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Amyloidosis refers to a group of degenerative diseases that are characterized by the deposition of misfolded protein fibrils in various organs. Deposited amyloid may be removed by a phagocyte-dependent innate immune system; however, the precise mechanisms during disease progression remain unclear. We herein investigated the properties of macrophages that contribute to amyloid degradation and disease progression using inducible apolipoprotein A-II amyloidosis model mice. Intravenously injected AApoAII amyloid was efficiently engulfed by reticuloendothelial macrophages in the liver and spleen and disappeared by 24 h. While cultured murine macrophages degraded AApoAII via the endosomal-lysosomal pathway, AApoAII fibrils reduced cell viability and phagocytic capacity. Furthermore, the depletion of reticuloendothelial macrophages before the induction of AApoAII markedly increased hepatic and splenic AApoAII deposition. These results highlight the physiological role of reticuloendothelial macrophages in the early stages of pathogenesis and suggest the maintenance of phagocytic integrity as a therapeutic strategy to inhibit disease progression.

Ischemic stroke (IS) is a major cause of disability and death in adults, and the immune response plays an indispensable role in its pathological process. After the onset of IS, an inflammatory storm, with the infiltration and mobilization of the mononuclear phagocyte system (MPS), is triggered in the brain. Microglia are rapidly activated in situ, followed by waves of circulating monocytes into the ischemic area. Activated microglia and monocytes/macrophages are mainly distributed in the peri-infarct area. These cells have similar morphology and functions, such as secreting cytokines and phagocytosis. Previously, the presence of the MPS was considered a marker of an exacerbated inflammatory response that contributes to brain damage. However, recent studies have suggested a rather complicated role of the MPS in IS. Here, we reviewed articles focusing on various functions of the MPS among different phases of IS, including recruitment, polarization, phagocytosis, angiogenesis, and interaction with other types of cells. Moreover, due to the characteristics of the MPS, we also noted clinical research addressing alterations in the MPS as potential biomarkers for IS patients for the purposes of predicting prognosis and developing novel therapeutic strategies., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Background and Aims: Crohn's disease [CD] and ulcerative colitis [UC] are distinct forms of inflammatory bowel disease. Heterogeneity of HLA-DR+SIRPα + mononuclear phagocytes [MNPs], including macrophages [MΦ], monocyte-derived [Mono] cells, and dendritic cells [DCs], was reported in gut tissue but not yet investigated in mesenteric lymph nodes [MLNs] of IBD patients. We here compared the phenotype, function, and molecular profile of HLA-DR+SIRPα + MNPs in CD and UC MLNs., Methods: Cell distribution, morphology, immune function, and transcriptomic [bulk RNAseq] and high-dimensional protein expression profiles [CyTOF] of HLA-DR+SIRPα + MNPs were examined in MLNs of UC [n = 14], CD [n = 35], and non-IBD [n = 12] patients., Results: Elevated frequencies of CD14+CD64+CD163+ [Mono/MΦ-like] MNPs displaying monocyte/MΦ morphology and phagocytic function were a distinct feature of UC MLNs. In CD, the proportion of CD14-CD64-CD163- [DC-like] cells was augmented relative to Mono/MΦ-like cells; DC-like cells drove naïve T cell proliferation, Th1 polarisation, and Th17 TCM plasticity. Gene expression profile corroborated the nature of DC-like cells, best represented by BTLA, SERPINF, IGJ and, of Mono/MΦ-like cells, defined by CD163, MARCO, MAFB, CD300E, S100A9 expression. CyTOF analysis showed that CD123+ plasmacytoid cells predominated over conventional DCs in DC-like cells. Four CD163+ clusters were revealed in Mono/MΦ-like cells, two of which were enriched in MARCO-CD68dimHLA-DRdim monocyte-like cells and MARCOhiCD68hiHLA-DRhi Mɸ, whose proportion increased in UC relative to CD., Conclusions: Defining the landscape of MNPs in MLNs provided evidence for expansion of CD163+ Mono/MΦ-like cells in UC only, highlighting a distinction between UC and CD, and thus the potential contribution of monocyte-like cells in driving colitis., (Copyright © 2019 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

The plasma protein fetuin-A mediates the formation of protein-mineral colloids known as calciprotein particles (CPP)-rapid clearance of these CPP by the reticuloendothelial system prevents errant mineral precipitation and therefore pathological mineralization (calcification). The mutant mouse strain D2,Ahsg-/- combines fetuin-A deficiency with the calcification-prone DBA/2 genetic background, having a particularly severe compound phenotype of microvascular and soft tissue calcification. Here we studied mechanisms leading to soft tissue calcification, organ damage and death in these mice. We analyzed mice longitudinally by echocardiography, X-ray-computed tomography, analytical electron microscopy, histology, mass spectrometry proteomics, and genome-wide microarray-based expression analyses of D2 wildtype and Ahsg-/- mice. Fetuin-A-deficient mice had calcified lesions in myocardium, lung, brown adipose tissue, reproductive organs, spleen, pancreas, kidney and the skin, associated with reduced growth, cardiac output and premature death. Importantly, early-stage calcified lesions presented in the lumen of the microvasculature suggesting precipitation of mineral containing complexes from the fluid phase of blood. Genome-wide expression analysis of calcified lesions and surrounding (not calcified) tissue, together with morphological observations, indicated that the calcification was not associated with osteochondrogenic cell differentiation, but rather with thrombosis and fibrosis. Collectively, these results demonstrate that soft tissue calcification can start by intravascular mineral deposition causing microvasculopathy, which impacts on growth, organ function and survival. Our study underscores the importance of fetuin-A and related systemic regulators of calcified matrix metabolism to prevent cardiovascular disease, especially in dysregulated mineral homeostasis., Competing Interests: The authors have declared that no competing interests exist.

Background: Myeloid cells, especially mononuclear phagocytes, which include monocytes, macrophages and dendritic cells (DC), play vital roles in innate immunity, and in the initiation and maintenance of adaptive immunity. While T cell-associated activation pathways and cytokines have been identified and evaluated in inflammatory bowel disease (IBD) patients (Neurath, Nat Rev Gastroenterol Hepatol 14:269-78, 1989), the role of mononuclear phagocytes are less understood. Recent reports support the crucial role of DC subsets in the development of acute colitis models (Arimura et al., Mucosal Immunol 10:957-70, 2017), and suggest they may contribute to the pathogenesis of ulcerative colitis (UC) by inducing Th1/Th2/Th17 responses (Matsuno et al., Inflamm Bowel Dis 23:1524-34, 2017)., Results: We performed in silico analysis and evaluated the enrichment of immune cells, with a focus on mononuclear phagocytes in IBD patient colonic biopsies. Samples were from different gut locations, with different levels of disease severity, and with treatment response to current therapies. We observe enrichment of monocytes, M1 macrophages, activated DCs (aDCs) and plasmacytoid dendritic cells (pDCs) in inflamed tissues from various gut locations. This enrichment correlates with disease severity. Additionally, the same mononuclear phagocytes subsets are among the top enriched cell types in both infliximab and vedolizumab treatment non-responder samples. We further investigated the enrichment of selected DC and monocyte subsets based on gene signatures derived from a DC- and monocyte-focused single cell RNA-seq (scRNA-seq) study (Villani et al., Science 356:eaah4573, 2017), and verified enrichment in both inflamed tissues and those with treatment resistance. Moreover, we validated an increased mononuclear phagocyte subset abundance in a Dextran Sulphate Sodium (DSS) induced colitis model in C57Bl/6 mice representative of chronic inflammation., Conclusions: We conducted an extensive analysis of immune cell populations in IBD patient colonic samples and identified enriched subsets of monocytes, macrophages and dendritic cells in inflamed tissues. Understanding how they interact with other immune cells and other cells in the colonic microenvironment such as epithelial and stromal cells will help us to delineate disease pathogenesis.

Members of the genus Brucella are Gram-negative pathogens that cause chronic systemic infection in farm animals and zoonotic infection in humans. Study of the genus Brucella has been hindered by the need for biosafety level 3 select agent containment. Brucella neotomae , originally isolated from the desert pack rat, presented an opportunity to develop an alternative, non-select agent experimental model. Our prior in vitro work indicated that the cell biology and type IV secretion system (T4SS) dependence of B. neotomae intracellular replication were similar to observations for human-pathogenic select agent Brucella species. Therefore, here, we investigated the pathobiology of B. neotomae infection in the BALB/c mouse. During a sustained infectious course, B. neotomae replicated and persisted in reticuloendothelial organs. Bioluminescent imaging and histopathological and PCR-based analysis demonstrated that the T4SS contributed to efficient early infection of the liver, spleen, and lymph nodes; granuloma formation and hepatosplenomegaly; and early induction of Th1-associated cytokine gene expression. The infectious course and pathologies in the murine model showed similarity to prior observations of primate and native host infection with zoonotic Brucella species. Therefore, the B. neotomae BALB/c infection model offers a promising system to accelerate and complement experimental work in the genus Brucella ., (Copyright © 2018 American Society for Microbiology.)

The lack of effective treatment options for chronic neurological conditions, such as multiple sclerosis (MS), highlights the need to re-evaluate disease pathophysiology in the process of identifying novel therapeutic targets. The persistent activation of mononuclear phagocytes (MPs) is one of the major drivers of neurodegeneration and it sustains central nervous system (CNS) damage. Mitochondrial metabolism influences the activity of MPs, and the metabolites that they produce have key signalling roles in inflammation. However, how changes in immune cell metabolism sustain a chronic state of neuroinflammation is not fully understood. Novel molecular and cellular therapies for chronic neuroinflammation should be developed to target mitochondrial metabolism in innate immune cells to prevent secondary neurological damage and the accumulation of irreversible disability in patients., (Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.)

In this study, we developed a mouse model and characterized the effects of intranasal inoculation of virulent Brucella melitensis strain 16M and its lipopolysaccharide (LPS). The effects of the exposure were compared with respective control groups. Both Brucella melitensis-infected and LPS-infected groups showed no significant clinical presentation with minor relevance in the mortality associated with the infection. In Brucella melitensis-infected group, significant histopathological changes in comparison to the LPS infected group with increase bacterial burden in the lungs, reproductive and reticuloendothelial organs were observed. However, both infected groups showed elevated levels of pro-inflammatory cytokine expression (IL-1β and IL6) and antibody production (IgM an IgG) as early as 3 days post-infection with predominance in LPS infected group. In contrast, low levels of sex related hormonal changes was recorded in both infected groups throughout the experimental period. This is the first detailed investigation comparing the infection progression and host responses in relation to the immunopathophysiological aspects in mouse model after intranasal inoculation with B. melitensis and its lipopolysaccharide. The study revealed a significant difference between infected and control groups with overlap in clinical, pathological, and immunological responses as well as sex related hormonal changes resulting from the infections., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The role of low-grade inflammation in the development of post‑infectious irritable bowel syndrome (PI‑IBS) has attracted increasing attention. Abnormal CD11c+ mononuclear phagocytes, such as dendritic cells (DCs), macrophages, and monocytes, are involved in the disruption of immune tolerance in organisms, which can lead to the development of chronic inflammatory diseases. The present study tested the hypothesis that CD11c+ lamina propria mononuclear phagocytes (CD11c+ LPMPs) contribute to increased mucosal permeability and visceral hypersensitivity in a PI‑IBS mouse model. CD11c+ LPMPs were isolated and purified via the digestion of intestinal tissues and magnetic‑activated cell sorting. We detected increased mucosal permeability, visceral hypersensitivity and intestinal inflammation during both the acute and chronic stages of Trichinella infection. Following the transfer of CD11c+ LPMPs from PI‑IBS mice into normal mice, low‑grade inflammation was detected, as demonstrated by increased IL‑4 expression in the ileum, as well as enhanced mucosal permeability, as indicated by decreased transepithelial electrical resistance and the pre-sence of ultrastructural alterations. More importantly, the mice that underwent adoptive transfer of CD11c+ LPMPs from the PI‑IBS mice also exhibited increased abdominal withdrawal reflex scores and a decreased threshold. Our data demonstrated that the CD11c+ LPMPs from this PI‑IBS mouse model were not only able to transfer enteric inflammation to the normal mice but also caused abnormal intestinal function, characterized by epithelial barrier disruption and visceral hyperalgesia.

Type 3 haemochromatosis (HFE3) is a rare genetic iron overload disease which ultimately lead to compromised organs functioning. HFE3 is caused by mutations in transferrin receptor 2 (TFR2) gene that codes for two main isoforms (Tfr2 α and Tfr2 β ). Tfr2 α is one of the hepatic regulators of iron inhibitor hepcidin. Tfr2 β is an intracellular isoform of the protein involved in the regulation of iron levels in reticuloendothelial cells. It has been recently demonstrated that Tfr2 is also involved in erythropoiesis. This study aims to further investigate Tfr2 erythropoietic role by evaluating the erythropoiesis of two Tfr2 murine models wherein either one or both of Tfr2 isoforms have been selectively silenced (Tfr2 KI and Tfr2 KO). The evaluations were performed in bone marrow and spleen, in 14 days' and 10 weeks' old mice, to assess erythropoiesis in young versus adult animals. The lack of Tfr2 α leads to macrocytosis with low reticulocyte number and increased hemoglobin values, together with an anticipation of adult BM erythropoiesis and an increased splenic erythropoiesis. On the other hand, lack of Tfr2 β (Tfr2 KI mice) causes an increased and immature splenic erythropoiesis. Taken together, these data confirm the role of Tfr2 α in modulation of erythropoiesis and of Tfr2 β in favoring iron availability for erythropoiesis.

Macrophages play a central role in mycobacterial pathogenesis. Recent work has highlighted the importance of diverse macrophage types and phenotypes that depend on local environment and developmental origins. In this review, we highlight how distinct macrophage phenotypes may influence disease progression in tuberculosis. In addition, we draw on work investigating specialized macrophage populations important in cancer biology and atherosclerosis in order to suggest new areas of investigation relevant to mycobacterial pathogenesis. Understanding the mechanisms controlling the repertoire of macrophage phenotypes and behaviors during infection may provide opportunities for novel control of disease through modulation of macrophage form and function., (© FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We previously developed a "cage"-like nano-formulation (nanozyme) for copper/Zinc superoxide dismutase (SOD1) by polyion condensation with a conventional block copolymer poly(ethylene glycol)-b-poly(L-lysine) (PEG-PLL) followed by chemical cross-linking. Herein we report a new SOD1 nanozyme based on PEG-b-poly(aspartate diethyltriamine) (PEG-PAsp(DET), or PEG-DET for short) engineered for chronic dosing. This new nanozyme was spherical (Rg/Rh=0.785), and hollow (60% water composition) nanoparticles with colloidal properties similar to PLL-based nanozyme. It was better tolerated by brain microvessel endothelial/neuronal cells, and accumulated less in the liver and spleen. This formulation reduced the infarct volumes by more than 50% in a mouse model of ischemic stroke. However, it was not effective at preventing neuromuscular junction denervation in a mutant SOD1(G93A) mouse model of amyotrophic lateral sclerosis (ALS). To our knowledge, this work is the first report of using PEG-DET for protein delivery and a direct comparison between two cationic block copolymers demonstrating the effect of polymer structure in modulating the mononuclear phagocyte system (MPS) accumulation of polyion complexes., (Copyright © 2016 Elsevier B.V. All rights reserved.)

In this study, we showed that the levels of EZH2 in bone marrow mononuclear cells (BMMNCs) isolated from individuals with chronic myeloid leukemia (CML) (n=12) were significantly greater than those in BMMNCs isolated from healthy volunteers (n=6) as well as individuals with Philadelphia chromosome-negative myeloproliferative neoplasms. Lentiviral transduction of the BCR/ABL gene in Ba/F3 cells increased EZH2 levels in parallel with phosphorylation of STAT5. Notably, chromatin immunoprecipitation assays showed that STAT5A bound to a promoter region of the EZH2 gene, resulting in an increase in the transcriptional activity of EZH2 in leukemia cells. Importantly, downregulation of EZH2 by short hairpin RNAs (shRNAs) inhibited the expression of XIAP and increased the miR-219 levels associated with a decrease in hypermethylation of miR-219-1 CpG islands. Moreover, overexpression of miR-219 decreased the levels of XIAP in CML cells. Since the 3'-untranslated region (3'-UTR) of XIAP contains miR219-5p-complementary binding site, miR-219 might modulate the expression of XIAP through binding of miR-219 on the 3'-UTR of XIAP. Taken together, BCR/ABL positively regulates the expression of EZH2 via STAT5 signaling. EZH2 modulates epigenetic changes at DNA methylated regions encoding miR-219 and downregulates the level of miR-219, resulting in upregulation of XIAP., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The Leishmania granuloma shares some, though not all, properties with that formed following mycobacterial infection. As a simplified, noncaseating granuloma composed of relatively few and largely mononuclear cell populations, it provides a tractable model system to investigate intra-granuloma cellular dynamics, immune regulation, and antimicrobial resistance. Here, the occurrence of granulomatous pathology across the spectrum of leishmaniasis, in humans and animal reservoir hosts, is first described. However, this review focuses on the process of hepatic granuloma formation as studied in rodent models of visceral leishmaniasis, starting from the initial infection of Kupffer cells to the involution of the granuloma after pathogen clearance. It describes how the application of intravital imaging and the use of computational modeling have changed some of our thoughts on granuloma function, and illustrates how host-directed therapies have been used to manipulate granuloma form and function for therapeutic benefit. Where appropriate, lessons that may be equally applicable across the spectrum of granulomatous diseases are highlighted.

Microglia are the resident mononuclear phagocytes of the central nervous system and have been implicated in the pathogenesis of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). During neurodegeneration, microglial activation is accompanied by infiltration of circulating monocytes, leading to production of multiple inflammatory mediators in the spinal cord. Degenerative alterations in mononuclear phagocytes are commonly observed during neurodegenerative diseases, yet little is known concerning the mechanisms leading to their degeneration, or the consequences on disease progression. Here we observed that the serotonin 2B receptor (5-HT2B), a serotonin receptor expressed in microglia, is upregulated in the spinal cord of three different transgenic mouse models of ALS. In mutant SOD1 mice, this upregulation was restricted to cells positive for CD11b, a marker of mononuclear phagocytes. Ablation of 5-HT2B receptor in transgenic ALS mice expressing mutant SOD1 resulted in increased degeneration of mononuclear phagocytes, as evidenced by fragmentation of Iba1-positive cellular processes. This was accompanied by decreased expression of key neuroinflammatory genes but also loss of expression of homeostatic microglial genes. Importantly, the dramatic effect of 5-HT2B receptor ablation on mononuclear phagocytes was associated with acceleration of disease progression. To determine the translational relevance of these results, we studied polymorphisms in the human HTR2B gene, which encodes the 5-HT2B receptor, in a large cohort of ALS patients. In this cohort, the C allele of SNP rs10199752 in HTR2B was associated with longer survival. Moreover, patients carrying one copy of the C allele of SNP rs10199752 showed increased 5-HT2B mRNA in spinal cord and displayed less pronounced degeneration of Iba1 positive cells than patients carrying two copies of the more common A allele. Thus, the 5-HT2B receptor limits degeneration of spinal cord mononuclear phagocytes, most likely microglia, and slows disease progression in ALS. Targeting this receptor might be therapeutically useful.

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.

Photoreceptor degeneration in age-related macular degeneration (AMD) is associated with an infiltration and chronic accumulation of mononuclear phagocytes (MPs). We have previously shown that Cx3cr1-deficient mice develop age- and stress- related subretinal accumulation of MPs, which is associated with photoreceptor degeneration. Cx3cr1-deficient MPs have been shown to increase neuronal apoptosis through IL-1β in neuroinflammation of the brain. The reason for increased IL-1β secretion from Cx3cr1-deficient MPs, and whether IL-1β is responsible for increased photoreceptor apoptosis in Cx3cr1-deficient mice, has not been elucidated. Here we show that Cx3cr1-deficient MPs express increased surface P2X7 receptor (P2RX7), which stimulates IL-1β maturation and secretion. P2RX7 and IL-1β inhibition efficiently blunted Cx3cr1-MP-dependent photoreceptor apoptosis in a monocyte/retina coculture system and in light-induced subretinal inflammation of Cx3cr1-deficient mice in vivo. Our results provide an explanation for increased CX3CR1-dependent IL-1β secretion and suggest that IL-1β or P2RX7 inhibition can help inhibit the inflammation-associated photoreceptor cell loss in late AMD, including geographic atrophy, for which no efficient treatment currently exists., (Copyright © 2015 the authors 0270-6474/15/356987-10$15.00/0.)

In the 1970s and 1980s the course of rheumatoid arthritis (RA) could be defined as fateful despite the introduction of methotrexate as well as other immunosuppressive treatments. In most patients at this time RA was combined with an early disability due a progressive destruction of joints. In addition, comorbidity was known to be one of the major causes for a decreased life expectancy. These less than optimal options for treating RA patients led to intensive research in the pathogenesis with the aim to develop new treatment principles. Based on the increasing knowledge of pathogenically important mechanisms, so-called biologicals were developed targeting T and B cells and proinflammatory cytokines, such as tumor necrosis factor alpha. Over the past 10 years the repertoire of biologicals for treating RA has steadily and significantly increased, which was necessary especially for those patients classified as non-responders to available biological compounds. In the present overview cellular structures, T and B cells as well as cells of the monocyte/macrophage system are discussed as targets for immune interventions.

Mycobacterium tuberculosis, the bacterium that causes tuberculosis (TB), is an intracellular pathogen of mononuclear phagocytes. Although M. tuberculosis has traditionally been thought to survive and replicate in macrophages, recent work in our laboratory and others has revealed that M. tuberculosis infects multiple subsets of mononuclear phagocytes in vivo and in vitro. In experimental animals, M. tuberculosis infects no fewer than five distinct cell subsets in the lungs, including resident alveolar macrophages and 4 types of cells that recruited to the lungs in response to inflammatory signals: neutrophils, monocytes, interstitial macrophages, and dendritic cells. A characteristic of the adaptive immune response in TB is that it is delayed for several weeks following infection, and we have determined that this delay is due to prolonged residence of the bacteria in lung phagocytes prior to acquisition of the bacteria by dendritic cells. Among the mechanisms used by M. tuberculosis to delay acquisition by dendritic cells is to inhibit apoptosis of alveolar macrophages and neutrophils, which sequester the bacteria and prevent their acquisition by dendritic cells in the early stages of infection. We hypothesize that each infected cell subset makes a distinct contribution to the overall biology of M. tuberculosis and allows the bacteria to evade elimination by T-cell responses and to avoid rapid killing by antimycobacterial drugs., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

AKI involves early Toll-like receptor (TLR)-driven immunopathology, and resolution of inflammation is needed for rapid regeneration of injured tubule cells. Notably, activation of TLRs also has been implicated in epithelial repair. We hypothesized that TLR signaling drives tubule regeneration after acute injury through the induction of certain ILs. Systematic screening in vitro identified IL-22 as a candidate proregeneratory factor in primary tubular cell recovery, and IL-22 deficiency or IL-22 blockade impaired post-ischemic tubular recovery after AKI in mice. Interstitial mononuclear cells, such as dendritic cells and macrophages, were the predominant source of IL-22 secretion, whereas IL-22 receptor was expressed by tubular epithelial cells exclusively. Depleting IL-22-producing cells during the healing phase impaired epithelial recovery, which could be rescued entirely by reconstituting mice with IL-22. In vitro, necrotic tubular cells and oxidative stress induced IL-22 secretion selectively through TLR4. Although TLR4 blockade during the early injury phase prevented tubular necrosis and AKI, TLR4 blockade during the healing phase suppressed IL-22 production and impaired kidney regeneration. Taken together, these results suggest that necrotic cell-derived TLR4 agonists activate intrarenal mononuclear cells to secrete IL-22, which accelerates tubular regeneration and recovery in AKI., (Copyright © 2014 by the American Society of Nephrology.)

This publication summarizes the scientific adventure with Professor Selye, and focuses on the specific effect of rare metal salts on reticuloendothelial functions. Rare earth metal ions markedly affect the functions of cells involved in inflammatory and immunological phenomena. The Kupffer cell blockade induced by GdCl3 is a generally accepted method for investigation of the physiological and pathophysiological roles of Kupffer cells. Potential beneficial effects of macrophage blockade have been demonstrated in different shock states, liver injury and obstructive jaundice.

In the experiment where rats were fed a diet with phytosterols and alkylglycerols for 1,5 months, changes were observed in morphometric parameters in the liver structure in rats. In animals, which were fed a diet with 20% replacement of the fat component (lard) on phytosterols (stanols derived from rapeseed and conifers), blood circulatory disorders of the liver were observed. There was dilatation of the lumens of the central veins and hepatic veins in the interlobular vascular bundles. On the periphery of the lobules, around the vascular bundles, abundant clusters of lymphocytes were revealed. In both groups of rats fed a diet containing various amounts of alkylglycerols obtained from Berrytenthis magister liver (7 and 50 mg per day) and lard as a fat component, in peripheral areas of hepatic lobules the reticuloendothelial cell count was increased as compared with the control group of animals fed a diet containing as fatty component a mixture of lard and sunflower oil (1:1). These cells contained polysaccharides in the cytoplasm and formed thin bands along the hepatic tubules. In addition, in all groups of rats receiving diets with lipid components (both stanols and alkylglycerols), the occurrence of reticuloendothelium proliferation foci in the middle and central zones of liver lobules were 1,8, 2,3 and 2,1 fold higher than in control group. As compared to control animals, the foci in the above groups contained 1,8, 1,7 and 1,6 fold more cells. Furthermore, the number of animals with reticuloendothelium proliferation foci in the groups receiving investigated lipid components was also increased by 2 fold, as compared to controls.

Background: During progressive simian immunodeficiency virus (SIV) infection, the ability of innate mononuclear phagocytes to function when responding to the invading pathogen has yet to be determined., Methods: We generated single-stranded RNA (ssRNA) oligonucleotides from the infecting strain of virus and utilized them to stimulate mononuclear phagocytes from blood and lymph nodes of naïve and SIVmac251-infected rhesus macaques., Results: Soon after infection and continuing through to chronic disease, plasmacytoid dendritic cells (pDC), monocytes, and macrophages from SIV-infected macaques were less able to produce pro-inflammatory cytokines after exposure to virus-derived toll-like receptor (TLR) agonists. In contrast, myeloid dendritic cells (mDC) became hyper-responsive during acute and stable chronic infection., Conclusions: Plasmacytoid dendritic cells, monocytes, and macrophages may not instigate continued immune activation by recognizing the single-stranded RNA from SIV as they are left dysfunctional after infection. Conversely, mDC functionality may be beneficial as their hyper-responsiveness is related to slowed disease progression., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The mononuclear phagocyte system is comprised of circulating monocytes, tissue macrophages and dendritic cells (DCs) that play key roles in tissue homeostasis, immune surveillance, and immune and non-immune-mediated tissue injury and repair. This review summarizes the various subsets within this system that exhibit significant functional and phenotypic diversity that can adapt to their surrounding microenvironments during inflammation and in response to colony-stimulating factor (CSF)-1. The current understanding of the co-ordination of monocyte infiltration into the homeostatic and diseased kidney through adhesion molecules, chemokines and chemokine receptors, and cytokines are described. Furthermore, the significant confusion and controversy associated with monocyte differentiation into renal macrophages and DCs following infiltration into the kidney, the considerable functional and phenotypic overlap between both tissue populations and their respective roles in immune and non-immune-mediated renal is also discussed. Understanding the factors that control the activation and recruitment of cells from the mononuclear phagocyte system during renal injury may offer an avenue for the development of new cellular and growth factor-based therapies in combination with existing therapies as an alternative treatment option for patients with renal disease., (© 2012 The Authors. Nephrology © 2012 Asian Pacific Society of Nephrology.)

Despite advances in non-invasive medical imaging, accurate nodal staging of malignancy continues to rely on surgery. Superparamagnetic iron oxide nanoparticles (IONP) with lymphotropic qualities have shown some promise as contrast agents for MRI of the lymph nodes, but recent large-scale studies failed to show consistent detection of tumours below 5 mm. Herein we compare imaging of splenic and lymph node tissue using iron/iron oxide core/shell nanoparticles (Fe NP) that have superior magnetic qualities to IONP, to determine whether improved negative contrast in T(2)-weighted MRI can enhance the diagnosis of small tumours in the reticuloendothelial system. To provide an in vivo pre-clinical model of human lymph node micrometastases, breast cancer cells were injected into the spleens of mice, providing localised areas of tumour growth. MR images of groups of tumour-bearing and sham-treated animals were generated using a 1.5 T imaging system and analysed by two independent, blinded radiologists. Fe NP improved the sensitivity and specificity of MRI when compared to IONP, enabling accurate detection of tumours as small as 1-3 mm. The use of Fe NP as contrast agents have the potential to improve the diagnostic accuracy of MRI in cancer patients, leading to more rapid and effective treatment.

Extensive research in the last two decades implemented that the inflammatory cell infiltrate, especially in solid tumors, is a major determinant for patient prognosis. Mononuclear phagocytes, i.e. monocytes/macrophages, dendritic cells and myeloid-derived suppressor cells, constitute the majority of tumor-associated immune cells. Instead of inducing anti-tumor immunity, mononuclear phagocytes are functionally subverted by tumor microenvironmental factors to support each stage of oncogenesis. Although mechanisms how tumors program their inflammatory infiltrate to support tumor development are ill-defined, few master regulators are beginning to emerge. One of them is the inflammatory eicosanoid prostaglandin E(2) (PGE(2)), produced by tumor cells or the infiltrating immune cells. In this review we summarize the impact of PGE(2) on mononuclear phagocytes in inflammation and cancer and discuss potential implications for cancer therapy., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

Iron chelation is essential to patients on chronic blood transfusions to prevent toxicity from iron overload and remove excess iron. Deferasirox (DFX) is the most commonly used iron chelator in the United States; however, some patients are relatively refractory to DFX therapy. We postulated that vitamin C supplementation would improve the availability of transfusional iron to DFX treatment by promoting iron's redox cycling, increasing its soluble ferrous form and promoting its release from reticuloendothelial cells. Osteogenic dystrophy rats (n = 54) were given iron dextran injections for 10 weeks. Cardiac and liver iron levels were measured after iron loading (n = 18), 12 weeks of sham chelation (n = 18), and 12 weeks of DFX chelation (n = 18) at 75 mg/kg/day. Ascorbate supplementation of 150 ppm, 900 ppm, and 2250 ppm was used in the chow to mimic a broad range of ascorbate status; plasma ascorbate levels were 5.4 ± 1.9, 8.2 ± 1.4, 23.6 ± 9.8 μM, respectively (p < 0.0001). The most severe ascorbate deficiency produced reticuloenthelial retention, lowering total hepatic iron by 29% at the end of iron loading (p < 0.05) and limiting iron redistribution from cardiac and hepatic macrophages during 12 weeks of sham chelation. Most importantly, ascorbate supplementation at 2250 ppm improved DFX efficiency, allowing DFX to remove 21% more hepatic iron than ascorbate supplementation with 900 ppm or 150 ppm (p < 0.05). We conclude that vitamin C status modulates the release of iron from the reticuloendothelial system and correlates positively with DFX chelation efficiency. Our findings suggest that ascorbate status should be probed in patients with unsatisfactory response to DFX., (Copyright © 2012 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.)

Glycogen storage disease type IV is a rare autosomal recessive disorder of glycogen metabolism caused by mutations in the GBE1 gene that encodes the 1,4-alpha-glucan-branching enzyme 1. Its clinical presentation is variable, with the most common form presenting in early childhood with primary hepatic involvement. Histologic manifestations in glycogen storage disease type IV typically consist of intracytoplasmic non-membrane-bound inclusions containing abnormally branched glycogen (polyglucosan bodies) within hepatocytes and myocytes. We report a female infant with classic hepatic form of glycogen storage disease type IV who demonstrated diffuse reticuloendothelial system involvement with the spleen, bone marrow, and lymph nodes infiltrated by foamy histiocytes with intracytoplasmic polyglucosan deposits. Sequence analysis of the GBE1 gene revealed compound heterozygosity for a previously described frameshift mutation (c.1239delT) and a novel missense mutation (c.1279G>A) that is predicted to alter a conserved glycine residue. GBE enzyme analysis revealed no detectable activity. A review of the literature for glycogen storage disease type IV patients with characterized molecular defects and deficient enzyme activity reveals most GBE1 mutations to be missense mutations clustering in the catalytic enzyme domain. Individuals with the classic hepatic form of glycogen storage disease type IV tend to be compound heterozygotes for null and missense mutations. Although the extensive reticuloendothelial system involvement that was observed in our patient is not typical of glycogen storage disease type IV, it may be associated with severe enzymatic deficiency and a poor outcome., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Transmissible spongiform encephalopathies (TSEs), or prion diseases, are neurological diseases that can be transmitted through a number of different routes. A wide range of mammalian species are affected by the disease. After peripheral exposure, some TSE agents accumulate in lymphoid tissues at an early stage of disease prior to spreading to the nerves and the brain. Much research has focused on identifying the cells and molecules involved in the transmission of TSE agents from the site of exposure to the brain and several crucial cell types have been associated with this process. The identification of the key cells that influence the different stages of disease transmission might identify targets for therapeutic intervention. This review highlights the involvement of mononuclear phagocytes in TSE disease. Current data suggest these cells may exhibit a diverse range of roles in TSE disease from the transport or destruction of TSE agents in lymphoid tissues, to mediators or protectors of neuropathology in the brain.

The aim of this investigation was to study the morphological changes of liver, lung, kidneys and spleen as well as of the cells of mononuclear pahagocyte system in 60 rats 1-40 days after a single intravenous injection of a suspension of magnetite nanoparticles. Moderate hemodynamic disturbances and focal necrotic changes were detected in the hepatic and renal parenchyma. In the lungs and spleen, only hemodynamic disturbances were found. The degree of morphological changes in rat liver, lungs, kidneys and spleen was decreased by day 10. Using Perls histochemical method, the accumulation of nanoparticles was detected in the cells of mononuclear phagocyte system of the organs studied.

The article describes changes in the morphology and localization of the cells of mononuclear phagocyte system of liver and lung in rats at different times after single and repeated intravenous administration of a suspension of nanoparticles of magnetite (NPM). Mechanisms for removal of nanoparticles of magnetite from the rat body with the participation of mononuclear phagocytes of the liver (removal of the particles by stellate macrophages in the gastroenteric tract with bile) and of the lung (by migration of the alveolar macrophages in the gleam of the bronchial tree) have been illustrated. It has been shown that intravenous application of nanomagnetite causes changes in the morphology of the internal organs of rats and the severity of these changes increases with increasing total dose injected magnetite.

Background:  STEALTH(®) liposomal CKD-602 (S-CKD602), a camptothecin analog, is eliminated by the reticuloendothelial system (RES), which consists of cells, including monocytes. We evaluated the relationship between monocyte and absolute neutrophil counts (ANCs) in the blood and pharmacokinetic disposition of S-CKD602 and nonliposomal CKD-602 (NL-CKD602) in patients., Methods:  As part of a phase I study of S-CKD602 and phase I and II studies of NL-CKD602, the percent decreases in ANC and monocytes at their nadir were calculated. After S-CKD602, the amount of CKD-602 recovered in urine was measured., Results:  For S-CKD602 in patients <60 years, the percent decrease in ANC and monocytes were 43  ±  31 and 58  ±  26%, respectively (P = 0.001). For S-CKD602 in patients ≥60, the percent decrease in ANC and monocytes were 41  ±  31 and 45  ±  36%, respectively (P =  0.50). For NL-CKD602 (n = 42), the percent decrease in ANC and monocytes were similar (P >  0.05). For S-CKD602, the relationship between the percent decrease in monocytes and CKD-602 recovered in urine was stronger in patients <60 (R(2) =  0.82), compared with patients ≥60 (R(2) =  0.30)., Conclusions:  Monocytes are more sensitive to S-CKD602, compared with neutrophils, and the increased sensitivity is related to the liposomal formulation, not CKD-602. These results suggest that monocytes engulf S-CKD602, which causes the release of CKD-602 from the liposome and toxicity to the monocytes, and that the effects are more prominent in patients <60.

Increased numbers of macrophages are found in the lungs of smokers and those with chronic obstructive pulmonary disease. Experimental evidence shows the central role of macrophages in elaboration of inflammatory mediators such as TNF-α and the progression toward cigarette smoke-induced emphysema. We investigated the role of CX3CR1 in recruitment of mononuclear phagocytes, inflammatory cytokine responses, and tissue destruction in the lungs after cigarette smoke exposure. Using mice in which egfp is expressed at the locus of the cx3cr1 gene, we show that alveolar macrophages increased transmembrane ligand CX3CL1 expression and soluble CX3CL1 was detectable in the airspaces, but cx3cr1(GFP/GFP) and cx3cr1(GFP/+) mice failed to show recruitment of CX3CR1(+) cells into the airspaces with cigarette smoke. In contrast, cigarette smoke increased the accumulation of CX3CR1(+)CD11b(+) mononuclear phagocytes that were spatially confined to the lung interstitium and heterogenous in their expression of CD11c, MHC class II, and autofluorescent property. Although an intact CX3CL1-CX3CR1 pathway amplified the percentage of CX3CR1(+)CD11b(+) mononuclear phagocytes in the lungs, it was not essential for recruitment. Rather, functional CX3CR1 was required for a subset of tissue-bound mononuclear phagocytes to produce TNF-α and IL-6 in response to cigarette smoke, and the absence of functional CX3CR1 protected mice from developing tissue-destructive emphysema. Thus, CX3CR1(+) "tissue resident" mononuclear phagocytes initiate an innate immune response to cigarette smoke by producing TNF-α and IL-6 and are capable of promoting emphysema.

The following functions of mononuclear phagocytes of 24 patients with rheumatoid arthritis, 24 their relatives, and 24 women, not hereditary tainted with autoimmune diseases (control) were compared: (1) engulfment and digestion (radioisotope method); (2) release of lysosomal glucuronidase during the interaction of cells with opsonized zymosan (fluorescent method). In rheumatoid arthritis the slowed down process of engulfment and preliminary extracellular digestion was combined with accelerated digestive potential. In relatives, the delayed and suppressed engulfment was associated with the decelerated digestive mononuclear phagocyte potential. The congenital peculiarity of the cell functioning was suggested, being due to the imperfect anti infectious defense in predisposed to the disease individuals, on one hand, and to the excessive damage of the surrounding tissues and to the provocation of autoimmune processes.

MPhi and DC are key elements in the control of tissue homeostasis and response to insult. In this work, we demonstrate that MPhi and DC are the major producers of the phenylalanine catabolizing enzyme IL-4-induced gene 1 (IL4I1) under inflammatory conditions. IL4I1 was first described in B cells, which indeed can produce IL4I1 in vitro, although at much lower levels. In vivo, IL4I1 is highly expressed by MPhi and DC of Th1 granulomas (sarcoidosis, tuberculosis) but poorly detected in Th2 granulomas (schistosomiasis). In vitro, expression of the enzyme is induced in mononuclear phagocytes by various pro-inflammatory stimuli through the activation of the transcription factors NF-kappaB and/or STAT1. B cells also express IL4I1 in response to NF-kappaB-activating stimuli such as CD40L; however, in contrast to myeloid cells, B cells are insensitive to IFN-gamma but respond to stimulation of the IL-4/STAT6 axis. As we show that the expression of IL4I1 by a monocytic cell line inhibits T-cell proliferation and production of IFN-gamma and inflammatory cytokines, we propose that IL4I1 participates in the downregulation of Th1 inflammation in vivo.

The effectiveness of rituximab in hepatitis C virus (HCV)-related mixed cryoglobulinemia (MC) has been shown. However, the risk of an increase in viral replication limits its use in cirrhosis, a condition frequently observed in patients with MC. In this prospective study, 19 HCV-positive patients with MC and advanced liver disease, who were excluded from antiviral therapy, were treated with rituximab and followed for 6 months. MC symptoms included purpura, arthralgias, weakness, sensory-motor polyneuropathy, nephropathy, and leg ulcers. Liver cirrhosis was observed in 15 of 19 patients, with ascitic decompensation in 6 cases. A consistent improvement in MC syndrome was evident at the end-of-treatment (EOT) and end-of-follow-up (EOF-U). Variable modifications in both mean viral titers and alanine aminotransferase values were observed at admission, EOT, third month of follow-up, and EOF-U (2.62 x 10(6), 4.28 x 10(6), 4.82 x 10(6), and 2.02 x 10(6) IU/mL and 63.6, 49.1, 56.6, and 51.4 IU/L, respectively). Improvement in liver protidosynthetic activity and ascites degree was observed at EOT and EOF-U, especially in more advanced cases. This study shows the effectiveness and safety of rituximab in MC syndrome with advanced liver disease. Moreover, the depletion of CD20(+) B cells was also followed by cirrhosis syndrome improvement despite the possibility of transient increases of viremia titers.

There is increasing evidence that not only T cells but also B cells may play an important role in the pathogenesis of idiopathic nephrotic syndrome (NS). We have evaluated the infiltrating immune cells found in renal biopsies from 38 children with NS using immunohistochemistry techniques involving antibodies against T cells (CD3, CD4, CD8, FoxP3), B cells (CD20), macrophages (CD68) and follicular dendritic cells (CD21). Kidney biopsies with thin basement membrane disease were used as controls. We found higher numbers of interstitial CD3-positive T cells and macrophages in patients with focal segmental glomerulosclerosis (FSGS) than in those with minimal change glomerulopathy (MCGN) and in the controls, and significantly lower FoxP3-positive cells in patients with FSGS, MCGN and steroid-dependent NS than in the controls. Significantly higher numbers of glomerular B cells were found in FSGN patients than in MCGN patients and controls. Of note, in three patients who were later successfully treated with anti-CD20 antibody rituximab, the number of renal B cells was negligible in the preceding biopsy. In conclusion, the higher numbers of interstitial CD3-positive T cells in renal biopsies of pediatric patients with FSGS argue for a higher inflammatory activity. The significantly higher number of glomerular B cells in FSGS patients may indicate a particular pathogenetic role or epiphenomenon in this disease. However, patients with no interstitial or glomerular B cells could also benefit from rituximab treatment.

The head and neck squamous cell carcinoma microenvironments contain many immune cells and their secretory products. Many of these cells belong to the mononuclear phagocyte system. The aim of this review is to study the interactions between mononuclear phagocytes and head and neck squamous cell carcinoma tissue. The role of inflammation in tumours and the cytokine interleukin-6 will be highlighted. Future therapy strategies in the treatment of head and neck cancer might be directed towards mononuclear phagocytes and their cytokine production.

Hemophagocytic syndrome (HPS) is an unusual but sometimes fatal disorder. We reported a case of 21-year-old man who developed HPS and SLE simultaneously. Febrile pancytopenia, hyperferritinemia, and abnormal liver function tests were observed. Hemophagocytic cells were observed by means of bone marrow biopsy and diagnosed as HPS. The patient was treated with high-dose prednisolone, resulting in an excellent outcome. Early diagnosis of HPS by bone marrow biopsy is important for the successful treatment.

Patients with sickle cell disease (SCD) appear to be at lower risk of endocrinopathies and cardiac dysfunction than those with thalassemia major (TM). Circulating redox active iron is lower in these patients, possibly due to increased systemic inflammation and circulating cytokines. Hepcidin synthesis is upregulated during chronic inflammation, reducing intestinal iron absorption and promoting retention of iron in the reticuloendothelial cells. Hence, we hypothesized that livers of patients with SCD would exhibit greater iron deposition in sinusoidal spaces relative to hepatocytes and less in portal tracts when compared to patients with TM. To test this hypothesis, iron scoring analysis was performed on 70 clinically indicated liver biopsy specimens from children and young adults with the two syndromes. Sinusoidal scores were lower in around 1 of 4 patients with TM but the relative iron loading in hepatocytes, and portal tracts was identical in both diseases. Sinusoidal iron burdens saturated at low hepatic iron concentration (HIC) while hepatocyte and portal iron depots increased proportionally to HIC. Liver fibrosis was increased in patients with TM regardless of their chronic hepatitis status. Overall, liver iron distribution was relatively insensitive to differences in disease type and to the presence or absence of hepatitis.

The presence of cells of the mononuclear phagocyte lineage surrounding neuritic and vascular beta-amyloid (Abeta) plaques is a hallmark of Alzheimer's disease (AD) neuropathology. The fractional Abeta peptide patterns released by human mononuclear phagocyte (MNP), lymphocyte and PBMC cultures were assessed by Abeta-SDS-PAGE/immunoblot and compared with the Abeta patterns in neuronal supernatants, in cerebrospinal fluid (CSF), and plasma. MNP released substantial amounts of Abeta peptides and the Abeta pattern contrasted with that in neuronal supernatants, CSF and plasma by reduced Abeta(1-42) and increased proportions of N-truncated Abeta species. MNP derived from early AD patients released significantly more total Abeta peptides than age-matched controls. The proportion of Abeta(1-42) was not altered.

Introduction: Oral lichen planus (OLP) is a relatively common inflammatory disease with a wide range of clinical forms. Its pathogenesis has not been fully elucidated although it is known to be mediated by lymphocytes with the participation of cytokines and other inflammatory cells, including type I and type II dermal dendrocytes (DD) (factor XIIIa+ DD and CD34+ DD, respectively)., Objectives: To describe the presence and tissue distribution of these cells, through immunohistochemistry, in 23 specimens from patients with clinical and histopathological criteria of OLP., Results: Factor XIIIa+ DD were mainly located in the superficial dermis (p < 0.0001) as opposed to the deep submucosa. These cells were abundant throughout the dermal-epidermal junction and closely related to lymphocyte infiltration. Moreover, factor XIIIa+ DD were also found in the epithelium and deep dermis. CD34+ DD were distributed mostly to the deep dermis directly below the lymphocyte infiltrate with few cells in the subepithelial region., Conclusions: DD were present in OLP, with distinct tissue distributions. Factor XIIIa+ DD were predominant in the superficial dermis while CD34+ DD could be found mostly in the deep dermis. These findings suggest that DD, and those positive for factor XIIIa+ in particular in view of their ability to express intercellular adhesion molecule-1 (ICAM-1) and tumor necrosis factor alpha (TNF-alpha), may play an important role in pathogenesis of OLP.

Purpose: To prospectively assess a dose-response relationship for the hepatic reticulo-endothelial system (RES) after small volume single fraction irradiation of liver parenchyma in vivo., Materials and Methods: Twenty-five liver tumors were treated by computed tomography (CT)-guided interstitial brachytherapy. Magnetic resonance imaging (MRI) was performed 1 day before and 3 days, 6, 12 and 24 weeks after therapy. MR-sequences included T2-w Turbo Spin Echo (TSE) enhanced by hepatic RES targeted Standard Superparamagnetic Iron Oxide (SSPIO). All MRI data sets were merged with three dimensional (3D) dosimetry data and evaluated by two radiologists. We estimated the threshold dose for either edema or function loss as the D90. A match-pair analysis was performed with another 25 liver tumors, which were treated the same but had MRI follow-up using the hepatocyte specific MRI contrast media Gadobenate dimeglumine (Gd-BOPTA)., Results: Three days post brachytherapy the D90 for hepatic RES function loss reached the 18.3 Gray (Gy) isosurface (Standard Deviation (SD) 7.7). At 6 weeks, the respective zone had increased significantly to the 12.9 Gy isosurface (SD 4.4). After 12 and 24 weeks, the dysfunction of liver volume decreased significantly to the 15 Gy and 20.4 Gy isosurface respectively (SD 7.1 and 10.0). Comparison to the hepatocyte function loss indicates a higher minimal threshold dose of the hepatic RES., Conclusion: Hepatic RES demonstrated a high regenerative capacity and a higher minimal threshold dose than hepatocytes. Temporary function loss was found from the 13 Gy isosurface.

Background: Recent evidence of lung injury from the infusion of unstable lipid injectable emulsions as all-in-one mixtures (AIOs) was shown in a guinea pig infusion model., Methods: We extended this research to a Sprague-Dawley rat infusion model, focusing our analyses on the dose of large-diameter fat globules (expressed as the volume-weighted percent of fat larger than 5 or 10 microm, PFAT5 or PFAT10) from the dispersed phase of emulsion mixtures of varying levels of stability, and the potential injurious effects on major tissues of the reticuloendothelial system (i.e., lungs and liver)., Results: Two identical infusion experiments (n=13 rats/study), involving stable (s-AIO) vs. unstable (u-AIO) mixtures were separately conducted, and differed in two respects: (1) duration of AIO infusion (24 h vs. 72 h) and, (2) starting PFAT5 levels for the u-AIO (24- vs. 72-h PFAT5: 0.682+/-0.055% vs. 0.117+/-0.024%, respectively). In both experiments, s-AIOs vs. u-AIOs were infused, and evidence of hepatic oxidative stress was noted by significantly higher tissue concentrations of malondialdehyde (MDA) during infusion of u-AIOs. The higher concentrations of MDA in the livers of animals receiving the u-AIOs were also accompanied by significantly higher plasma concentrations of AST in both infusion experiments suggesting injury. Levels of cytokines (IL-1beta, TNFalpha) in the lungs and livers in both infusion studies were variable., Conclusions: These results demonstrate the infusion of u-AIOs with starting PFAT5 levels of approximately 0.1% show evidence of pathological consequences to the liver and lungs, and therefore, such unstable AIO mixtures should probably be avoided in the clinical setting.

Background: Myofibroblasts, proposed as being derived from circulating fibrocytes, are considered to be important cells in thickening of the basement membrane in patients with asthma. We have studied the correlation of tissue fibrocyte levels to basement membrane thickness and the presence of fibrocytes in bronchoalveolar lavage fluid (BALF) in steroid-naive patients with mild asthma and controls., Methods: Patients with mild asthma (n = 9) were recruited and divided into two categories based on whether or not fibroblast-like cells could be established from BALF. Non-asthmatic healthy subjects (n = 5) were used as controls. Colocalization of the fibrocyte markers CD34, CD45RO, procollagen I, and alpha-smooth muscle actin (alpha-SMA) were identified in bronchial biopsies from patients and controls by confocal microscopy. Kruskall-Wallis method was used to calculate statistical significance and Spearman coefficient of rank correlation was used to assess the degree of association., Results: In patients with BALF fibroblasts, a 14-fold increase of tissue cells expressing CD34/CD45RO/alpha-SMA and a 16-fold increase of tissue cells expressing CD34/procollagen I was observed when compared to controls (p < 0.05). In contrast, patients without BALF fibroblasts displayed a 2-fold increase when compared to controls (p < 0.05). Fibrocytes were localized close to the basement membrane which was significantly thicker in patients with BALF fibroblasts when compared to the other two groups of subjects. Furthermore, basement membrane thickness could be correlated to the number of fibrocytes in tissue (r = 0.711). Fibroblasts-like cells were cultured from BALF where 17.6% of these cells expressed CD34, CD45RO and alpha-SMA., Conclusion: These findings indicate a correlation between recruited fibrocytes in tissue and thickness of basement membrane. Fibroblast progenitor cells may therefore be important in airway remodeling in steroid-naive patients with mild asthma.

Background: Hemoglobin-vesicles (HbVs; diameter, 251 +/- 81 nm) are artificial O(2) carriers. Their efficacy for acute exchange transfusion has been characterized in animal models. However subsequent profiles of recovery involving the degradation of HbV in the reticuloendothelial system (RES) and hematopoiesis remain unknown., Study Design and Methods: Isovolemic 40 percent exchange transfusion was performed in 60 male Wistar rats with HbV suspended in 5 g per dL recombinant human serum albumin (rHSA; HbV/rHSA, [Hb] = 8.6 g/dL), stored rat RBCs suspended in rHSA (sRBC/rHSA), or rHSA alone. Hematological and plasma biochemical analyses and histopathological examination focusing on the spleen were conducted for the subsequent 14 days., Results: The reduced hematocrit (Hct) level (26%) for the HbV/rHSA and rHSA groups returned to its original level (43%) in 7 days. Plasma erythropoietin was elevated in all groups: the rHSA group showed the highest value on Day 1 (321 +/- 123 mIU/mL) relating to the anemic conditions (HbV/rHSA, 153 +/- 22; sRBC/rHSA, 63 +/- 7; baseline, 21 +/- 3). Simultaneously, splenomegaly occurred in all the groups as HbV/rHSA > rHSA > sRBC/rHSA. Histopathologically, the accumulated HbV in the spleen was undetectable by Day 14, but hemosiderin was deposited in slight quantities for both the HbV/rHSA and sRBC/rHSA groups. Considerable amounts of erythroblasts were apparent in the spleens of both the rHSA and the HbV/rHSA groups., Conclusion: HbVs were phagocytized and degraded in RES, a physiological compartment for the degradation of RBCs, and the elevated erythropoietic activity resulted in the complete recovery of Hct within 7 days in the rat model.