The Protective Function of Neutrophil Elastase Inhibitor in Liver Ischemia/Reperfusion Injury

Abstract

Background A neutrophil elastase (NE) inhibitor, Sivelestat, has been approved for the treatment of acute lung injury associated with systemic inflammation in humans. Some reports have also shown its protective effects in liver inflammatory states. We have recently documented the importance of NE in the pathophysiology of liver ischemia and reperfusion injury (IRI), a local Ag-independent inflammation response. This study was designed to explore putative cytoprotective functions of clinically available Sivelestat in liver IRI. Methods Partial warm ischemia was produced in the left and middle hepatic lobes of C57BL/6 mice for 90 min, followed by 6 or 24 h of reperfusion. Mice were given Sivelestat (100 mg/kg, s.c.) at 10 min prior to ischemia, 10 min prior to reperfusion, and at 1 h and 3 h of reperfusion thereafter. Results Sivelestat treatment significantly reduced serum ALT levels and NE activity, as compared with controls. Histological liver examination has revealed that unlike in controls, Sivelestat ameliorated the hepatocellular damage and decreased local neutrophil activity and infiltration. The expression of pro-inflammatory cytokines (TNF-α, IL-6), chemokines (CXCL-1, CXCL-2, CXCL-10) and TLR4 was significantly reduced in the treatment group, along with diminished apoptosis via caspase-3 pathway. Moreover, in vitro studies confirmed downregulation of pro-inflammatory cytokine and chemokine programs in mouse macrophage cell cultures, along with depression of innate TLR4 signaling. Conclusion Sivelestat-mediated NE inhibition may represent an effective therapeutic option in liver transplantation and other inflammation disease states.

Paeoniflorin attenuates hepatic ischemia/reperfusion injury via anti-oxidative, anti-inflammatory and anti-apoptotic pathways

“…In addition, PF has been shown to protect the blood-brain barrier following cerebral perfusion during ischemia, and promote the recovery of cerebral blood flow in the early period of reperfusion. PF can also significantly increase SOD levels in rat brain tissue, decrease malondialdehyde (MDA) levels, and alleviate oxidative stress injury in brain tissue caused by cerebral ischemia (16). Previous studies have demonstrated that PF may markedly reduce the expression levels of nuclear factor (NF)-κB (15,17).…”

“…Furthermore, Cao et al (15) demonstrated a protective effect of PF on the blood-brain barrier following cerebral ischemia, as well as on local cerebral blood flow and brain edema. Furthermore, it has been indicated that PF may have a significant protective role in focal cerebral ischemic injury, by inhibiting intracellular calcium overload, protecting against free radicals, and improving cerebral vasomotor dysfunction caused by ischemia and anoxia (16). In addition, PF has been shown to protect the blood-brain barrier following cerebral perfusion during ischemia, and promote the recovery of cerebral blood flow in the early period of reperfusion.…”

The role of neutrophils in the development of liver diseases

“…The expression of L-selectin and b2 integrin (CD11b/CD18) on neutrophils has been shown to be important for adherence to the surface of sinusoidal endothelial cells and hepatocytes. 20 Furthermore, CD44 plays a pivotal role in neutrophil infiltration in murine hepatic I/R injury. Liver histology confirmed that the administration of an anti-CD44 antibody decreased the number of infiltrating neutrophils and improved sinusoidal congestion and hepatocellular necrosis.…”

Synthesis, antielastase, antioxidant and radical scavenging activities of 4-(aza substituted) methylene substituted dihydroxy coumarines

“…Excessive neutrofil elastase activity can lead to severe pathology through the degradation of elastin and collagen in the airways, resulting in microvascular injury and interstitial edema 6 . The human neutrophil elastase (HNE) is believed to play an important role in the pathophysiology of an array of inflammatory diseases, including chronic obstructive pulmonary disease (COPD) 7 , cystic fibrosis 8 , acute respiratory distress syndrome 9 , and ischemia/reperfusion injury 10 . Coumarins and their derivatives have been found to exhibit a variety of biological and pharmacological activities and have raised considerable interest because of their potential beneficial effects on human health 11 .…”