Biomimetic carbon monoxide delivery based on hemoglobin vesicles ameliorates acute pancreatitis in mice via the regulation of macrophage and neutrophil activity

Abstract

Macrophages play a central role in various inflammatory disorders and are broadly divided into two subpopulations, M1 and M2 macrophage. In the healing process in acute inflammatory disorders, shifting the production of M1 macrophages to M2 macrophages is desirable, because M1 macrophages secrete pro-inflammatory cytokines, whilst the M2 variety secrete anti-inflammatory cytokines. Previous findings indicate that when macrophages are treated with carbon monoxide (CO), the secretion of anti-inflammatory cytokine is increased and the expression of pro-inflammatory cytokines is inhibited, indicating that CO may have a potential to modulate the production of macrophages toward the M2-like phenotype. In this study, we examined the issue of whether CO targeting macrophages using a nanotechnology-based CO donor, namely CO-bound hemoglobin vesicles (CO-HbV), modulates their polarization and show therapeutic effects against inflammatory disorders. The results showed that the CO-HbV treatment polarized a macrophage cell line toward an M2-like phenotype. Furthermore, in an in vivo study using acute pancreatitis model mice as a model of an inflammatory disease, a CO-HbV treatment also tended to polarize macrophages toward an M2-like phenotype and inhibited neutrophil infiltration in the pancreas, resulting in a significant inflammation. In addition to the suppression of acute pancreatitis, CO-HbV diminished a subsequent pancreatitis-associated acute lung injury. This could be due to the inhibition of the systemic inflammation, neutrophil infiltration in the lungs and the production of HMGB-1. These findings suggest that CO-HbV exerts superior anti-inflammatory effects against inflammatory disorders via the regulation of macrophage and neutrophil activity.

Emerging Delivery Strategies of Carbon Monoxide for Therapeutic Applications: from CO Gas to CO Releasing Nanomaterials

“…Afterward, the anti‐inflammatory effect of CO releasing nanocomposites has also been confirmed in inflammation‐related animal models such as colitis and acute pancreatitis . Nagao et al investigated the therapeutic potential of CO‐hemoglobin vesicles (CO‐HbV) in dextran sulfate sodium (DSS)‐induced murine colitis models.…”

“…The protective effects of CO‐HbV on colitis can owe to the reduction of neutrophil accumulation as well as the decrease of oxidative injuries. Taguchi et al reported that in acute pancreatitis mice model, CO derived from CO‐HbV could not only attenuate the infiltration of neutrophils in pancreatic tissue, but also skew the polarization of macrophage toward an M2‐like phenotype, ultimately leading to a dramatical suppression in the intensity of pancreatic injury. Apart from the attenuation of acute pancreatitis, CO‐HbV nanocomposites could also diminish the pancreatitis‐associated damage to distal organs including liver, kidneys and lungs .…”

“…Taguchi et al reported that in acute pancreatitis mice model, CO derived from CO‐HbV could not only attenuate the infiltration of neutrophils in pancreatic tissue, but also skew the polarization of macrophage toward an M2‐like phenotype, ultimately leading to a dramatical suppression in the intensity of pancreatic injury. Apart from the attenuation of acute pancreatitis, CO‐HbV nanocomposites could also diminish the pancreatitis‐associated damage to distal organs including liver, kidneys and lungs . In a carrageenan‐induced rat paw edema model, CORM‐2‐loaded lipid nanoparticles with extended CO release half‐life and improved water solubility displayed higher anti‐inflammatory effects compared to both indomethacin and CORM‐2 solution (Figure a) .…”

Current trends in pharmacological approaches for treatment and management of acute pancreatitis – a review

“…This study proved the protective effect of CO-HbV in AP-induced multiorgan damage. [63,64] In another study, two-generation 5 (G5) polyamidoamine (PAMAM) dendrimers with distinct surface groups G5-OH and G4.5-COOH were investigated for their potential to treat pancreatic injury in caerulein-induced mouse model of AP. Both the dendrimers significantly reduced inflammatory infiltration of macrophages into the pancreatic tissues thereby decreasing the pathological changes in pancreas.…”

Drug discovery and formulation development for acute pancreatitis

“…It may be due to the inhibition of systemic inflammation, lung neutrophil infiltration and HMGB-1 production. Biomimetic CO delivery based on the hemoglobin vesicle was also found to improve acute pancreatitis treatment by regulating the polarization of its macrophages toward M2-type (Taguchi et al., 2018 ). Peritoneal puncture and drainage can improve the therapeutic effect of acute pancreatitis by regulating the M2-type polarization of macrophages (Liu et al., 2018 ), which suggests that macrophages might serve as therapeutic target in pancreatitis.…”