A novel IkappaB kinase-beta inhibitor ameliorates bleomycin-induced pulmonary fibrosis in mice.
BACKGROUND
IkappaB kinase-beta is a critical regulator in the activation of nuclear factor-kappaB (NF-kappaB), a transcription factor related to the expression and regulation of proinflammatory cytokines.


OBJECTIVE
To evaluate if inhibition of IkappaB kinase-beta ameliorates pneumonitis and pulmonary fibrosis.


METHODS
We examined whether a novel IkappaB kinase-beta inhibitor, IMD-0354, attenuates bleomycin-induced pulmonary fibrosis in mice.


RESULTS
Administration of IMD-0354 significantly improved the loss of body weight and survival of mice treated with bleomycin, whereas IMD-0354 alone did not cause any morphologic change in the lung. When mice were evaluated 28 d after bleomycin administration, IMD-0354 dose-dependently reduced the collagen content and fibrotic scores as shown by histologic examination. The findings in the bronchoalveolar lavage demonstrated that the proportions of neutrophils and lymphocytes were decreased in mice treated with IMD-0354 on Day 7 and 14, respectively. IMD-0354 treatment was confirmed to inhibit the activation of NF-kappaB, but not activator protein-1, in the lungs treated with bleomycin. The production of inflammatory cytokines tumor necrosis factor-alpha and interleukin-1beta was reduced in the lungs of mice treated with IMD-0354.


CONCLUSIONS
These results suggest that IMD-0354 might be useful to ameliorate the inflammation in the lungs induced by fibrotic injury and the subsequent fibrogenesis via inhibiting the expression of profibrotic cytokines related to the activation of NF-kappaB.
Inayama
Mami
M
Department of Internal Medicine and Molecular Therapeutics, Institute of Health Biosciences, the University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan.
Nishioka
Yasuhiko
Y
Azuma
Momoyo
M
Muto
Susumu
S
Aono
Yoshinori
Y
Makino
Hideki
H
Tani
Kenji
K
Uehara
Hisanori
H
Izumi
Keisuke
K
Itai
Akiko
A
Sone
Saburo
S
D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D001761:Bleomycin; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D005260:Female; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors*; D007375:Interleukin-1 / Q000378:metabolism; D053583:Interleukin-1beta; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000378:metabolism / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D001549:Benzamides; D007375:Interleukin-1; D053583:Interleukin-1beta; D010446:Peptide Fragments; D014409:Tumor Necrosis Factor-alpha; C052994:interleukin-1beta (163-171); D001761:Bleomycin; C492919:N-(3,5-bis(trifluoromethyl)phenyl)-5-chloro-2-hydroxybenzamide; D051550:I-kappa B Kinase