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Relationships between Early Inflammatory Response to Bleomycin and Sensitivity to Lung Fibrosis

A Role for Dipeptidyl-Peptidase I and Tissue Inhibitor of Metalloproteinase-3?

¹ Centre National de la Recherche Scientifique and Institut de Pharmacologie Moléculaire et Cellulaire, Université de Nice Sophia Antipolis, UMR6097, Sophia Antipolis, France; ² Département de Médecine, Centre de Recherche, Centre Hospitalier de l'Université de Montréal Hôtel-Dieu, Montréal, Quebec, Canada; ³ Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, California; and ⁴ Institut National de la Santé et de la Recherche Médicale U618, Protéases et Vectorisation Pulmonaires, Université François Rabelais, Tours, France

Correspondence and requests for reprints should be addressed to Pascal Barbry, Ph.D., IPMC, CNRS UMR6097, 660, route des Lucioles, F06560 Sophia Antipolis, France. E-mail: barbry{at}ipmc.cnrs.fr

Rationale: Different sensitivities to profibrotic compounds such as bleomycin are observed among mouse strains.

Objectives: To identify genetic factors contributing to the outcome of lung injury.

Methods: Physiological comparison of C57BL/6 (sensitive) and BALB/c (resistant) mice challenged by intratracheal bleomycin instillation revealed several early differences: global gene expression profiles were thus established from lungs derived from the two strains, in the absence of any bleomycin administration.

Measurements and Main Results: Expression of 25 genes differed between the two strains. Among them, two molecules, not previously associated with pulmonary fibrosis, were identified. The first corresponded to dipeptidyl-peptidase I (DPPI), a cysteine peptidase (also known as cathepsin C) essential for the activation of serine proteinases produced by immune/inflammatory cells. The second corresponded to tissue inhibitor of matrix metalloproteinase-3, which also inhibits members of the ADAM (a disintegrin and metalloproteinase) family, such as the tumor necrosis factor–converting enzyme. In functional studies performed in the bleomycin-induced lung fibrosis model, the level of expression of these two genes was closely correlated with specific early events associated with lung fibrosis, namely activation of polymorphonuclear neutrophil–derived serine proteases and tumor necrosis factor-–dependent inflammatory syndrome. Surprisingly, genetic deletion of DPPI in the context of a C57BL/6 genetic background did not protect against bleomycin-mediated fibrosis, suggesting additional function(s) for this key enzyme.

Conclusions: This study highlights the importance of the early inflammatory events that follow bleomycin instillation in the development of lung fibrosis, and describes for the first time the roles that DPPI and tissue inhibitor of matrix metalloproteinase-3 may play in this process.

Key Words: microarray • tumor necrosis factor- • neutral serine proteases • matrix metalloproteinase • apoptosis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Physiological alterations produced by bleomycin in lung are well characterized in human and animal models, but early mechanisms leading to lung injury have not been explored. What This Study Adds to the Field DPPI (cathepsin C), TIMP-3, and TACE appear to participate in early inflammatory events following bleomycin instillation into the lungs.

 

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