Ulinastatin is a novel candidate drug for sepsis and secondary acute lung injury, evidence from an optimized CLP rat model

Wang, Ning; Liu, Xin; Zheng, Xinchuan; Cao, Hongwei; Guo, Wei; Zhu, Yuanfeng; Fan, Shijun; Zhou, Hong; Zheng, Jie

doi:10.1016/j.intimp.2013.09.004

Cited by 33 publications

(21 citation statements)

References 27 publications

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“…Consistent with previous studies (Fang et al, 2011;Wang et al, 2013), UTI administration improved survival rate and attenuated lung inflammatory injury after CLP, as revealed by decreased hemorrhage, edema, and inflammatory cell infiltration, as well as expression of TNF-a and IL-6. In addition, we also evaluated the lung tissue injury by semiquantitative Smith scoring (Smith et al, 1997) and TEM analysis.…”

Section: Discussionsupporting

confidence: 91%

“…It is reported that in addition to inhibiting plasmin, trypsin, chymotrypsin, elastase, and various pancreatic enzymes (Nishiyama et al, 1996), UTI also suppresses activation of inflammatory cells (e.g., neutrophils and leukocytes) and the production of inflammatory mediators such as tumor necrosis factor (TNF)-a, and interleukin (IL)-1β, IL-6, IL-8, and IL-15 (Ito et al, 2005;Fang et al, 2011;Cao et al, 2012;Shen et al, 2012;Wang et al, 2013). Therefore, UTI is suggested to be a potential therapeutic agent for ALI (Ito et al, 2005;Fang et al, 2011;Shen et al, 2012;Wang et al, 2013). However, the mechanism of UTI treatment of ALI has not been fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

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Effect of ulinastatin on HMGB1 expression in rats with acute lung injury induced by sepsis

Wang

et al. 2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to investigate the influence of ulinastatin (UTI) on high mobility group box 1 (HMGB1), tumor necrosis factor (TNF)-a, and interleukin (IL)-6 expression in acute lung injury (ALI) rats with sepsis caused by cecal ligation and puncture (CLP) surgery, as well as to examine the underlying biological mechanism. Thirty rats were randomly and evenly divided into sham (control), CLP, and CLP + UTI groups. Thirty minutes after the surgery, the rats in the CLP + UTI group received UTI via the caudal vein, while normal saline was administered to rats in the other groups. Blood, lung tissues, and bronchoalveolar lavage fluid (BALF) were collected at different time points (6, 12, 24, and 48 h) after surgery for determination of related indicators. Compared with the CLP group, rats in the CLP + UTI group exhibited higher seven day survival rates, less lung injury, and decreased HMGB1 expression in the lung tissue, serum, and BALF. In addition, the levels of TNF-a and IL-6 at 24 h in the CLP + UTI group were markedly lower than those in the CLP group. These results suggest that 4345 UTI effects on HMGB1 expression in ALI rats ©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 14 (2): 4344-4353 (2015) by deregulation, UTI might decrease the lung injury and increase the survival time of ALI rats by downregulating HMGB1 expression as well as by inhibiting TNF-α and IL-6 levels in serum and BALF.

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Effect of ulinastatin on HMGB1 expression in rats with acute lung injury induced by sepsis

Wang

et al. 2015

Genet. Mol. Res.

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“…Previous studies have demonstrated that UTI inhibits the inflammatory response and mitigates sepsis-induced ALI (18,20). As is already known, the etiologies of ALI are complex, and additional mechanisms through which UTI exerts protective effects against LPS-induced lung injury need to be further investigated.…”

Section: Discussionmentioning

confidence: 98%

“…Ulinastatin (UTI) is a serine protease inhibitor that modulates innate immunity and pro-inflammatory signaling in sepsis (17,18). The administration of UTI has been shown to decrease the LPS-induced increase in TLR4 expression (19), and to attenuate sepsis-induced nuclear factor-κB (NF-κB) activity (20).…”

Section: Introductionmentioning

confidence: 99%

Ulinastatin post-treatment attenuates lipopolysaccharide-induced acute lung injury in rats and human alveolar epithelial cells

Luo

Che

Zhao

2016

International Journal of Molecular Medicine

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Ulinastatin (UTI), a serine protease inhibitor, possesses anti-inflammatory properties and has been suggested to modulate lipopolysaccharide (LPS)-induced acute lung injury (ALI). High-mobility group box 1 (HMGB1), a nuclear DNA-binding protein, plays a key role in the development of ALI. The aim of this study was to investigate whether UTI attenuates ALI through the inhibition of HMGB1 expression and to elucidate the underlying molecular mechanisms. ALI was induced in male rats by the intratracheal instillation of LPS (5 mg/kg). UTI was administered intraperitoneally 30 min following exposure to LPS. A549 alveolar epithelial cells were incubated with LPS in the presence or absence of UTI. An enzyme-linked immunosorbent assay was used to detect the levels of inflammatory cytokines. Western blot analysis was performed to detect the changes in the expression levels of Toll-like receptor 2/4 (TLR2/4) and the activation of nuclear factor-κB (NF-κB). The results revealed that UTI significantly protected the animals from LPS-induced ALI, as evidenced by the decrease in the lung wet to dry weight ratio, total cells, neutrophils, macrophages and myeloperoxidase activity, associated with reduced lung histological damage. We also found that UTI post-treatment markedly inhibited the release of HMGB1 and other pro-inflammatory cytokines. Furthermore, UTI significantly inhibited the LPS-induced increase in TLR2/4 protein expression and NF-κB activation in lung tissues. In vitro, UTI markedly inhibited the expression of TLR2/4 and the activation of NF-κB in LPS-stimulated A549 alveolar epithelial cells. The findings of our study indicate that UTI attenuates LPS-induced ALI through the inhibition of HMGB1 expression in rats. These benefits are associated with the inhibition of the activation of the TLR2/4-NF-κB pathway by UTI.

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“…This process subsequently leads to translocation of the free NF-kB to the nucleus where it promotes the expression of proinflammatory genes such as the proinflammatory [9].Urinary trypsin inhibitor (UTI) is one of the Kunitztype protease inhibitors found in urine [10].With its anti-protease and anti-inflammatory effects, UTI has been widely used as a drug for patients with acute inflammatory disorders, such as disseminated intravascular pancreatitis, shock, and coagulation [11]. Earlier, we showed that Ulinastatin produces in vivo antiinflammatory effects [12]. Although the anti-inflammatory effects of Ulinastatin in the periphery have been documented, its effects on cells in the CNS, specifically the hippocampal astrocyte in vitro, are not known.…”

Section: Introductionmentioning

confidence: 99%

Ulinastatin suppresses lipopolysaccharide induced neuro-inflammation through the downregulation of nuclear factor-κB in SD rat hippocampal astrocyte

Zhao

et al. 2015

Biochemical and Biophysical Research Communications

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Ulinastatin is a novel candidate drug for sepsis and secondary acute lung injury, evidence from an optimized CLP rat model

Cited by 33 publications

References 27 publications

Effect of ulinastatin on HMGB1 expression in rats with acute lung injury induced by sepsis

Effect of ulinastatin on HMGB1 expression in rats with acute lung injury induced by sepsis

Ulinastatin post-treatment attenuates lipopolysaccharide-induced acute lung injury in rats and human alveolar epithelial cells

Ulinastatin suppresses lipopolysaccharide induced neuro-inflammation through the downregulation of nuclear factor-κB in SD rat hippocampal astrocyte

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