High-mobility group box 1 protein and its role in severe acute pancreatitis

Table 1 Systemic inflammatory response syndrome

Finding	Value
Temperature	< 36 °C or > 38 °C
Heart rate	> 90 beats/min
Respiratory rate	> 20/min or PaCO2 < 32 mmHg (4.3 kPa)
WBC	< 4 × 109/L (< 4000/mm³), > 12 × 109/L (> 12000/mm³), or > 10% bands

WBC: White blood cell.

Table 2 Relationship between high mobility group box 1 protein and severe acute pancreatitis

Ref.	Journal	Country	Subject	Method	Result
Yasuda et al[75]	Pancreas	Japan	Patients with SAP	Control group: healthy volunteers (n = 8); Experimental group: patients with SAP (n = 45)	Serum HMGB1 levels were significantly increased in patients with SAP and were correlated with disease severity
Kocsis et al[78]	Pancreatol	Hungary	Patients with AP	Control group: healthy volunteers (n = 20); AP group: patients with pancreatitis and divided into mild (n = 32) and severe (n = 30) subgroups; Sepsis group: patients with sepsis (n = 20)	HMGB1 was significantly elevated in the plasma of SAP patients compared with healthy and mild pancreatitis patients, and was correlated with procalcitonin concentrations. There was an inverse correlation between the levels of sRAGE and HMGB1 in patients with SAP. Circulating DNA was significantly elevated in patients with severe pancreatitis or sepsis and was related to the severity scores
Lindström et al[80]	Pancreas	Finland	Patients with AP	Grade 0: mild AP (n = 282); Grade 1: SAP without organ failure (n = 135); Grade 2: SAP with organ failure (n = 38)	Serum HMGB1 level is comparable in three groups, but sRAGE is significantly higher in AP patients who develop organ failure compared to AP patients who recover without organ failure
Yuan et al[84]	Pancreas	China	Male ICR mice	Control group: SAP mice (n = 24); Treatment group: SAP mice treated with recombinant HMGB1 A box protein 12 (n = 12) and 24 h (n = 12) after the modeling injection	HMGB1 A box can decrease the serum HMGB1 levels, attenuate organ dysfunction and improve the survival of SAP mice. Thus, it has a remarkable protective effect against pancreatitis and associated organ injury
Luan et al[82]	Immunobiol	China	Male Wistar rats	Control group: sham operation; SAP group: SAP-induced rats; Treated groups: SAP-induced rats treated with pRNA-U6.1/Neo-HMGB1 (containing siRNA targeting human HMGB1)	Downregulation of HMGB1 by using siRNA could inhibit the activation of NF-κB in SAP rats so as to decrease the levels of downstream inflammatory cytokines, alleviate endothelial permeability and attenuate severe pancreatitis-associated acute lung injury
Kang et al[86]	Gastroenterol	United States	HMGB1 flox/flox and Pdx1-Cre transgenic mice	AP group: AP-induced mice; Control group: administered with saline as a control	Deficiency of endogenous HMGB1 could escalate local inflammation through destabilization of the nucleus and enable rapid DNA and histone release, resulting in accelerated tissue injury and lethality, indicating that intracellular HMGB1 appears to have a protective effect against inflammation

AP: Acute pancreatitis; HMGB1: High mobility group box 1 protein; SAP: Severe acute pancreatitis; sRAGE: Soluble receptors for advanced glycation end-products.

Table 3 Effect of high mobility group box 1 protein inhibitors in preventing against severe acute pancreatitis

Ref.	Journal	Country	Subject	HMGB1 inhibitor	Method	Result
Sawa et al[76]	World J Gastroenterol	Japan	Female C3H/HeN mice	Anti-HMGB1 neutralizing antibody	Group A: sham, laparotomy with saline injection (n = 6); Group B: SAP, SAP with saline injection (n = 20); Group C: HMGB1 Ab + SAP, SAP with anti-HMGB1 antibody injection (n = 12)	Blockade of HMGB1 in the early phase is useful as a new therapeutic option against the inflammatory response and MODS in patients with SAP
Yang et al[96]	Crit Care Med	United States	Male C57BL/6 mice	EP	RLS group: mice were injected with RLS; REPS group: mice were treated with REPS; Control group: mice were injected with PBS	Delayed treatment with EP downregulated the inflammatory response through decreasing the release of pro-inflammatory cytokines and attenuated the development of both local and distant organ dysfunction, improving survival in a murine model of severe necrotizing pancreatitis
Cheng et al[97]	Pancreas	China	Male Wistar rats	EP	Group A: SAP-induced rats; Group B: moderate pancreatitis-induced rats; Group C: mild pancreatitis-induced rats; Control group: rats received the same dose of vehicle solution	A strong correlation between levels of HMGB1 and severity of acute pancreatitis. Treatment with EP significantly protected against SAP lethality and ameliorated extrapancreatic tissue and organ injury or dysfunction in rats with SAP
Yang et al[112]	World J Gastroenterol	China	Male Wistar rats	EP	Group I: sham operation (n = 32); Groups II: SAP-induced rats and treated with EP (n = 32); Groups III: SAP-induced rats (n = 32)	Serum HMGB1 evaluated significantly in SAP rats, whereas delayed EP administration can significantly reduce the serum level of HMGB1 as well as AST, ALT and Cr level and prolong the survival time in rats
Yang et al[99]	J Surg Res	United States	Male C57Bl/6 mice	EP	Control group: injected with PBS; EP group: SAP-induced mice and treated with EP; RLS group: SAP-induced mice and treated with RLS	EP is able to inhibit NF-κB DNA binding, decrease the level of both early inflammatory cytokines such as TNF-α, IL-6, COX-2, and iNOS and late proinflammatory mediator (HMGB1), reduce inflammatory cells infiltration, and reverse hepatic oxidative stress, thus protecting hepatocytes from SAP-induced injury. Thus, treatment with EP ameliorates hepatocellular injury and redox stress in the setting of SAP
Luan et al[81]	Pancreas	China	Male Wistar rats	EP	Control group: sham operation (n = 20); SAP group: SAP-induced rats (n = 20); EP-treated group: SAP-induced rats and treated with EP (n = 20)	HMGB1 contributes to the development of gut barrier dysfunction after SAP. Intestinal HMGB1 levels were significantly increased in rats with SAP and were correlated with the severity of intestinal barrier dysfunction
Luan et al[100]	Pancreas	China	Male Wistar rats	EP	Control group: sham operation (n = 8); SAP group: SAP-induced rats (n = 8); EP-treated group: SAP-induced rats and treated with EP (n = 8)	EP administration inhibits NF-κB activation to suppress the expression of both early (TNF-α, IL-1β) and late (HMGB1) cytokines that mediate liver injury after SAP and reduces liver injury in SAP rats. Thus EP can provide durable protection against the deleterious effects of proinflammatory cytokines and HMGB1
Luan et al[98]	J Surg Res	China	Male Wistar rats	EP	Control group: sham procedure (n = 48); SAP group: SAP-induced rats (n = 48); EP-treated group: SAP-induced rats and treated with EP (n = 48)	EP attenuates taurocholate-induced pancreatitis and pancreas injury, decreases the taurocholate-induced pancreatic expression of TNF-α and HMGB1, alleviates neutrophil infiltration and lipid peroxidation in the pancreas and decreases NF-κB DNA binding activity as well
Luan et al[113]	Clin Exp Immunol	China	Male Wistar rats	EP	Control group: sham procedure (n = 48); SAP group: SAP-induced rats (n = 48); EP-treated group: SAP-induced rats and treated with EP (n = 48)	EP can reduce the lung permeability index in mice with LPS-induced acute lung injury in a dose-dependent way. The protective effect is associated with a reduction in both early (TNF-α and IL-1β) and late (HMGB1) cytokine levels by inhibiting NF-κB activity
Zhang et al[103]	Dig Dis Sci	China	Male Sprague-Dawley rats	antioxidant PDTC	Sham operation group (n = 48); SAP group (n = 48); PDTC-treated group (n = 48)	HMGB1 is a late cytokine mediator that plays an important role in the pathogenesis of SAP. PDTC pre-administration might inhibit NF-κB activation to inhibit the production of HMGB1 and reduce pancreas injury in SAP rats; but PDTC was less effective when it was given 2 h after the induction of pancreatitis
Jo et al[107]	World J Gastroenterol	Korea	C57BL/6 mice	SSM	Control group: mice were treated with saline; AP group: mice with induced AP; SSM group: divided into three subgroups: SSM 0.1 g/kg + AP; SSM 0.5 g/kg + AP; SSM 1 g/kg + AP	SSM pre-treat decreased HMGB1 and other cytokines such as TNF-α and IL-1β in AP mice. It also played a protective role during the development of AP and pancreatitis-associated lung injury via deactivating c-Jun NH2-terminal kinase, p38 and NF-κB

MODS: Multiorgan dysfunction; ALT: Alanine transaminase; AP: Acute pancreatitis; AST: Aspartate transaminase; COS: Cyclooxygenase; Cr: Creatinine; EP: Ethyl pyruvate; IL: Interleukin; iNOS: Inducible nitric oxide synthase; LPS: Lipopolysaccharide; NF: Nuclear factor; PDTC: Pyrrolidine dithiocarbamate; REPS: Ringer’s ethyl pyruvate solution; RLS: Ringer’s lactate solution; SSM: Scolopendra subspinipes mutilans; TNF: Tumor necrosis factor.