Ulinastatin activates haem oxygenase 1 antioxidant pathway and attenuates allergic inflammation.
OBJECTIVE
Ulinastatin (UTI), a serine protease inhibitor, was recently found to have an anti-inflammatory action. However, the mechanisms mediating this anti-inflammatory effect are not well understood. This study tested the hypothesis that UTI suppresses allergic inflammation by inducing the expression of haem oxygenase 1 (HO1).


METHODS
Control mice and mice sensitized (on days 1, 9 and 14) and challenged (on days 21 to 27) with ovalbumin (OVA) were treated with UTI. The effects of UTI on basal expression of HO1 and that induced by OVA challenge were examined. The involvement of UTI-induced HO1 expression in anti-inflammatory and antioxidant effects of UTI was also evaluated.


RESULTS
UTI markedly increased basal HO1 protein expression in lungs of control mice in a time- and dose-dependent manner, and augmented HO1 protein expression induced by OVA. The up-regulation of HO1 mediated by UTI in sensitized and OVA-challenged mice was associated with reduced airway inflammation, alleviated tissue injury, reduced oxidant stress and enhanced antioxidant enzyme activities. Inhibition of HO1 activity using HO1 inhibitor, zinc protoporphyrin, attenuated inhibitory effects of UTI on inflammation and oxidant stress, and its stimulant effects on antioxidant enzyme activities. Mechanistic analysis showed that UTI increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2), stimulated Nrf2 DNA binding activity and concomitantly up-regulated HO1 mRNA expression.


CONCLUSIONS
UTI is a potent and naturally occurring inducer of HO1 expression. HO1 up-regulation contributes significantly to the anti-inflammatory and organ-protective effects of UTI, which has important research and therapeutic implications.
Department of Allergy and Otolaryngology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Dongmei
D
Song
Geng
G
Song
Yinghao
Y
Niu
Wei
W
Song
Jiantao
J
Wang
Lei
L
Yu
Jianwang
J
Yang
Xin
X
Lv
Harry
H
Steinberg
Shu Fang
SF
Liu
Baoshan
B
Wang
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D016207:Cytokines / Q000235:genetics / Q000276:immunology; D004790:Enzyme Induction; D005978:Glutathione / Q000378:metabolism; D006023:Glycoproteins / Q000494:pharmacology* / Q000627:therapeutic use*; D051547:Heme Oxygenase-1 / Q000096:biosynthesis; D006967:Hypersensitivity / Q000097:blood / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007073:Immunoglobulin E / Q000097:blood; D007958:Leukocyte Count; D008168:Lung / Q000378:metabolism; D008315:Malondialdehyde / Q000378:metabolism; D008565:Membrane Proteins / Q000096:biosynthesis; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D050050:Protein Carbonylation; D013482:Superoxide Dismutase / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D006023:Glycoproteins; D008565:Membrane Proteins; D007073:Immunoglobulin E; D008315:Malondialdehyde; D010047:Ovalbumin; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D013482:Superoxide Dismutase; D005978:Glutathione; C028665:urinastatin