Protective Effects of Ulinastatin against Ischemia–Reperfusion Injury

Okuhama, Yukihiro; Shiraishi, Masayuki; Higa, Takeshi; Tomori, Hirofumi; Taira, Kaoru; Mamadi, Toure; Muto, Yoshihiro

doi:10.1006/jsre.1998.5496

Cited by 44 publications

(27 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Strong adhesion and transmigration processes trigger the exocytosis of gelatinase granules from neutrophils, which liberate matrix metalloproteinases [39]. Several in vivo and in vitro experiments have demonstrated that protease inhibitors exert a hepatoprotective effect against IRI, in association with suppression of the aforementioned factors [40][41][42][43]. However, few studies have focused on the Fig.…”

Section: Discussionmentioning

confidence: 99%

Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

et al. 2013

View full text Add to dashboard Cite

Background Sivelestat sodium hydrate (sivelestat) is a specific neutrophil elastase inhibitor that is effective in treating acute lung injury associated with systemic inflammatory response syndrome. As such, it may be useful in treating hepatic ischemia-reperfusion injury (IRI), a condition in which neutrophils transmigrate into the interstitium, leading to release of neutrophil elastase from neutrophils and consequent damage to the affected tissue, particularly in cases of hepatic failure after liver transplantation or massive liver resection. Aims The purpose of this study was to examine whether treatment with sivelestat inhibits neutrophil adhesion and migration to the vessel wall and suppresses hepatic IRI. Methods Whether and, if so, the extent to which sivelestat suppresses the adhesion and migration of neutrophils and reduces liver damage in hepatic IRI was examined in a human umbilical vein endothelial cell (HUVEC) model and a rat hepatic IRI model. Results In the HUVEC model, the extent of the adhesion and migration of neutrophils stimulated by platelet-activating factor were found to be dose-dependently inhibited by sivelestat treatment (p \ 0.05). In the rat model, serum liver enzyme levels were significantly lower at 12 h after reperfusion, and the number of neutrophils that had migrated to extravascular sites was significantly less in the treatment group compared to the control group (p \ 0.05). Conclusion Sivelestat inhibits the adhesion and migration of neutrophils to vascular endothelium in hepatic IRI, thereby suppressing liver injury.

show abstract

Section: Discussionmentioning

confidence: 99%

Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

et al. 2013

View full text Add to dashboard Cite

show abstract

“…[10,11] . Apart from blocking of the protease pathway, ulinastatin has been proven to be effective in suppressing the production of tumor necrosis factor and IL-1 from monocytes stimulated with endotoxin as well as in downregulating the arachidonic acid metabolism in human monocytes [25][26][27] . Due to these inhibitory properties, ulinastatin has been extensively used to treat patients with acute inflammatory disorders such as shock and pancreatitis, especially in Japan and China [7,11] .…”

Section: Discussionmentioning

confidence: 99%

Protective Effects of Ulinastatin on Proliferation and Cytokine Release of Splenocytes from Rats with Severe Acute Pancreatitis

Kang

Shao

et al. 2006

Eur Surg Res

View full text Add to dashboard Cite

Aim: To clarify the contributions of ulinastatin to cellular immune responses in vivo, we examined the functional alterations of splenocytes and quantitatively evaluated the effects of ulinastatin on the splenocyte function during experimental severe acute pancreatitis. Methods: Severe acute pancreatitis was induced in rats by retrograde injection of 3% sodium deoxycholate. Thirty minutes after induction of pancreatitis, the rats were randomly assigned to four groups, receiving either saline or 50,000 U/kg of ulinastatin, respectively. Splenocytes were obtained aseptically and stimulated with concanavalin A for 24 h. Then the proliferative activity of cultured splenocytes was measured by using an MTT cellular proliferation assay, and the cytokine concentrations in the culture supernatants were measured by enzyme-linked immunosorbent assays. Results: Upon stimulation, the release of interleukin-2, interleukin-10, and interferon-γ was significantly decreased in the splenocytes from rats with pancreatitis as compared with those from sham operation and control groups. The splenocyte proliferation was also significantly suppressed in this group. In contrast, the proliferative as well as the cytokine-releasing capacities of the splenocytes from rats treated with ulinastatin were significantly increased as compared with those from rats with pancreatitis. Conclusions: The deficiencies in proliferation and cytokine release in response to antigen stimulation demonstrated an anergic state of splenocytes during severe acute pancreatitis. Treatment with ulinastatin contributed to the recovery of the immune function by improving proliferative responses and cytokine release of splenocytes. These data suggest that a protease-modulating therapy may be an effective strategy for the treatment of immunosuppression induced by severe acute pancreatitis.

show abstract

“…Prosurvival pathways involving PI3K-Akt and ERK1/2 have been shown to prevent cellular damage by converging on the mPTP and inhibiting its opening [1,21,22,23,24,25,26]. Moreover, UTI has been shown to protect mitochondrial function during I/R by directly inhibiting lysosomal enzymes and free radicals [8] or reducing Ca 2+ overload in injured cells [9]. Further studies defining the role of mPTP in UTI-induced myocardial protection against I/R injury may be needed.…”

Section: Discussionmentioning

confidence: 99%

“…Its protective effect on I/R injury is partly mediated by inhibition of lysosomal enzymes and free radicals [8] or reduction in Ca 2+ overload [9]. UTI has also been shown to inhibit the production of tumor necrosis factor-α in lipopolysaccharide-stimulated human monocytes [10] and the expression of lipopolysaccharide-stimulated interleukin-8 genes in HL60 cells [11].…”

Section: Introductionmentioning

confidence: 99%

Urinary Trypsin Inhibitors Afford Cardioprotective Effects through Activation of PI3K-Akt and ERK Signal Transduction and Inhibition of p38 MAPK and JNK

Kim

Yoo²,

Jeong³

et al. 2009

Cardiology

View full text Add to dashboard Cite

Background: We determined the effect of urinary trypsin inhibitors (UTI) in regional myocardial ischemia/reperfusion (I/R) injury and its underlying mechanisms involving the role of prosurvival kinases such as phosphatidylinositol-3-OH kinases (PI3K)-Akt and extracellular signal-regulated kinases (ERK 1/2) and apoptotic kinases such as p38 and JNK. Methods: The rats were anesthetized and subjected to an I/R insult consisting of 30-min left anterior descending coronary artery (LAD) occlusion followed by reperfusion. Infarct size was measured after 120 min of reperfusion. UTI was given alone or along with wortmannin (inhibitor of PI3K) or PD098059 (inhibitor of ERK1/2) before LAD occlusion. The phosphorylation of Akt, ERK1/2, p38 and JNK was determined by immunoblotting after 5 min of reperfusion. UTI was administered 10 min before LAD occlusion, and wortmannin and PD098059 were administered 20 min before LAD occlusion. Results: UTI significantly reduced the infarct size compared with the control. Wortmannin or PD098059 alone did not affect the infarct size, but they abolished the UTI-induced cardioprotective effect. UTI significantly reduced the phosphorylation of p38 and JNK, while it enhanced that of Akt and ERK1/2. Conclusions: UTI has a protective effect against regional myocardial I/R injury through activation of survival kinases PI3K-Akt and ERK1/2 and attenuation of p38 and JNK.

show abstract

Protective Effects of Ulinastatin against Ischemia–Reperfusion Injury

Cited by 44 publications

References 27 publications

Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

Sivelestat Sodium Hydrate Inhibits Neutrophil Migration to the Vessel Wall and Suppresses Hepatic Ischemia–Reperfusion Injury

Protective Effects of Ulinastatin on Proliferation and Cytokine Release of Splenocytes from Rats with Severe Acute Pancreatitis

Urinary Trypsin Inhibitors Afford Cardioprotective Effects through Activation of PI3K-Akt and ERK Signal Transduction and Inhibition of p38 MAPK and JNK

Contact Info

Product

Resources

About