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Microvesicles (MVs), a plasma membrane-derived subclass of extracellular vesicles, are produced and released into the circulation during systemic inflammation, yet little is known of cell/tissue-specific uptake of MVs under these conditions. We hypothesized that monocytes contribute to uptake of circulating MVs and that their increased margination to the pulmonary circulation and functional priming during systemic inflammation produces substantive changes to the systemic MV homing profile. Cellular uptake of i.v.-injected, fluorescently labelled MVs (J774.1 macrophage-derived) in vivo was quantified by flow cytometry in vascular cell populations of the lungs, liver and spleen of C57BL6 mice. Under normal conditions, both Ly6Chigh and Ly6Clow monocytes contributed to MV uptake but liver Kupffer cells were the dominant target cell population. Following induction of sub-clinical endotoxemia with low-dose i.v. LPS, MV uptake by lung-marginated Ly6Chigh monocytes increased markedly, both at the individual cell level (~2.5-fold) and through substantive expansion of their numbers (~8-fold), whereas uptake by splenic macrophages was unchanged and uptake by Kupffer cells actually decreased (~50%). Further analysis of MV uptake within the pulmonary vasculature using a combined model approach of in vivo macrophage depletion, ex vivo isolated perfused lungs and in vitro lung perfusate cell-based assays, indicated that Ly6Chigh monocytes possess a high MV uptake capacity (equivalent to Kupffer cells), that is enhanced directly by endotoxemia and ablated in the presence of phosphatidylserine (PS)-enriched liposomes and β3 integrin receptor blocking peptide. Accordingly, i.v.-injected PS-enriched liposomes underwent a redistribution of cellular uptake during endotoxemia similar to MVs, with enhanced uptake by Ly6Chigh monocytes and reduced uptake by Kupffer cells. These findings indicate that monocytes, particularly lung-marginated Ly6Chigh subset monocytes, become a dominant target cell population for MVs during systemic inflammation, with significant implications for the function and targeting of endogenous and therapeutically administered MVs, lending novel insights into the pathophysiology of pulmonary vascular inflammation. [ABSTRACT FROM AUTHOR]

Prolonged hypothermic storage elicits severe ischemia-reperfusion injury (IRI) to renal grafts, contributing to delayed graft function (DGF) and episodes of acute immune rejection and shortened graft survival. Organoprotective strategies are therefore needed for improving long-term transplant outcome. The aim of this study is to investigate the renoprotective effect of xenon on early allograft injury associated with prolonged hypothermic storage. Xenon exposure enhanced the expression of heat-shock protein 70 (HSP-70) and heme oxygenase 1 (HO-1) and promoted cell survival after hypothermia-hypoxia insult in human proximal tubular (HK-2) cells, which was abolished by HSP-70 or HO-1 siRNA. In the brown Norway to Lewis rat renal transplantation, xenon administered to donor or recipient decreased the renal tubular cell death, inflammation, and MHC II expression, while delayed graft function (DGF) was therefore reduced. Pathological changes associated with acute rejection, including T-cell, macrophage, and fibroblast infiltration, were also decreased with xenon treatment. Donors or recipients treated with xenon in combination with cyclosporin A had prolonged renal allograft survival. Xenon protects allografts against delayed graft function, attenuates acute immune rejection, and enhances graft survival after prolonged hypothermic storage. Furthermore, xenon works additively with cyclosporin A to preserve post-transplant renal function. [ABSTRACT FROM AUTHOR]

Surgery is of paramount importance in the management of solid tumors as definitive resection can be totally curative. Nonetheless, metastatic recurrence after surgery remains a major cause of morbidity and mortality. Interest in the impact of the perioperative period on cancer recurrence is now growing rapidly, with recent research suggesting that some anesthetics or anesthetic techniques may influence the pathophysiology of postoperative metastatic spread. Our review examines the most widely postulated mechanisms for this, including the impact of anesthesia on neuroendocrine and immune function. We also consider evidence for a direct impact on tumor cell signaling pathways based on findings from organ protection research. These studies have demonstrated that certain volatile anaesthetics confer cytoprotective properties to exposed cells and lead to significant upregulation of Hypoxia Inducible Factor-1α (HIF-1α). This ubiquitous transcription factor exerts many effects in cancer: its activity has been linked with more aggressive phenotypes and poorer clinical prognosis. It is proposed that such an upregulation of HIFs in tumor cells by these anesthetics may contribute to a tumor's recurrence by stimulating cytoprotective or protumorigenic behavior in residual cells. Conversely, other anesthetic agents appear to downregulate HIFs or cause negligible effect and thus may prove more suitable for use in cancer surgery. As anesthetic drugs are given at a point of potentially high vulnerability in terms of dissemination and establishment of metastases, there is an urgent need to determine the most appropriate anesthetic strategy for surgical oncology so that the optimal techniques are used to maximize long-term survival. [ABSTRACT FROM AUTHOR]

Objective: Although postoperative cognitive dysfunction (POCD) often complicates recovery from major surgery, the pathogenic mechanisms remain unknown. We explored whether systemic inflammation, in response to surgical trauma, triggers hippocampal inflammation and subsequent memory impairment, in a mouse model of orthopedic surgery.Methods: C57BL/6J, knock out (lacking interleukin [IL]-1 receptor, IL-1R(-/-)) and wild type mice underwent surgery of the tibia under general anesthesia. Separate cohorts of animals were tested for memory function with fear conditioning tests, or euthanized at different times to assess levels of systemic and hippocampal cytokines and microglial activation; the effects of interventions, designed to interrupt inflammation (specifically and nonspecifically), were also assessed.Results: Surgery caused hippocampal-dependent memory impairment that was associated with increased plasma cytokines, as well as reactive microgliosis and IL-1beta transcription and expression in the hippocampus. Nonspecific attenuation of innate immunity with minocycline prevented surgery-induced changes. Functional inhibition of IL-1beta, both in mice pretreated with IL-1 receptor antagonist and in IL-1R(-/-) mice, mitigated the neuroinflammatory effects of surgery and memory dysfunction.Interpretation: A peripheral surgery-induced innate immune response triggers an IL-1beta-mediated inflammatory process in the hippocampus that underlies memory impairment. This may represent a viable target to interrupt the pathogenesis of postoperative cognitive dysfunction. [ABSTRACT FROM AUTHOR]