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A Role for Collagenase (Matrix Metalloproteinase-1) in Pulmonary Emphysema^*

^* From the Division of Molecular Medicine, Department of Medicine (Drs. D’Armiento, Dalal, Imai, and Mercer), College of Physicians and Surgeons of Columbia University, New York, NY; the Department of Biochemistry (Dr. Chada), University of Medicine and Dentistry, Newark, NJ; and the Department of Pathology (Dr. Okada), Keio University, Shinanomachi, Japan.

Correspondence to: Jeanine D’Armiento, MD, Assistant Professor of Medicine, Columbia University, 630 W. 168th St, PH 8-101, New York, NY 10032

	Introduction

TOP Introduction

 
Abbreviations: dpc = days postcoitum; MMP = matrix metalloproteinase; RT-PCR = reverse transcriptase-polymerase chain reaction

Transgenic mice were generated that expressed collagenase matrix metalloproteinase [MMP]-1 in the lung, and these animals developed pulmonary emphysema. These studies not only developed an animal model of emphysema, but directly implicated collagenase (MMP-1) in the disease process. We undertook extensive morphometric analysis on three of the transgenic lines with variable levels of transgene expression (Col 34, Col 50, and Col 64). Temporal expression of the transgene demonstrated earliest expression of the transgene in line 50 at 12 days postcoitum. Morphometric analysis demonstrated that the lungs in all of the animals were normal at birth, and only line 50 exhibited morphometric changes at 5 days of age. The mice from lines 34 and 64 were normal up until 4 weeks of age, when they began to develop changes in their mean linear intercept, which progressed over time. These animals are an ideal model in which to study the human disease.

In a second series of experiments, we performed reverse transcriptase-polymerase chain reaction analysis on human lung tissue and demonstrated the presence of interstitial collagenase (MMP-1) RNA, protein, and activity in the lung of patients suffering from emphysema and not in the lung of normal control subjects. In contrast, metalloelastase (MMP-12) expression was absent in these samples. In situ hybridization and immunohistochemistry studies on adjacent sections localized MMP-1 expression to the alveolar epithelial cells of the lung. This is the first direct demonstration of a degradative enzyme in human emphysema tissue. These data demonstrate that the lung is altered in emphysema such that the type II pneumocyte secretes MMP-1, and suggests that MMP-1 is a critical enzyme in the continued destruction of the tissue in the human disease. The combination of the mouse and human data suggests that MMP-1 inhibitors may be useful in preventing the progression of the disease.

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