EDITORIAL article Front. Physiol., 01 March 2023Sec. Vascular Physiology Volume 14 - 2023 | https://doi.org/10.3389/fphys.2023.1161720

Ischemia and reperfusion of intestinal tissue (intestinal I/R) induce disruption of ileal contractility and chain responses of inflammatory. The aim of this study was to reveal whether therapeutic value of cannabinoid 2 (CB2) receptor activity in the intestinal I/R, via to the exogenous administration of CB2 agonist (AM-1241). Intestinal I/R injury were performed through 30-min ischemia and 150-min reperfusion of mesenteric artery in Wistar rats. The pre-administered doses of 0.1, 1, and 5 mg/kg of CB2 agonist were studied to inhibit inflammation of intestinal I/R injury including ileum smooth muscle contractility, polymorphonuclear cell migration, oxidant/antioxidant defense system, and provocative cytokines. Pre-administration with CB2 receptor agonist ensured to consider improving the disrupted contractile responses in ileum smooth muscle along with decreased the formation of MDA that production of lipid peroxidation, reversed the depleted glutathione, inhibited the expression of TNF-alpha and of IL-1 beta in the intestinal I/R of rats. Taken together results of this research, the agonistic activity of CB2 receptor for healing of intestinal I/R injury is ensuring associated with anti-inflammatory mechanisms such as the inhibiting of migration of inflammatory polymorphonuclear cells that origin of acute and initial responses of inflammation, the inhibiting of production of provocative and pro-inflammatory cytokines like TNF-alpha and IL-1 beta, the rebalancing of oxidant/antioxidant redox system disrupted in injury of reperfusion period and the supporting of physiologic defensive systems in endothelial and inducible inflammatory cells.

BACKGROUND Tetrahydrobiopterin (BH4), an endogenous nucleic acid derivative, acts as an important cofactor for several enzymes found within the vascular endothelium, which is deranged in sepsis. OBJECTIVE We hypothesized that BH4 would improve capillary density and decrease inflammation within the intestinal microcirculation of septic rats. METHODS We conducted a randomized, controlled trial using two previously validated models of sepsis in rats: 1) A fecal peritonitis model using a stent perforating the ascending colon, and 2) An endotoxemia model using lipopolysaccharide (LPS) toxin from E. coli. Experimental groups receiving BH4 (60 mg/kg) were compared to otherwise healthy controls and to untreated groups with sepsis-like physiology. RESULTS BH4 decreased leukocyte-endothelial adhesion by 55% and 58% (P < 0.05) in the peritonitis model and endotoxemia models, respectively. In the endotoxemia model but not the peritonitis model, BH4 improved functional capillary density in capillary beds within the intestine (141.3 vs. 106.7 mm/cm2, p < 0.05). Macrohemodynamic parameters were no different between placebo treatment and BH4-treated groups. CONCLUSIONS This study demonstrates that BH4 improves capillary density and inflammation in two separate models of sepsis. BH4 may represent a novel adjunct in the treatment of sepsis and septic shock in clinical practice. Further dose-finding studies and clinical trials are warranted.

The ocular microcirculation represents an important target to treat inflammatory diseases of eye, where impairment of microvascular blood flow plays key role as, for example, in anterior uveitis. To evaluate novel interventions targeting the microcirculation, appropriate and reliable tools to study this particular microvascular bed are needed. Intravital microscopy (IVM) belongs to several methods allowing evaluation of microcirculation experimentally, even in small animals. The aim of our study was to examine the iridial microcirculation (IMIC) in uveitis induced by local or systemic endotoxin administration in rats and mice by IVM and to propose new parameters to quantify the changes within the IMIC. Systemic inflammation was induced in rats by intravenous endotoxin administration, control group received normal saline intravenously. Local inflammation was induced in mice by intravitreal endotoxin administration, the control group received normal saline intravitreally. IVM of IMIC was performed in animals receiving systemic endotoxin prior injection and 1 and 2 h afterwards, respectively, in animals receiving intravitreal endotoxin/saline prior local injection and 5 h afterwards. Obtained video recordings were analyzed off-line. Functional capillary density (FCD) and dysfunctional capillary density (DCD) were evaluated for description of IMIC, and calculation of FCD/DCD ratio was performed. In systemic inflammation, FCD was significantly decreased compared to control animals. In local inflammation, the number of functional capillaries in the IMIC was significantly reduced following the endotoxin challenge. Analysis of the DCD revealed a significant increase in capillaries with reduced perfusion after intravitreal endotoxin administration and right shift of the FCD/DCD ratio was observed after endotoxin local injection. Detecting and quantifying changes in IMIC during systemic or local inflammation in experimental animals by IVM was feasible. Therefore, IVM of the IMIC represents a valuable tool to evaluate and quantify inflammatory changes in experimental eye disease.

Intravital microscopy of the intestine is a sophisticated technique that allows qualitative and quantitative in vivo observation of dynamic cellular interactions and blood flow at a high resolution. Physiological conditions of the animal and in particular of the observed organ, such as temperature and moisture are crucial for intravital imaging. Often, the microscopy stage with the animal or the organ of interest imposes limitations on how well the animal can be maintained. In addition, the access for additional oxygen supply or drug administration during the procedure is rather restricted. To address these limitations, we developed a novel intravital microscopy platform, allowing us to have improved access to the animal during the intravital microscopy procedure, as well as improved microenvironmental maintenance. The production process of this prototype platform is based on 3D printing of device parts in a single-step process. The simplicity of production and the advantages of this versatile and customizable design are shown and discussed in this paper. Our design potentially represents a major step forward in facilitating intestinal intravital imaging using fluorescent microscopy.

The endocannabinoid system (ECS) is involved in many physiological processes and has been suggested to play a critical role in the immune response and the central nervous system (CNS). Therefore, ECS modulation has potential therapeutic effects on immune dysfunctional disorders, such as sepsis and CNS injury-induced immunodeficiency syndrome (CIDS). In sepsis, excessive release of pro- and anti-inflammatory mediators results in multi-organ dysfunction, failure, and death. In CIDS, an acute CNS injury dysregulates a normally well-balanced interplay between CNS and the immune system, leading to increased patients’ susceptibility to infections. In this review, we will discuss potential therapeutic modulation of the immune response in sepsis and CNS injury by manipulation of the ECS representing a novel target for immunotherapy.

Proliferative vitreoretinopathy (PVR) can develop after ocular trauma or inflammation and is a common complication of surgery to correct retinal detachment. Currently, there are no pharmacological treatments for PVR. Cannabinoids acting at cannabinoid 2 receptor (CB2R) can decrease inflammation and fibrosis. The objective of this study was to examine the anti-inflammatory actions of CB2R as a candidate novel therapeutic target in experimental PVR. PVR was induced by intravitreal injection of dispase in wild-type (WT) and CB2R genetic knockout (CB2R(-/-)) mice. Ocular pathology was studied at 24 h or one week after dispase injection. CB2R modulation was examined in WT mice, using the CB2R agonist, HU308, and the CB2R antagonist, AM630. Histopathological scoring and quantification of microglia was used to evaluate tissue pathology. Quantitative PCR and multiplex assays were used to assess changes in proinflammatory cytokines. Intravital microscopy (IVM) was used to visualize and quantify leukocyte endothelial adhesion to the iridial microcirculation. Activation of CB2R with HU308 in WT mice with PVR decreased mean histopathological scores, the number of microglia, and leukocyte adhesion compared to vehicle-treated animals. Conversely, an increase in histopathological scores and activated microglia was observed in PVR animals after treatment with AM630. CB2R(-/-) mice with PVR exhibited exacerbated ocular histopathology, increased microglia numbers, and elevated protein levels of cytokines as compared to WT mice. In conclusion, our results indicate that intervention at early stage PVR with CB2R agonists reduces ocular inflammation and disease severity. CB2R may represent a therapeutic target to prevent PVR progression and vision loss.This article is part of the Special Issue entitled `Lipid Sensing G Protein-Coupled Receptors in the CNS'. Crown Copyright (C) 2016 Published by Elsevier Ltd. All rights reserved.

Central nervous system (CNS) injury, such as stroke, is known to increase susceptibility to infections that adversely affect clinical outcome. This impaired immune response to infection is termed CNS injury-induced immune deficiency syndrome (CIDS). Activation of the cannabinoid 2 receptor (CB2R) suppresses immune function suggesting that antagonism of this receptor may overcome CIDS. The main purpose of this study was to determine the impact of CB2R inhibition on leukocyte activation within the microcirculation following endotoxin challenge in an experimental stroke model.

Since iron can contribute to detrimental radical generating processes through the Fenton and Haber-Weiss reactions, it seems to be a reasonable approach to modulate iron-related pathways in inflammation. In the human organism a counterregulatory reduction in iron availability is observed during inflammatory diseases. Under pathological conditions with reduced or increased baseline iron levels different consequences regarding protection or susceptibility to inflammation have to be considered. Given the role of iron in development of inflammatory diseases, pharmaceutical agents targeting this pathway promise to improve the clinical outcome. The objective of this review is to highlight the mechanisms of iron regulation and iron chelation, and to demonstrate the potential impact of this strategy in the management of several acute and chronic inflammatory diseases, including cancer.

SummaryFor microcirculation research there is a need for baseline data and feasibility protocols describing microcirculation of various organs. The aim of our study was to examine the reliability and reproducibility of sidestream dark‐field (SDF) imaging within the renal cortical microcirculation in rats. Renal microcirculation was observed using SDF probe placed on the exposed renal surface via the upper midline laparotomy. Video sequences recorded intermittently in short apneic pauses were analyzed off‐line by using AVA 3.0 software (MicroVision Medical, Amsterdam, the Netherlands). Results are expressed as mean (SD) or median (25–75% percentiles). We obtained 60 clear sequences from all recorded analyzable videos from all the animals. The total small vessel and all vessel density (in mm.mm–2) were (28.79 ± 0.40) and (28.95 ± 0.40), respectively. The perfused small and all vessel density were (28.79 ± 0.40) and (28.95 ± 0.40), respectively. The DeBacker Score was (19.14 ± 0.43), the proportion of perfused vessels was 100% (100–100%) and the microvascular flow index was 3.49 (3–3.75). We conclude SDF imaging provides a reliable method to examine the renal microvascular bed in vivo and thus can be used for the study of the renal cortical vascular network in various experimental diseases models and clinical settings.

BACKGROUND:Leukocyte adhesion to the endothelium and decreased microvascular blood flow causing microcirculatory dysfunction are hallmarks of systemic inflammation. We studied the impact of cannabinoid receptor activation on the iridial microcirculation, which is accessible non-invasively in vivo, in systemic inflammation induced by endotoxin challenge. METHODS:40 Lewis rats were used in the experiments. Endotoxemia was induced by 2 mg/kg i.v. lipopolysaccharide (LPS). Cannabinoid receptors (CBRs) were stimulated by i.v. administration of WIN 55212-2 (WIN; 1 mg/kg). CB1R antagonist (AM281; 2.5 mg/kg i.v.) or CB2R antagonist (AM630; 2.5 mg/kg i.v.) treatment prior to WIN was applied to identify the anti-inflammatory effects underlying each CBR subtype. Leukocyte-endothelial interactions were examined in rat iridial microvas culature by intravital microscopy at baseline and 1 and 2 h post-LPS. Additionally, systemic (mean arterial pressure, heart rate) and local (laser Doppler flow) hemodynamic variables were measured prior to and during cannabinoid treatments. RESULTS:Endotoxemia resulted in severe inflammation as shown by significantly increased numbers of adherent leukocytes at 1 and 2 h observation time post-LPS challenge and decreased microcirculatory blood flow at 2 h within the iridial microcirculation. WIN treatment significantly reduced leukocyte adhesion in iridial microvessels with a diameter greater and less than 25 μm during endotoxemia (p <  0.05). Pre-treatment of animals by CB1R antagonist, AM281, did not affect WIN effects on LPS-induced leukocyte adhesion. When pre-treated with the CB2R antagonist, AM630, a reversal of the WIN-induced reduction in leukocyte adhesion was noticed in vessels with a diameter of less than 25 μm (p <  0.05). Cannabinoid treatment significantly increased the local iridial microcirculatory blood flow 2 hours after systemic LPS administration (p <  0.05). CONCLUSIONS:Systemic administration of the CBR agonist, WIN, decreased leukocyte-adhesion and improved iridial microvascular blood flow. This effect is most likely mediated by CB2R activation. Our findings indicate that the iris microvasculature can serve as a model to study the microcirculation during systemic inflammation and help to identify potential therapies to treat microcirculatory dysfunction in diseases such as sepsis.