Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model

Song, Yukang; Miao, Shixing; Li, Yexuzi; Fu, Hui

doi:10.1002/jcb.27396

Cited by 17 publications

(13 citation statements)

References 25 publications

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“…Even though we did not detect the changes of inflammatory mediators in the abdominal cavity, we here observed that acetic acid-induced infiltration of inflammatory cells in the peritoneum tissue decreased significantly after systemic administration of ulinastatin in H&E staining assay, which reinforced previous study that ulinastatin ameliorated the number of infiltrated inflammatory cell in cecal ligation and puncture induced sepsis. 59 In addition to the local inflammation evoked by acetic acid, the role of spinal inflammatory reaction, including glial activation and pro-inflammatory cytokines release, in acetic acidinduced writhing response has also been reported. [60][61][62] Previous studies verified that both minocycline and fluorocitrate were able to markedly reduce acetic acid-induced acute visceral nociception.…”

Section: Discussionmentioning

confidence: 99%

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation

Zhan¹,

Tang²,

Lu³

et al. 2021

JPR

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Introduction Ulinastatin, a broad-spectrum serine protease inhibitor, has been widely used to treat various diseases clinically. However, so far, the antinociceptive effect of ulinastatin remains less studied experimentally and the underlying mechanisms of ulinastatin for pain relief remain unclear. This study aimed to find evidence of the analgesic effect of ulinastatin on acute somatic and visceral pain. Methods The analgesic effect of ulinastatin on acute somatic and visceral pain was evaluated by using formalin and acetic acid-induced writhing test. The analgesic mechanism of ulinastatin was verified by detecting the peripheral inflammatory cell infiltration and spinal glial activation with hematoxylin-eosin (H&E) and immunohistochemistry staining. Results We found that both of intraperitoneal (i.p.) pre-administration and post-administration of ulinastatin could reduce the total number of flinching and the licking duration following intraplantar formalin injection in a dose-related manner. However, the inhibitory effect of ulinastatin existed only in the second phase (Phase 2) of formalin-induced spontaneous pain response, with no effect in the first phase (Phase 1). The formalin-induced edema and ulcer were also improved by i.p. administration of ulinastatin. Moreover, i.p. administration of ulinastatin was also able to delay the occurrence of acetic acid-induced writhing and reduced the total number of writhes dose-dependently. We further demonstrated that ulinastatin significantly decreased the local inflammatory cell infiltration in injured paw and peritoneum tissue under formalin and acetic acid test separately. The microglial and astrocytic activation in the spinal dorsal horn induced by intraplantar formalin and i.p. acetic acid injection were also dramatically inhibited by i.p. administration of ulinastatin. Conclusion Our results for the first time provided a new line of evidence showing that ulinastatin could attenuate acute somatic and visceral pain by inhibiting the peripheral and spinal inflammatory reaction.

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Section: Discussionmentioning

confidence: 99%

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation

Zhan¹,

Tang²,

Lu³

et al. 2021

JPR

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“…At present, there are no studies on the concentration of HNE adducts in sepsis patients in the literature. However, studies using animal models of sepsis showed an increased HNE concentration in blood or overexpression in organ tissues after sepsis initiation [ 26 , 28 , 29 ].…”

Section: Discussionmentioning

confidence: 99%

Glutathione Reductase Is Associated with the Clinical Outcome of Septic Shock in the Patients Treated Using Continuous Veno-Venous Haemofiltration

et al. 2021

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Background and objectives: At present, there is insufficient evidence to support the use of continuous veno-venous haemofiltration (CVVH) in the early treatment of septic shock. This study focuses on the association between survival and different parameters of oxidative stress (RedOx). Thereby, we evaluated whether RedOx markers are associated with the outcome of septic shock in patients under early-initiated CVVH treatment. Materials and Methods: We conducted a prospective observational study of 65 patients with septic shock who started CVVH within 12 h after hospital admission. Blood samples were taken from each patient prior to the start of CVVH. The following RedOx markers were measured: glutathione peroxidase, glutathione reductase (GR), total antioxidant capacity, superoxide dismutase, nitric oxide, malondialdehyde and 4-hydroxynonenal. The odds ratio (OR) was calculated using binary logistic regression and stepwise multivariable regression. Results: The 65 patients had a median age of 66 years and 39 were male. Based on the outcome, the patients were divided into two groups—non-survivors (n = 29) and survivors (n = 36)—and the levels of RedOx markers were compared between them. Of all the markers, only higher GR activity was found to be significantly associated with the fatal outcome; 100.3 U/L versus 60.5 U/L, OR = 1.027 (95% CI, 1.010–1.044). Following adjustment for the sequential organ failure assessment score and other parameters, GR activity still presented a significant association with the fatal outcome, OR = 1.020 (95% CI, 1.002–1.038). Conclusions: GR activity is associated with in-hospital fatal outcomes among septic shock patients under early-initiated CVVH treatment. Septic shock patients who have a lower GR activity at hospital admission may have a favourable outcome of the early initiation of CVVH.

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“…Reprogramming of inflammation signaling is an important therapeutic target. In recent studies, ulinastatin has been demonstrated to attenuate I/R injury (including cerebral ischemia) in multiple stressed organs by suppressing inflammation (23,26,27). ICAM-1 is a chemokine that recruits immune cells to evoke an inflammatory response; IL-6, IL-1β, and IL-18 were important inflammatory cytokines secreted under nucleotide oligomerization domain (NOD)-like receptor 3 (NLRP3)enabled inflammation (28).…”

Section: Discussionmentioning

confidence: 99%

Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway

Cui¹,

Cao²,

Xia³

et al. 2020

Ann Transl Med

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Background: Ulinastatin, a urinary trypsin inhibitor, is one of the widely used auxiliary drugs in the rescue of acute circulatory failure. This study aims to explore the protective mechanisms of ulinastatin on cerebral ischemia-reperfusion (I/R) injury.Methods: A cerebral MCAO was established with middle cerebral artery occlusion (MCAO) in Sprague Dawley (SD) rats. Western blotting was employed to show protein expression. Oxidative stress markers [reactive oxygen species (ROS), superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione (GSH)] and inflammatory cytokines were analyzed to show oxidative stress and inflammation. Hematoxylin and eosin (HE) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and triphenyltetrazolium chloride (TTC) staining were applied to show brain injury.Results: HE, TUNEL and TTC staining indicated that ulinastatin significantly ameliorated cerebral I/R injury and reduced apoptotic cells in the MCAO brain tissue. Ulinastatin also reduced the MCAO-induced expression of intercellular adhesion molecule 1(ICAM-1)/caspase-3. Additionally, the highly expressed ROS, MDA and inflammatory cytokines (IL-6, IL-1β and IL-18) were significantly suppressed, and the inhibited SOD and GSH were recovered with ulinastatin treatment. Consequently, the expression of nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) (which was significantly inhibited by MCAO) was re-activated by ulinastatin and/or TBHQ (an Nrf-2 activator), and treatment with ML-385 (an Nrf-2 inhibitor) blocked the inhibition of apoptosis, inflammation, and oxidative stress by ulinastatin. Our results indicate that the Nrf-2/HO-1 signaling pathway may be involved in the pharmacological mechanism of ulinastatin in cerebral I/R injury.Conclusions: Ulinastatin protected against inflammation and oxidative stress in cerebral I/R injuries via activation of the Nrf-2/HO-1 signaling pathway.

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Ulinastatin attenuates liver injury and inflammation in a cecal ligation and puncture induced sepsis mouse model

Cited by 17 publications

References 25 publications

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation

Ulinastatin Exhibits Antinociception in Rat Models of Acute Somatic and Visceral Pain Through Inhibiting the Local and Central Inflammation

Glutathione Reductase Is Associated with the Clinical Outcome of Septic Shock in the Patients Treated Using Continuous Veno-Venous Haemofiltration

Ulinastatin alleviates cerebral ischemia-reperfusion injury in rats by activating the Nrf-2/HO-1 signaling pathway

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