Human thrombin-derived host defense peptides inhibit neutrophil recruitment and tissue injury in severe acute pancreatitis

Abstract

Severe acute pancreatitis (AP) is characterized by leukocyte infiltration and tissue injury. Herein, we wanted to examine the potential effects of thrombin-derived host defense peptides (TDPs) in severe AP. Pancreatitis was provoked by infusion of taurocholate into the pancreatic duct or by intraperitoneal administration of l-arginine in C57BL/6 mice. Animals were treated with the TDPs GKY20 and GKY25 or a control peptide WFF25 30 min before induction of AP. TDPs reduced blood amylase levels, neutrophil infiltration, hemorrhage, necrosis, and edema formation in the inflamed pancreas. Treatment with TDPs markedly attenuated the taurocholate-induced increase in plasma levels of CXCL2 and interleukin-6. Moreover, administration of TDPs decreased histone 3, histone 4, and myeloperoxidase levels in the pancreas in response to taurocholate challenge. Interestingly, administration of TDPs abolished neutrophil expression of Mac-1 in mice with pancreatitis. In addition, TDPs inhibited CXCL2-induced chemotaxis of isolated neutrophils in vitro. Fluorescent-labeled TDP was found to directly bind to isolated neutrophils. Finally, a beneficial effect of TDPs was confirmed in l-arginine-induced pancreatitis. Our novel results demonstrate that TDPs exert protective effects against pathological inflammation and tissue damage in AP. These findings suggest that TDPs might be useful in the management of patients with severe AP.

Research update for articles published in EJCI in 2014

“…In the 2 years following the publication of the study ‘Treatment with Evasin‐3 abrogates neutrophil‐mediated inflammation in mouse acute pancreatitis’ , two studies confirmed our results about the chemokine upregulation in mouse models of acute pancreatitis . Specifically, Merza and co‐workers observed a 20‐fold increase of CXCL2, whereas data from Yu et al .…”

The Thrombin-Derived Host Defense Peptide GKY25 Inhibits Endotoxin-Induced Responses through Interactions with Lipopolysaccharide and Macrophages/Monocytes

“…Previous results show that the prototypic GKY25 inhibits the proinflammatory response, reduces tissue factor-mediated coagulation, as well as mortality in experimental models of endotoxin shock and P. aeruginosa sepsis (17). Furthermore, in a nonbacterial but TLR4-dependent murine pancreatitis model, GKY25 demonstrates potent anti-inflammatory effects (36). In the present study, the insights on the peptide's interference with TLR signaling, along with the demonstration that the peptide binds to monocytic cells also in vivo, thus indicate that GKY25 mediates its activity during infection and inflammation via multiple interactions involving bacteria, endotoxins, and inflammatory cells.…”

HMGB1 and Histones Play a Significant Role in Inducing Systemic Inflammation and Multiple Organ Dysfunctions in Severe Acute Pancreatitis

“…The inflammatory cytokines play a crucial role in the pathogenesis of SAP [6, 7, 15, 16] and the late proinflammatory cytokine HMGB1 is particularly important in SAP [17, 18], because the circulating HMGB1 levels can reflect the disease severity and are potent in augmenting systemic inflammation [17, 18], and emerging evidence shows that HMGB1 is also an important factor that mediates 85% of the gut BT in acetaminophen hepatotoxicity [19]; therefore, it is possible that HMGB1 also mediates BT in SAP. Except HMGB1, new investigations show that extracellular histones and DNAs might also significantly contribute to multiple organ injury during SAP [20–23]. Because hepatic KCs are the predominant source of circulating inflammatory cytokines (including HMGB1) in SAP [8], and new evidence indicates that hepatocyte is another important source of circulating HMGB1 in SAP [15, 16]; therefore, the inflamed liver is an important contributor to the circulating HMGB1 and the liver is a promising therapeutic target to prevent BT and systemic inflammation during SAP.…”

“…The necrotic tissue/the dying cells release HMGB1 and histones as DAMPs [57]; therefore, circulating histones are significantly increased in both SAP patients and experimental animals with SAP [20–23] and the circulating histones levels reflect the disease severity in experimental AP [21]. …”

“…Reduced pancreatic injury is associated with decreased histones 3 and histone 4 levels in the pancreas in response to taurocholate challenge [23], suggesting that histones are associated with pancreatic injury during SAP. The extracellular histones kill endothelial cells and are one of the major mediators of death in sepsis [58].…”