. Dunsmore, SE, Saarialho-Kere, UK, Roby, JD, et al (1998) Matrilysin expression and function in airway epithelium. J Clin Invest 102,1321-1331[ISI][Medline]
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  6. Suga, M, Iyonaga, K, Okamoto, T, et al (2000) Characteristic elevation of matrix metalloproteinase activity in idiopathic interstitial pneumonias. Am J Respir Crit Care Med 162,1949-1956[Abstract/Free Full Text]



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