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Objectives: Severe acute pancreatitis is a highly lethal disease caused by systemic inflammatory response syndrome, leading to multiple organ failure. We recently showed that histidine-rich glycoprotein (HRG) supplemental therapy ameliorated septic acute respiratory distress syndrome due to unnecessary neutrophil activation and immunothrombosis formation. Here, we evaluated the effect of HRG on lung inflammation followed by pancreatitis in a severe acute pancreatitis mouse model., Methods: Mice received intraperitoneal injections of cerulein 7 times (100 μg/kg each) at 1-hour intervals to induce acute pancreatitis. Immediately after the first cerulein injection, phosphate-buffered saline, human serum albumin (20 mg/kg), or HRG (20 mg/kg) was intravenously injected. One hour after the last cerulein injection, phosphate-buffered saline or lipopolysaccharide (5 mg/kg) was intravenously injected into the tail vein. We evaluated lung inflammatory level after pancreatitis., Results: We observed significantly decreased plasma HRG levels in an acute pancreatitis mouse model. Histidine-rich glycoprotein treatment inhibited lung edema and the accumulation of neutrophil in severe acute pancreatitis, but HRG did not directly affect pancreatitis. Moreover, HRG suppressed tumor necrosis factor α, inducible nitric oxide synthase, interleukin 6, and neutrophil elastase mRNA expression and myeloperoxidase activity in the lung., Conclusions: These data suggested that HRG ameliorated lung inflammation secondary to pancreatitis.

Objectives: Many biomarkers for sepsis are used in clinical practice; however, few have become the standard. We measured plasma histidine-rich glycoprotein levels in patients with systemic inflammatory response syndrome. We compared histidine-rich glycoprotein, procalcitonin, and presepsin levels to assess their significance as biomarkers., Design: Single-center, prospective, observational cohort study., Setting: ICU at an university-affiliated hospital., Patients: Seventy-nine ICU patients (70 with systemic inflammatory response syndrome and 9 without systemic inflammatory response syndrome) and 16 healthy volunteers., Interventions: None., Measurements and Main Results: We collected blood samples from patients within 24 hours of ICU admission. Histidine-rich glycoprotein levels were determined using enzyme-linked immunosorbent assay. The median histidine-rich glycoprotein level in healthy volunteers (n = 16) was 63.00 µg/mL (interquartile range, 51.53-66.21 µg/mL). Histidine-rich glycoprotein levels in systemic inflammatory response syndrome patients (n = 70; 28.72 µg/mL [15.74-41.46 µg/mL]) were lower than those in nonsystemic inflammatory response syndrome patients (n = 9; 38.64 µg/mL [30.26-51.81 µg/mL]; p = 0.049). Of 70 patients with systemic inflammatory response syndrome, 20 had sepsis. Histidine-rich glycoprotein levels were lower in septic patients than in noninfective systemic inflammatory response syndrome patients (8.71 µg/mL [6.72-15.74 µg/mL] vs 33.27 µg/mL [26.57-44.99 µg/mL]; p < 0.001) and were lower in nonsurvivors (n = 8) than in survivors (n = 62) of systemic inflammatory response syndrome (9.06 µg/mL [4.49-15.70 µg/mL] vs 31.78 µg/mL [18.57-42.11 µg/mL]; p < 0.001). Histidine-rich glycoprotein showed a high sensitivity and specificity for diagnosing sepsis. Receiver operating characteristic curve analysis for detecting sepsis within systemic inflammatory response syndrome patients showed that the area under the curve for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.97, 0.82, and 0.77, respectively. In addition, survival analysis in systemic inflammatory response syndrome patients revealed that the Harrell C-index for histidine-rich glycoprotein, procalcitonin, and presepsin was 0.85, 0.65, and 0.87, respectively., Conclusions: Histidine-rich glycoprotein levels were low in patients with sepsis and were significantly related to mortality in systemic inflammatory response syndrome population. Furthermore, as a biomarker, histidine-rich glycoprotein may be superior to procalcitonin and presepsin.

Background and Purpose: High mobility group box-1 (HMGB1) exhibits inflammatory cytokine-like activity in the extracellular space. We previously demonstrated that intravenous injection of anti-HMGB1 monoclonal antibody (mAb) remarkably ameliorated brain infarction induced by middle cerebral artery occlusion in rats. In the present study, we focused on the protective effects of the mAb on the marked translocation of HMGB1 in the brain, the disruption of the blood-brain barrier (BBB), and the resultant brain edema., Methods: Middle cerebral artery occlusion in the rat was used as the ischemia model. Rats were treated with anti-HMGB1 mAb or control IgG intravenously. BBB permeability was measured by MRI. Ultrastructure of the BBB unit was observed by transmission electron microscope. The in vitro BBB system was used to study the direct effects of HMGB1 in BBB components., Results: HMGB1 was time-dependently translocated and released from neurons in the ischemic rat brain. The mAb reduced the edematous area on T2-weighted MRI. Transmission electron microscope observation revealed that the mAb strongly inhibited astrocyte end feet swelling, the end feet detachment from the basement membrane, and the opening of the tight junction between endothelial cells. In the in vitro reconstituted BBB system, recombinant HMGB1 increased the permeability of the BBB with morphological changes in endothelial cells and pericytes, which were inhibited by the mAb. Moreover, the anti-HMGB1 mAb facilitated the clearance of serum HMGB1., Conclusions: These results indicated that the anti-HMGB1 mAb could be an effective therapy for brain ischemia by inhibiting the development of brain edema through the protection of the BBB and the efficient clearance of circulating HMGB1.

Objective: High-mobility group box protein 1 (HMGB1) is a DNA-binding protein and cytokine highly expressed in atherosclerotic lesions, but its pathophysiological role in atherosclerosis is unknown. We investigated its role in the development of atherosclerosis in ApoE-/- mice., Methods and Results: Apolipoprotein E-deficient (ApoE-/-) mice fed a high-fat diet were administered a monoclonal anti-HMGB1 neutralizing antibody, and the effects on lesion size, immune cell accumulation, and proinflammatory mediators were assessed using Oil Red O, immunohistochemistry, and real-time polymerase chain reaction. As with human atherosclerotic lesions, lesions in ApoE-/- mice expressed HMGB1. Treatment with the neutralizing antibody attenuated atherosclerosis by 55%. Macrophage accumulation was reduced by 43%, and vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 expression was attenuated by 48% and 72%, respectively. CD11c+ dendritic cells were reduced by 65%, and the mature (CD83+) population was reduced by 60%. Treatment also reduced CD4+ cells by nearly 50%. mRNAs in lesions encoding tumor necrosis factor-α and interleukin-1β tended to be reduced. Mechanistically, HMGB1 stimulated macrophage migration in vitro and in vivo; in vivo, it markedly augmented the accumulation of F4/80+Gr-1(Ly-6C)+ macrophages and also increased F4/80+CD11b+ macrophage numbers., Conclusions: HMGB1 exerts proatherogenic effects augmenting lesion development by stimulating macrophage migration, modulating proinflammatory mediators, and encouraging the accumulation of immune and smooth muscle cells.

The activation of T cells plays a role in antitumor response. Monocytes activate T cells by inducing the cell-to-cell interaction that involves the engagement of adhesion molecules with their ligands, and the production of IL-18. The authors examined the effect of the quinazoline-based alpha1-adrenergic receptor antagonists bunazosin, doxazosin, prazosin, and terazosin on the expression of adhesion molecules such as ICAM-1, B7.1, B7.2, CD40, and CD40L on monocytes isolated from human peripheral blood mononuclear cells. Doxazosin, prazosin, and terazosin induced the expression of ICAM-1 and CD40 but had no effect on the expression of B7.1, B7.2, and CD40L. Moreover, IL-18 was detected in the medium of incubated monocytes treated with doxazosin, prazosin, and terazosin. Bunazosin did not affect adhesion molecule expression and IL-18 production, suggesting that the chemical structure of quinazoline might not be related to the effect of doxazosin, prazosin, and terazosin. Although caspase-1 inhibitor completely abolished the production of IL-18, anti-IL-18 mAb and caspase-1 inhibitor partially inhibited the increase in ICAM-1 and CD40 expression induced by doxazosin, prazosin, and terazosin. Doxazosin, prazosin, and terazosin can induce monocyte activation with a specific pattern of expression of adhesion molecules and IL-18 production, and this may lead to T-cell activation through the cell-to-cell interaction. The activation of T cells induced by the increase of the expression of ICAM-1 and CD40 and the production of IL-18 may be involved in the anti-cancer effects of doxazosin, prazosin, and terazosin.

Background: The plasma interleukin (IL)-18 level is elevated in acute rejection after organ transplantation. Although beta2-adrenergic receptor (AR) agonists suppress the rejection of organ and tissue transplants, little is known about their action mechanisms. We examined the effects of endogenous catecholamines and beta2-AR agonists on the expression of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, CD40, and CD40 ligand (CD40L) in human mixed lymphocyte reaction (MLR) and in an in vitro model of acute rejection in the presence or absence of IL-18., Methods: ICAM-1, B7.1 B7.2, CD40, and CD40L expression on monocytes was measured by flow cytometry, and the production of interferon (IFN)-gamma and IL-12 was determined by enzyme-linked immunosorbent assay. Lymphocytes proliferation in MLR was measured by [3H]-thymidine uptake. The relevant AR subtypes were characterized using subtype-selective agonists and antagonists., Results: beta2-AR agonists inhibited the expression of ICAM-1 and CD40 during MLR in the absence of IL-18. Among IL-18-induced expression of ICAM-1, B7.1, B7.2, CD40, and CD40L, beta2-AR agonists inhibited ICAM-1 and CD40 expression. beta2-AR agonists prevented the production of IFN-gamma and IL-12 in the presence of IL-18 but had no effect in the absence of IL-18. beta2-AR agonists inhibited lymphocyte proliferation in IL-18-treated MLR., Conclusions: We found that beta2-AR agonists strongly inhibited the expression of ICAM-1 and CD40, irrespective of the presence or absence of IL-18, which is different from that of histamine and prostaglandin E2.

Background: The elevation of plasma interleukin (IL)-18 levels and the expression of intercellular adhesion molecule (ICAM)-1 and B7 on monocytes are involved in acute rejection. Prostaglandin (PG) E2 suppresses the rejection in animal transplantation models; however, little is known about its action mechanism. We examined the effect of PGE2 on the expression of ICAM-1 and B7 in the human mixed leukocyte reaction (MLR) in the presence or absence of IL-18., Methods: We measured the expression of ICAM-1, B7.1, and B7.2 on human monocytes by flow cytometry and determined the associated production of interferon-gamma and IL-12 by enzyme-linked immunosorbent assay. The modulatory effects of PGE2 and the relevant PGE2 receptor subtypes were characterized pharmacologically., Results: PGE2 inhibited the expression of ICAM-1, B7.1, and B7.2 on monocytes in MLR in a concentration-dependent manner. Whereas IL-18 significantly induced the expression of ICAM-1, B7.1, and B7.2 on monocytes in MLR and the production of interferon-gamma and IL-12, PGE2 inhibited these IL-18-initiated enhancements. The effects of PGE2 were mimicked by selective EP2 and EP4 agonists, but not by EP1 and EP3 agonists., Conclusion: PGE2 strongly inhibited MLR with respect to the expression of ICAM-1, B7.1, and B7.2 via the EP2 and EP4 receptors, irrespective of the presence or absence of IL-18. In the previous study, histamine inhibited ICAM-1 expression in the presence of IL-18 but had no effect in the absence of IL-18. These results indicate that the inhibitory effect of PGE2 may be more general and stronger than that of histamine and may play an important role in future immunosuppressive strategies.