Durvalumab plus carboplatin-etoposide treatment in a patient with small-cell lung cancer on hemodialysis: a case report and literature review.

Little is known about the efficacy and safety of durvalumab plus carboplatin-etoposide treatment in patients with extensive-disease (ED) small-cell lung cancer (SCLC) on hemodialysis. Here, we present a case of a 67-year-old man with pleuroperitoneal communication on continuous ambulatory peritoneal dialysis who was diagnosed with ED-SCLC based on a cytological analysis of the peritoneal fluid. He was switched from peritoneal dialysis to hemodialysis and received durvalumab (1500 mg/body on day 1) plus carboplatin (area under the concentration-time curve = 5, 125 mg on day 1) and etoposide (50 mg/m2 on days 1 and 3) as first-line therapy. During the first cycle, grade 2 anemia, grade 3 neutropenia, and grade 3 upper gastrointestinal bleeding occurred; therefore, durvalumab and reduced doses of carboplatin and etoposide were administered. No other severe adverse events occurred, and a partial response was observed after four cycles. Our findings indicate that durvalumab plus carboplatin-etoposide treatment is safe and effective even in patients on hemodialysis.

Complement terminal pathway inhibition reduces peritoneal injuries in a rat peritonitis model.

Peritonitis and the resulting peritoneal injuries are common problems that prevent long-term peritoneal dialysis (PD) therapy in patients with end-stage kidney diseases. Previously, we have analyzed the relationship between the complement system and progression of peritoneal injuries associated with PD, particularly focusing on the early activation pathways and effects of the anaphylatoxins. We here utilized a novel mAb 2H2 that blocks assembly of the membrane attack complex (MAC) to investigate roles of the complement terminal pathway in PD-associated peritoneal injury. We intraperitoneally injected mAb 2H2 anti-C5b-7 (2.5 or 5 mg/rat) once or twice over the five-day course of the experiment to investigate the effects of inhibiting formation of MAC in a fungal rat peritonitis model caused by repeated intraperitoneal administration of zymosan after methylglyoxal pretreatment (Zy/MGO model). Rats were sacrificed on day 5 and macroscopic changes in both parietal and visceral peritoneum evaluated. Peritoneal thickness, the abundance of fibrinogen and complement C3 and MAC deposition in tissue and accumulation of inflammatory cells were pathologically assessed. The results showed that mAb 2H2, but not isotype control mAb, reduced peritoneal thickness and accumulation of inflammatory cells in a dose and frequency-dependent manner in the Zy/MGO model. These effects were accompanied by decreased C3, MAC, and fibrinogen deposition in peritoneum. In conclusion, in the rat Zy/MGO model, complement terminal pathway activation and MAC formation substantially contributed to development of peritoneal injuries, suggesting that MAC-targeted therapies might be effective in preventing development of peritoneal injuries in humans.

Peritoneal Expression of Membrane Complement Regulators Is Decreased in Peritoneal Dialysis Patients with Infected Peritonitis.

In peritoneal dialysis (PD) patients, fungi and Pseudomonas aeruginosa are considered important causative microorganisms for peritonitis with poor prognosis. Our objective was to explore expressions of membrane complement (C) regulators (CRegs) and tissue injuries in the peritoneum of patients with PD-related peritonitis, including fungal and Pseudomonas aeruginosa peritonitis. In peritoneal biopsy tissues obtained at PD catheter removal, we investigated the severity of peritonitis-associated peritoneal injuries and the expression of CRegs, CD46, CD55, and CD59 against peritoneal tissues without any episode of peritonitis. In addition, we evaluated peritoneal injuries among fungal and Pseudomonas aeruginosa-peritonitis (P1) and Gram-positive bacterial peritonitis (P2). We also observed deposition of C activation products such as activated C and C5b-9 and measured sC5b-9 in the PD fluid of patients. As a result, the severity of peritoneal injuries correlated inversely with the expression of peritoneal CRegs. Peritoneal CReg expression in peritonitis was significantly reduced compared to no peritonitis. Peritoneal injuries were more severe in P1 than in P2. CReg expression was further decreased and C5b-9 further increased in P1 than in P2. In conclusion, severe peritoneal injuries due to fungal and Pseudomonas aeruginosa-peritonitis decreased CReg expression and increased deposition of activated C3 and C5b-9 in the peritoneum, suggesting that peritonitis, particularly fungal and Pseudomonas aeruginosa-peritonitis, might induce susceptibility to further peritoneal injuries due to excessive C activation.

Serum and plasma levels of Ba, but not those of soluble C5b-9, might be affected by renal function in chronic kidney disease patients.

BACKGROUND: During the last few decades, pathogenic mechanisms associated with uncontrolled activation of the complement (C) system and development of anti-C agents have been closely investigated in the field of nephrology. The usefulness of some C products such as C5a and sC5b-9 for diagnostic and prognostic purposes remains controversial. On the other hand, decreased renal function is being observed in many patients with or without nephritis as a background factor in progressively aging societies. We therefore investigated whether renal function influenced the evaluation of various complement components and activation products. METHODS: To investigate the influence of renal function on evaluations of C3, C4, CH50, Ba, C5a and sC5b-9, 40 patients were retrospectively chosen from among 844 patients without active glomerulonephritis from 2009 to 2016. We measured plasma and serum levels of C3, C4, CH50, Ba, C5a and sC5b-9 using enzyme-linked immunosorbent assays and compared the findings with inulin clearance (Cin) as a marker of preserved renal function. RESULTS: Both plasma and serum levels of Ba correlated significantly with Cin, but other values did not. Compared with patients with Cin ≥ 60 or ≥ 30 mL/min/1.73 m2, plasma and serum levels of Ba were increased in patients with Cin decreased to < 60 or < 30 mL/min/1.73 m2, but levels of C5a and sC5b-9 were not. CONCLUSION: The influence of renal function might need to be considered when evaluating Ba, but not C5a and sC5b-9, in plasma and serum samples from chronic kidney disease patients.

Interleukin-6 blockade reduces salt-induced cardiac inflammation and fibrosis in subtotal nephrectomized mice.

Cardiovascular disease is the most common comorbidity in patients with chronic kidney disease (CKD), affecting both their prognosis and quality of life. Cardiac fibrosis is common in patients with CKD with left ventricular diastolic dysfunction, and it is associated with increased risk of heart failure and mortality. Recent evidence suggests that high salt intake activates immune responses associated with local accumulation of sodium. We reported that high salt intake promotes cardiac inflammation in subtotal nephrectomized (Nx) mice. We investigated the effects of administration of MR16-1, a rat anti-mouse monoclonal interleukin (IL)-6 receptor antibody, in Nx mice with salt loading (Nx-salt). Expression of monocyte chemoattractant protein-1, tumor necrosis factor-α, IL-1ß, and IL-6 mRNAs and macrophage infiltration was significantly reduced in the heart of Nx-salt mice treated with MR16-1 (Nx-salt-MR16-1) compared with Nx-salt mice treated with control rat rat IgG1 (Nx-salt-rat IgG1). Correspondingly, cardiac fibrosis was significantly attenuated in Nx-salt-MR16-1 mice compared with Nx-salt-rat IgG1 mice. Furthermore, in the heart of Nx-salt-MR16-1 mice, expression of mRNA for nicotinamide adenine dinucleotide phosphate oxidase-2, an oxidative stress marker, was significantly downregulated compared with Nx-salt-rat IgG1 mice. Increases in cardiac metabolites, including histidine and γ-butyrobetaine, were also reversed by IL-6 blockade treatment. In conclusion, IL-6 blockade exerts anti-inflammatory, antifibrotic, and partial antioxidative effects in the heart of Nx-salt mice.NEW & NOTEWORTHY In the present study, IL-6 blockade exerted anti-inflammatory, antifibrotic, and partial antioxidative effects on the hearts of mice with CKD on a high-salt diet. Therefore, IL-6 potentially mediates cardiac fibrosis induced by high salt intake in patients with CKD, a finding with therapeutic implications. Of note, the next therapeutic implication may simply be the reinforcement of low-salt diets or diuretics and further research on the anti-inflammatory effects of these measures rather than IL-6 blockade with high-salt diet.

Long-term peritoneal dialysate exposure modulates expression of membrane complement regulators in human peritoneal mesothelial cells.

The membrane complement regulators (CRegs) CD46, CD55, and CD59 are highly expressed on human peritoneal mesothelial cells. However, how mesothelial CRegs change according to the peritoneal dialysis (PD) history of patients has remained unclear. We therefore examined longitudinal changes in CRegs in primary cultured mesothelial cells from PD patients (human peritoneal mesothelial cells; HPMCs) and examined which components of PD fluid (PDF) affect CRegs in vitro. We measured levels of soluble C5b-9 in overnight-dwelling PDF in PD patients and also evaluated changes in CRegs expression on HPMCs collected from PDF using flow cytometry and polymerase chain reaction at a 1-year interval of PD therapy. We also evaluated changes in CReg expressions with stimulation by each component of PDF (glucose, lactic acid and pH) using the Met5A human mesothelial cell line. Levels of sC5b-9 in PDF decreased significantly during 1 year, while expressions of CD46 and CD59 proteins and mRNAs increased significantly in HPMCs during 1 year. Analyzing Met-5A cells, we observed that expressions of the three CRegs were increased by glucose and lactic acid in a concentration-dependent manner, but conversely that expressions of CRegs were decreased by lower pH stimulation. History of PD might influence expression of CRegs by HPMCs through properties of PDF such as glucose, lactic acid, and pH. These results suggest that mesothelial cells may alter expression of CRegs for the purpose of protecting the peritoneum and the presence of PDF might affect peritoneal homeostasis associated with the complement system.

C1 inhibitor mitigates peritoneal injury in zymosan-induced peritonitis.

Peritonitis, due to a fungal or bacterial infection, leads to injury of the peritoneal lining and thereby forms a hazard for the long-term success of peritoneal dialysis (PD) and remains a lethal complication in patients with PD. This study investigated whether C1 inhibitor (C1-INH) could protect against the progression of peritoneal injuries with five daily administrations of zymosan after mechanical scraping of the rat peritoneum to mimic fungal peritonitis. Severe peritoneal injuries were seen in this model, accompanied by fibrinogen/fibrin exudation and peritoneal deposition of complement activation products such as activated C3 and C5b-9. However, intraperitoneal injection of C1-INH decreased peritoneal depositions of activated C3 and C5b-9, ameliorated peritoneal thickening, reduced the influx of inflammatory cells, and prevented the production of peritoneal fibrous layers with both one and two doses of C1-INH each day. Our results suggest that C1-INH might be useful to protect against peritoneal injuries after causes of peritonitis such as fungal infection. This clinically available agent may thus help extend the duration of PD.NEW & NOTEWORTHY Peritoneal injuries associated with peritonitis comprise an important issue to prevent long-term peritoneal dialysis (PD) therapy. Here, we showed that C1 inhibitor (C1-INH), as an anticomplement agent, protected against peritoneal injuries in a peritonitis animal model related to fungal infection. Therefore, C1-INH might be useful to protect against peritoneal injuries after peritonitis due to fungal infection. This clinically available agent may thus help extend the duration of PD.

Refractory Hypotension Caused by Selenium Deficiency in a Patient on Peritoneal Dialysis.

Selenium is essential for human health; its deficiency leads to cardiac dysfunction. We herein report a 79-year-old man on peritoneal dialysis who presented with refractory hypotension caused by selenium deficiency. He was admitted to our hospital with bacterial pneumonia and hypotension and abnormal electrocardiogram (ECG) findings. Despite improvement of pneumonia, his hypotension continued, and intravenous noradrenalin could not be discontinued. His serum selenium level was extremely low, and he was started on intravenous selenium. His hypotension and ECG findings gradually improved, and noradrenalin was discontinued. Physicians should consider selenium deficiency when patients on peritoneal dialysis show refractory hypotension.

Oral Antibiotics are Effective for Preventing Colonoscopy-associated Peritonitis as a Preemptive Therapy in Patients on Peritoneal Dialysis.

Objective In patients on peritoneal dialysis (PD), it was reported that colonoscopy, but not upper gastrointestinal endoscopy, could cause peritonitis as a complication. A guideline of the International Society for Peritoneal Dialysis recommends preemptive intravenous antibiotics administration of ampicillin and aminoglycoside with or without metronidazole, to prevent colonoscopy-associated peritonitis. In this study, we retrospectively evaluated the effects of preemptive antibiotics therapy by oral administration instead of intravenous administration. Methods We investigated the incidence of colonoscopy-associated peritonitis in a single center. In 170 patients undergoing PD between January 2010 and December 2019, 50 colonoscopies were performed, including 49 with oral administration of amoxicillin and ciprofloxacin and/or metronidazole as preemptive therapy 1 hour before the colonoscopy procedure, and 1 without. Results We observed no incidence of colonoscopy-associated peritonitis. Conclusion Generally, oral administration of preemptive antibiotics is less painful and more convenient than intravenous administration, especially in outpatient procedures, such as a colonoscopy. Our results suggest that oral antibiotic administration might be effective for preventing colonoscopy-associated peritonitis in PD patients.

Differential contribution of C5aR and C5b-9 pathways to renal thrombic microangiopathy and macrovascular thrombosis in mice carrying an atypical hemolytic syndrome-related factor H mutation.

Atypical hemolytic uremic syndrome (aHUS) is a form of thrombotic microangiopathy (TMA) caused by dysregulated complement activation. Clinically, aHUS is effectively treated by an anti-C5 monoclonal antibody (mAb) but whether the disease is mediated by the C5a receptor (C5aR) or C5b-9 pathway, or both, is unknown. Here we address this in a factor H mutant mouse (FHR/R) which developed complement-mediated TMA as well as macrovascular thrombosis caused by an aHUS-related factor H point mutation (mouse W1206R, corresponding to human W1183R). C5 deficiency and anti-C5 mAb treatment blocked all disease manifestations in FHR/R mice. C5aR1 gene deficiency prevented macrovascular thrombosis in various organs but did not improve survival or reduce renal TMA. Conversely, C6 or C9 deficiency significantly improved survival and markedly diminished renal TMA but did not prevent macrovascular thrombosis. Interestingly, as they aged both FHR/R C6-/- and FHR/R C9-/- mice developed glomerular disease reminiscent of C3 glomerulonephritis. Thus, C5aR and C5b-9 pathways drove different aspects of disease in FHR/R mice with the C5aR pathway being responsible for macrovascular thrombosis and chronic inflammatory injury while the C5b-9 pathway caused renal TMA. Our data provide new understanding of the pathogenesis of complement-mediated TMA and macrovascular thrombosis in FHR/R mice and suggest that C5 blockade is more effective for the treatment of aHUS than selectively targeting the C5aR or C5b-9 pathway alone.

Complement Factor H Mutation W1206R Causes Retinal Thrombosis and Ischemic Retinopathy in Mice.

Single-nucleotide polymorphisms and rare mutations in factor H (FH; official name, CFH) are associated with age-related macular degeneration and atypical hemolytic uremic syndrome, a form of thrombotic microangiopathy. Mice with the FH W1206R mutation (FHR/R) share features with human atypical hemolytic uremic syndrome. Herein, we report that FHR/R mice exhibited retinal vascular occlusion and ischemia. Retinal fluorescein angiography demonstrated delayed perfusion and vascular leakage in FHR/R mice. Optical coherence tomography imaging of FHR/R mice showed retinal degeneration, edema, and detachment. Histologic analysis of FHR/R mice revealed retinal thinning, vessel occlusion, as well as degeneration of photoreceptors and retinal pigment epithelium. Immunofluorescence showed albumin leakage from blood vessels into the neural retina, and electron microscopy demonstrated vascular endothelial cell irregularity with narrowing of retinal and choroidal vessels. Knockout of C6, a component of the membrane attack complex, prevented the aforementioned retinal phenotype in FHR/R mice, consistent with membrane attack complex-mediated pathogenesis. Pharmacologic blockade of C5 also rescued retinas of FHR/R mice. This FHR/R mouse strain represents a model for retinal vascular occlusive disorders and ischemic retinopathy. The results suggest complement dysregulation can contribute to retinal vascular occlusion and that an anti-C5 antibody might be helpful for C5-mediated thrombotic retinal diseases.

Blocking Properdin Prevents Complement-Mediated Hemolytic Uremic Syndrome and Systemic Thrombophilia.

Background Properdin (P) is a positive regulator of the alternative pathway of complement activation. Although P inhibition is expected and has been shown to ameliorate the alternative pathway of complement-mediated tissue injury in several disease models, it unexpectedly exacerbated renal injury in a murine model of C3 glomerulopathy. The role of P in atypical hemolytic uremic syndrome (aHUS) is uncertain.Methods We blocked P function by genetic deletion or mAb-mediated inhibition in mice carrying a factor H (FH) point mutation, W1206R (FHR/R), that causes aHUS and systemic thrombophilia with high mortality.Results P deficiency completely rescued FHR/R mice from premature death and prevented thrombocytopenia, hemolytic anemia, and renal disease. It also eliminated macrovessel thrombi that were prevalent in FHR/R mice. All mice that received a function-blocking anti-P mAb for 8 weeks survived the experimental period and appeared grossly healthy. Platelet counts and hemoglobin levels were significantly improved in FHR/R mice after 4 weeks of anti-P mAb treatment. One half of the FHR/R mice treated with an isotype control mAb but none of the anti-P mAb-treated mice developed stroke-related neurologic disease. Anti-P mAb-treated FHR/R mice showed largely normal renal histology, and residual liver thrombi were detected in only three of 15 treated mice.Conclusions These results contrast with the detrimental effect of P inhibition observed in a murine model of C3 glomerulopathy and suggest that P contributes critically to aHUS pathogenesis. Inhibition of P in aHUS may be of therapeutic benefit.

Investigation on the benefits of mycophenolate mofetil and therapeutic drug monitoring in the treatment of Japanese patients with lupus nephritis.

BACKGROUND: Mycophenolate mofetil (MMF) is recommended as a first-line immunosuppressant to treat lupus nephritis (LN). Prognosis and therapeutic response in LN are known to vary depending on race. We investigated the benefits of MMF and therapeutic drug monitoring (TDM) in the treatment of Japanese LN patients. METHODS: In this retrospective cohort study, a total of 20 patients with LN who started MMF treatment were included. Clinical data were collected regularly after MMF administration. We evaluated complete remission (CR) rate as the primary outcome. Predictors of CR were identified using univariate and multivariate analyses. In the research of TDM, the correlation with the area under the curve (AUC) was analyzed at MMF dose, single-point value, treatment response, and adverse events. RESULTS: Overall, 70% of cases showed CR; both flare-ups and refractory cases had favorable results. Cases of LN with nephrotic syndrome (NS) or class III/IV + V showed a significantly lower CR rate (p < 0.005). The ratio of maintaining CR after MMF therapy was as high as 85.7%. In multivariate analysis, NS was an independent negative predictor of CR (HR 0.09, 95% confidence interval 0.01-0.81; p = 0.03). The relationship between AUC and MMF dose was low, and AUC correlated with trough level (r = 0.73). AUC tended to be high in the treatment responder (p = 0.09), but did not correlate with adverse events of infection (p = 0.92). CONCLUSION: MMF is a beneficial treatment option for Japanese LN patients, and further investigation on TDM-based therapy is needed.

Single-dose Rituximab Therapy for Refractory Idiopathic Membranous Nephropathy: A Single-center Experience.

To date, a recognized treatment for refractory membranous nephropathy (MN) has not been established. Recently, several reports have indicated the efficacy of rituximab as a novel treatment option. However, only a few published accounts exist of rituximab therapy for idiopathic MN (IMN) in the Asian population. We present the cases of three IMN patients who were treated with single-dose rituximab after they showed no response to conventional therapies, including corticosteroids, cyclosporine, cyclophosphamide, mizoribine, and mycophenolate mofetil. Although one case showed no response, a complete or incomplete remission was achieved in the other two cases. Rituximab may therefore be a beneficial treatment option for IMN.

Transfusion of CD206+ M2 Macrophages Ameliorates Antibody-Mediated Glomerulonephritis in Mice.

Macrophages are multifunctional immune cells that may either drive or modulate disease pathogenesis, depending on the activated phenotype. In this study, we investigated the protective effects of CD206+ M2 macrophages against nephrotoxic serum nephritis in mice. We found that these immunosuppressive macrophages, derived from bone marrow and stimulated with IL-4/IL-13 [CD206+ M2 bone marrow-derived macrophages (M2BMMs)], protected against renal injury, decreased proteinuria, and diminished the infiltration of CD68+ macrophages, neutrophils, and T cells into glomerular tissue. Comparable therapeutic results were obtained with CD206+ M2 cells derived from induced pluripotent stem cells. Notably, CD206+ M2BMMs, which retained an M2 signature, could elicit a switch of M1 to M2 phenotype in co-cultured macrophages. Moreover, these cells were found to induce the production of regulatory T cells in the spleen and renal draining lymph node. Accordingly, mRNA expression of the T helper 1 cytokines tumor necrosis factor-α, interferon-ß, interferon-γ, and IL-12 was significantly reduced in kidneys from mice treated with CD206+ M2BMMs. Taken together, the data suggest that CD206+ M2 may have therapeutic potential against antibody-mediated glomerular injury and presents its therapeutic value for the treatment of crescentic nephritis in humans.

Urinary soluble CD163 level reflects glomerular inflammation in human lupus nephritis.

BACKGROUND: In addition to classically activated macrophages that have effector roles in tissue injury, alternatively activated M2 macrophages are involved in the resolution of inflammation in animal models of kidney disease. To clarify the clinical relevance of macrophage phenotypes in human glomerular diseases, we evaluated the renal accumulation of macrophages and plasma and urine levels of CD163, an M2 marker, in lupus nephritis (LN) patients. METHODS: Kidney biopsies and plasma and urine samples were obtained from LN patients who underwent renal biopsy between 2008 and 2012. CD163+, CD68+ and CD204+ cells were counted in paraffin-embedded and frozen sections. LN histological activity was evaluated semiquantitatively using the biopsy activity index. Plasma and urinary soluble CD163 (sCD163) concentrations were also measured and evaluated for their significance as potential LN biomarkers. RESULTS: Immunohistological analysis of glomeruli from LN patients revealed that >60% of CD68+ macrophages had merged with CD163+ cells. The increased number of glomerular CD163+ macrophages was correlated with LN severity, as determined by the biopsy active index (r = 0.635). Urinary (u-) sCD163 level was strongly correlated with glomerular CD163+ cell counts and histological disease score as well as urinary monocyte chemoattractant protein 1 levels (r = 0.638 and 0.592, respectively). Furthermore, the u-sCD163 level was higher in patients with active LN than in those with other diseases. CONCLUSIONS: Glomerular CD163+ macrophages are the predominant phenotype in the kidneys of lupus patients. These findings indicate that the u-sCD163 level can serve as a biomarker for macrophage-dependent glomerular inflammation in human LN.

Therapeutic Potential of Stem Cells from Human Exfoliated Deciduous Teeth in Models of Acute Kidney Injury.

BACKGROUND: Acute kidney injury (AKI) is a critical condition associated with high mortality. However, the available treatments for AKI are limited. Stem cells from human exfoliated deciduous teeth (SHED) have recently gained attention as a novel source of stem cells. The purpose of this study was to clarify whether SHED have a therapeutic effect on AKI induced by ischemia-reperfusion injury. METHODS: The left renal artery and vein of the mice were clamped for 20 min to induce ischemia. SHED, bone marrow derived mesenchymal stem cells (BMMSC) or phosphate-buffered saline (control) were administered into the subrenal capsule. To confirm the potency of SHED in vitro, H2O2 stimulation assays and scratch assays were performed. RESULTS: The serum creatinine and blood urea nitrogen levels of the SHED group were significantly lower than those of the control group, while BMMSC showed no therapeutic effect. Infiltration of macrophages and neutrophils in the kidney was significantly attenuated in mice treated with SHED. Cytokine levels (MIP-2, IL-1ß, and MCP-1) in mice kidneys were significantly reduced in the SHED group. In in vitro experiments, SHED significantly decreased MCP-1 secretion in tubular epithelial cells (TEC) stimulated with H2O2. In addition, SHED promoted wound healing in the scratch assays, which was blunted by anti-HGF antibodies. DISCUSSION: SHED attenuated the levels of inflammatory cytokines and improved kidney function in AKI induced by IRI. SHED secreted factors reduced MCP-1 and increased HGF expression, which promoted wound healing. These results suggest that SHED might provide a novel stem cell resource, which can be applied for the treatment of ischemic kidney injury.

Rat adipose tissue-derived stem cells attenuate peritoneal injuries in rat zymosan-induced peritonitis accompanied by complement activation.

BACKGROUND AIMS: In patients receiving peritoneal dialysis, fungal or yeast peritonitis has a poor prognosis. In rat peritoneum with mechanical scraping, severe peritonitis can be induced by zymosan, a component of yeast (Zy/scraping peritonitis). Administration of rat adipose tissue-derived stromal cells (ASCs) potentially can improve several tissue injuries. The present study investigated whether rat ASCs could improve peritoneal inflammation in Zy/scraping peritonitis. METHODS: Rat ASCs were injected intraperitoneally on a daily basis in rats with Zy/scraping peritonitis. RESULTS: Peritoneal inflammation accompanied by accumulation of inflammatory cells and complement deposition was suppressed by day 5 after injection of rat ASCs. The peritoneal mesothelial layer in Zy/scraping peritonitis with rat ASC treatment was restored compared with the peritoneal mesothelial layer without rat ASC treatment. Injected rat ASCs co-existed with mesothelial cells in the sub-peritoneal layer. In vitro assays showed increased cellular proliferation of rat mesothelial cells combined with rat ASCs by co-culture assays, confirming that fluid factors from rat ASCs might play some role in facilitating the recovery of rat mesothelial cells. Hepatocyte growth factor was released from rat ASCs, and administration of recombinant hepatocyte growth factor increased rat mesothelial cell proliferation. CONCLUSIONS: Because the peritoneal mesothelium shows strong expression of membrane complement regulators such as Crry, CD55 and CD59, restoration of the mesothelial cell layer by rat ASCs might prevent deposition of complement activation products and ameliorate peritoneal injuries. This study suggests the therapeutic possibilities of intraperitoneal rat ASC injection to suppress peritoneal inflammation by restoring the mesothelial layer and decreasing complement activation in fungal or yeast peritonitis.

Serum-starved adipose-derived stromal cells ameliorate crescentic GN by promoting immunoregulatory macrophages.

Mesenchymal stromal cells (MSCs) derived from adipose tissue have immunomodulatory effects, suggesting that they may have therapeutic potential for crescentic GN. Here, we systemically administered adipose-derived stromal cells (ASCs) in a rat model of anti-glomerular basement membrane (anti-GBM) disease and found that this treatment protected against renal injury and decreased proteinuria, crescent formation, and infiltration by glomerular leukocytes, including neutrophils, CD8(+) T cells, and CD68(+) macrophages. Interestingly, ASCs cultured under low-serum conditions (LASCs), but not bone marrow-derived MSCs (BM-MSCs), increased the number of immunoregulatory CD163(+) macrophages in diseased glomeruli. Macrophages cocultured with ASCs, but not with BM-MSCs, adopted an immunoregulatory phenotype. Notably, LASCs polarized macrophages into CD163(+) immunoregulatory cells associated with IL-10 production more efficiently than ASCs cultured under high-serum conditions. Pharmaceutical ablation of PGE2 production, blocking the EP4 receptor, or neutralizing IL-6 in the coculture medium all significantly reversed this LASC-induced conversion of macrophages. Furthermore, pretreating LASCs with aspirin or cyclooxygenase-2 inhibitors impaired the ability of LASCs to ameliorate nephritogenic IgG-mediated renal injury. Taken together, these results suggest that LASCs exert renoprotective effects in anti-GBM GN by promoting the phenotypic conversion of macrophages to immunoregulatory cells, suggesting that LASC transfer may represent a therapeutic strategy for crescentic GN.