Ulinastatin as a neuroprotective and anti‐inflammatory agent in infant piglets model undergoing surgery on hypothermic low‐flow cardiopulmonary bypass

Wang, Xiao-cou; Xue, Qiang; Yan, Fuxia; Li, Lihuan; Liu, Jinping; Li, Shoujun; Hu, Shengshou

doi:10.1111/pan.12073

Cited by 23 publications

(23 citation statements)

References 22 publications

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“…Activation of PAR-2 signal sensitize peripheral nociceptors and leads to a inflammatory pain. UTI is known to inhibit serine proteases, stabilize lysosomal membranes, and inhibit inflammatory cytokine production [7,18]. Thus, it was hypothesized that the inhibition of pro-inflammatory cytokine production by UTI may prevent the initiation of persistent neuropathic pain.…”

Section: Discussionmentioning

confidence: 99%

Urinary trypsin inhibitor attenuates the development of neuropathic pain following spinal nerve ligation

Lee

et al. 2015

Neuroscience Letters

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Section: Discussionmentioning

confidence: 99%

Urinary trypsin inhibitor attenuates the development of neuropathic pain following spinal nerve ligation

Lee

et al. 2015

Neuroscience Letters

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“…Although information is not available on the neuroprotective properties of the blood plasma derived IAIP complex (Lim, 2013), the light chain of IAIP exhibits neuroprotective properties and blocks production of inflammatory cytokines after ischemic injury in somatic organs (Cao, et al, 2000, El Maradny, et al, 1996, Kaga, et al, 1996, Kakinuma, et al, 1997, Koga, et al, 2010, Nakahama, et al, 1996, Shu, et al, 2011, Wang, et al, 2013, Yano, et al, 2003). Therefore, findings of the present study are the first to demonstrate that the blood plasma derived complex form of IAIP exhibits important neuroprotective properties.…”

Section: Discussionmentioning

confidence: 99%

“…The present results along with increasing evidence suggesting the efficacy of the IAIP derived light chain ( e.g . urinary trypsin inhibitor (UTI)) also known as ulinastatin or bikunin, to attenuate inflammation and reduce brain injury, emphasize the great potential for the blood plasma derived IAIP to attenuate neonatal brain injury (Baek, et al, 2003, Chaaban, et al, 2010, Chaaban, et al, 2009, Koga, et al, 2010, Singh, et al, 2010, Wang, et al, 2013, Yano, et al, 2003). We have previously demonstrated high levels of IAIPs in the brain of fetal, newborn, and adult sheep and in cerebral spinal fluid of fetal sheep (Spasova, et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

Effects of inter-alpha inhibitor proteins on neonatal brain injury: Age, task and treatment dependent neurobehavioral outcomes

Threlkeld

Gaudet

Rue

et al. 2014

Experimental Neurology

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Hypoxic-ischemic (HI) brain injury is frequently associated with premature and/or full term birth related complications. HI injury often results in learning and processing deficits that reflect widespread damage to an extensive range of cortical and sub-cortical brain structures. Further, inflammation has been implicated in the long-term progression and severity of HI injury. Recently, Inter-alpha Inhibitor Proteins (IAIPs) have been shown to attenuate inflammation in models of systemic infection. Importantly, preclinical studies of neonatal HI injury and neuroprotection often focus on single time windows of assessment or single behavioral domains. This approach limits translational validity, given evidence for a diverse spectrum of neurobehavioral deficits that may change across developmental windows following neonatal brain injury. Therefore, the aims of this research were to assess the effects of human IAIPs on early neocortical cell death (72 hours post insult), adult regional brain volume measurements (cerebral cortex, hippocampus, striatum, corpus callosum) and long-term behavioral outcomes in juvenile (P38-50) and adult (P80+) periods across two independent learning domains (spatial and non-spatial learning), after postnatal day 7 HI injury in rats. Here, for the first time, we show that IAIPs reduce acute neocortical neuronal cell death and improve brain weight outcome 72 hours following HI injury in the neonatal rat. Further, these longitudinal studies are the first to show age, task and treatment dependent improvements in behavioral outcome for both spatial and non-spatial learning following systemic administration of IAIPs in neonatal HI injured rats. Finally, results also show sparing of brain regions critical for spatial and non-spatial learning in adult animals treated with IAIPs at the time of injury onset. These data support the proposal that Inter-alpha Inhibitor Proteins may serve as novel therapeutics for brain injury associated with premature birth and/or neonatal brain injury and highlight the importance of assessing multiple ages, brain regions and behavioral domains when investigating experimental treatment efficacy.

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“…In addition, previous studies have demonstrated that UTI suppresses the elevation of IL-6 and IL-8 levels in patients undergoing coronary artery bypass grafting under extracorporeal circulation (18), alleviates forebrain I/R injury by inhibiting the production of superoxide radicals and intercellular adhesion molecule-1 (19) and improves oleic acid-induced acute lung injury by reducing TNF-α levels and inducing leukocyte activation (20). In addition, UTI has been proposed as a therapeutic option for endotoxin-associated inflammatory disorders, including acute lung and liver injuries (21), due to its anti-inflammatory properties (22)(23)(24). However, whether UTI protects against brain injury by inhibiting the inflammatory responses following CA is yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Postconditioning improvement effects of ulinastatin on brain injury following cardiopulmonary resuscitation

Sui

2014

Exp Ther Med

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Abstract. The aim of the present study was to determine the effects of ulinastatin (UTI) on brain injury in rats subjected to cardiopulmonary resuscitation (CPR) following asphyxial cardiac arrest (CA) and identify the underlying mechanisms. In total, 100 healthy male Wistar rats were randomly divided into control and treatment groups (n=50). After 4 min of asphyxial CA, all the rats were immediately subjected to CPR. The treatment group animals were administered 15 mg/kg UTI at the onset of resuscitation. The mortality rate in the two groups was recorded at 24 h post-resuscitation. In addition, neurological function was evaluated at 24, 48 and 72 h post-resuscitation using a neurological deficit scale (NDS). Furthermore, the effects of UTI on the Toll-like receptor 4 (TLR4) signaling pathway in brain tissues were determined by assessing TLR4 mRNA expression, nuclear factor (NF)-κB activity and tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels at 1, 3, 6, 12, 24, 48 and 72 h post-resuscitation. After 24 h, the mortality rate significantly decreased in the treatment group when compared with the control animals (10 vs. 30%; P<0.05). Additionally, an overt improvement was observed in the NDS score following UTI treatment when compared with the control (P<0.01). Finally, statistically significant decreases in the levels of TLR4 mRNA expression, NF-κB activity and TNF-α and IL-6 were observed in the treatment group at each time point (P<0.01). Therefore, UTI treatment at the onset of CPR significantly inhibits the TLR4 signaling pathway, thereby alleviating the inflammatory responses following resuscitation and improving neurological function.

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Ulinastatin as a neuroprotective and anti‐inflammatory agent in infant piglets model undergoing surgery on hypothermic low‐flow cardiopulmonary bypass

Abstract: In our study, HLF CPB on infant piglets resulted in brain injury, and ulinastatin might reduce the extent of such injury.

Cited by 23 publications

References 22 publications

Urinary trypsin inhibitor attenuates the development of neuropathic pain following spinal nerve ligation

Urinary trypsin inhibitor attenuates the development of neuropathic pain following spinal nerve ligation

Effects of inter-alpha inhibitor proteins on neonatal brain injury: Age, task and treatment dependent neurobehavioral outcomes

Postconditioning improvement effects of ulinastatin on brain injury following cardiopulmonary resuscitation

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