Inhibition of nuclear factor-kappaB in T cells suppresses lung fibrosis.
BACKGROUND
Cytokines secreted by T cells play a pivotal role in the pathogenesis of lung injury and fibrosis, and the transcription factors nuclear factor (NF)-kappaB and activator protein (AP)-1 are involved in the expression of cytokines from T cells during lung injury.


OBJECTIVE
We assessed the potential therapeutic effect of SP100030, a specific inhibitor of T-cell NF-kappaB and AP-1 in lung fibrosis.


METHODS
The effect of SP100030 was evaluated using a mouse model of chronic lung fibrosis.


RESULTS
Mice treated with SP100030, as compared with untreated mice, had significantly less cachexia and less lung injury and had decreased levels of inflammatory cytokines and growth factors, decreased activation of coagulation activation, and decreased collagen deposition in the lung. The inhibitory activity of SP100030 was dose dependent and was effective in acute and chronic phases of lung fibrosis. SP100030 inhibited the activation of the protein kinase C-isoform in T-cell lines and suppressed NF-kappaB-driven cytokine expression in CD4(+) and CD8(+) T cells.


CONCLUSIONS
These results suggest that the specific inhibition of NF-kappaB could be useful for the treatment of lung fibrosis.
Fujimoto
Hajime
H
Department of Pulmonary and Critical Care Medicine, Mie University Graduate School of Medicine, Edobashi 2-174, Tsu City, Mie, Japan.
D'Alessandro-Gabazza
Corina N
CN
Palanki
Moorthy S S
MS
Erdman
Paul E
PE
Takagi
Takehiro
T
Gabazza
Esteban C
EC
Bruno
Nelson E
NE
Yano
Yutaka
Y
Hayashi
Tatsuya
T
Tamaki
Shigenori
S
Sumida
Yasuhiro
Y
Adachi
Yukihiko
Y
Suzuki
Koji
K
Taguchi
Osamu
O
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D019169:Jurkat Cells; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects*; D009930:Organic Chemicals / Q000494:pharmacology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*; D013601:T-Lymphocytes / Q000187:drug effects*; D000813:Anilides; D001549:Benzamides; D011743:Pyrimidines
D007166:Immunosuppressive Agents; D016328:NF-kappa B; D009930:Organic Chemicals; C102914:N-(3,5-bis(trifluoromethyl)phenyl)-2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxamide; D000813:Anilides; D001549:Benzamides; D011743:Pyrimidines