Relationships between early inflammatory response to bleomycin and sensitivity to lung fibrosis: a role for dipeptidyl-peptidase I and tissue inhibitor of metalloproteinase-3?
BACKGROUND
Different sensitivities to profibrotic compounds such as bleomycin are observed among mouse strains.


OBJECTIVE
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.


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-alpha-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.
Pottier
Nicolas
N
IPMC, CNRS UMR6097, 660, route des Lucioles, F06560 Sophia Antipolis, France.
Chupin
Cécile
C
Defamie
Virginie
V
Cardinaud
Bruno
B
Sutherland
Rachel
R
Rios
Géraldine
G
Gauthier
Francis
F
Wolters
Paul J
PJ
Berthiaume
Yves
Y
Barbry
Pascal
P
Mari
Bernard
B
D051722:ADAM Proteins / Q000378:metabolism; D000072198:ADAM17 Protein; D000818:Animals; D017209:Apoptosis; D001761:Bleomycin / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D020789:Cathepsin C / Q000172:deficiency / Q000378:metabolism*; D004802:Eosinophilia / Q000139:chemically induced / Q000209:etiology; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D007322:Instillation, Drug; D015848:Interleukin-5 / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D009504:Neutrophils / Q000201:enzymology; D020411:Oligonucleotide Array Sequence Analysis; D011014:Pneumonia / Q000139:chemically induced* / Q000378:metabolism* / Q000503:physiopathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000235:genetics*; D012697:Serine Endopeptidases / Q000378:metabolism; D013045:Species Specificity; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000378:metabolism*; D014132:Trachea; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015848:Interleukin-5; D019717:Tissue Inhibitor of Metalloproteinase-3; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D020789:Cathepsin C; D012697:Serine Endopeptidases; D051722:ADAM Proteins; D020782:Matrix Metalloproteinases; D000072198:ADAM17 Protein