RATIONALE. Different sensitivities to pro-fibrotic 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 with intra tracheal 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 one corresponds to dipeptidyl peptidase I (DPPI), a cysteine dipeptidyl peptidase (also known as cathepsin C) essential for the activation of serine proteinases produced by immune/inflammatory cells. The second corresponds to TIMP-3, an inhibitor of matrix metalloproteases and of ADAMs such as the TNFconverting 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 PMN-derived serine proteases and TNF-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 TIMP-3 may play in this process.