Modulation of cytokine production and silica-induced lung fibrosis by inhibitors of aminopeptidase N and of dipeptidyl peptidase-IV-related proteases.
OBJECTIVE
Dipeptidyl peptidase IV (DP IV)-related proteases and aminopeptidase N (APN) are drug targets in various diseases. Here we investigated for the first time the effects of DP-IV-related protease inhibitors and APN inhibitors on chronic inflammatory lung diseases.


METHODS
A murine model of silica (SiO2)-induced lung fibrosis and in vitro cultures of human lung epithelial cells and monocytes have been used and the influence of silica-treatment and inhibitors on inflammation and fibrosis has been measured.


RESULTS
We found increased inflammation and secretion of the chemokines IL-6, MCP-1 and MIP-alpha 2 weeks after SiO2 application, and increased lung fibrosis after 3 months. Treatment with the APN inhibitor actinonin reduced chemokine secretion in the lung and bronchoalveolar lavage fluid, and in cell culture, and decreased the level of fibrosis after 3 months. Treatment with inhibitors of DP-IV-related proteases, or a combination of DP IV inhibitors and APN inhibitors, had no significant effect. We found no obvious side effects of long-term treatment with inhibitors of APN and DP IV.


CONCLUSIONS
Overall, our findings show that actinonin, an inhibitor of aminopeptidase N, might modulate chemokine secretion in the lung and thus attenuate the development of lung fibrosis. Additional targeting of DP-IV-related proteases had no significant effect on these processes.
Kühlmann
Ulrike C
UC
Institute of Immunology, Otto-von-Guericke-University-Magdeburg, Leipziger-Str. 44, 39120 Magdeburg, Germany.
Chwieralski
Caroline E
CE
van den Brule
Sybille
S
Röcken
Christoph
C
Reinhold
Dirk
D
Welte
Tobias
T
Bühling
Frank
F
D000818:Animals; D018826:CD13 Antigens / Q000037:antagonists & inhibitors*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000209:etiology; D012822:Silicon Dioxide / Q000633:toxicity*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D016207:Cytokines; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006877:Hydroxamic Acids; D015850:Interleukin-6; D016209:Interleukin-8; D011480:Protease Inhibitors; D016212:Transforming Growth Factor beta; D012822:Silicon Dioxide; D018826:CD13 Antigens; C010531:actinonin