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Macrophage Infiltration (macrophage + infiltration)
Selected AbstractsMACROPHAGE INFILTRATION AND INDUCTION OF P75 NTR AND IL-1B IN THE NERVE OF DIABETIC RATSJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2000G. Conti Recently, inflammation has been involved in the pathogenesis of diabetic neuropathy, and activated macrophages have been found in the peripheral nervous system of diabetic rats, with a possible role in chemotaxis and regeneration. In this study, we obtained sciatic nerve specimens from diabetic rats at different time points following STZ administration. Macrophages infiltration, IL-1b and p75NTR induction were analyzed by immunocytochemistry on frozen sections and on teased nerve fibers. Apoptosis was detected on teased nerve fibers by TUNEL and DAPI staining. Cell phenotype was characterized by double-staining with antibodies specific for Schwann cells and macrophages. The nerves obtained from STZ-diabetic rats showed macrophages infiltration by day 14 following STZ administration, with complete clearance by day 35. Fifteen percent of these cells were TUNEL positive. IL-1B induction was concomitant with macrophages infiltration and not detectable by day 35. p75NTR expression began by day 21, peaking by day 35, and dropping to barely detectable levels by day 105. These findings seem to indicate that the concomitance of these processes may be crucial in the regulation of nerve damage and in promoting an attempt of regeneration at the early stages of STZ diabetic neuropathy. [source] Chronic Ethanol-Induced Insulin Resistance Is Associated With Macrophage Infiltration Into Adipose Tissue and Altered Expression of AdipocytokinesALCOHOLISM, Issue 9 2007Li Kang Background:, Chronic ethanol consumption disrupts glucose homeostasis and is associated with the development of insulin resistance. While adipose tissue and skeletal muscle are the two major organs utilizing glucose in response to insulin, the relative contribution of these two tissues to impaired glucose homeostasis during chronic ethanol feeding is not known. As other models of insulin resistance, such as obesity, are characterized by an infiltration of macrophages into adipose tissue, as well as changes in the expression of adipocytokines that play a central role in the regulation of insulin sensitivity, we hypothesized that chronic ethanol-induced insulin resistance would be associated with increased macrophage infiltration into adipose tissue and changes in the expression of adipocytokines by adipose tissue. Methods:, Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. The effects of chronic ethanol feeding on insulin-stimulated glucose utilization were studied using the hyperinsulinemic-euglycemic clamp technique, coupled with the use of isotopic tracers. Further, macrophage infiltration into adipose tissue and expression of adipocytokines were also assessed after chronic ethanol feeding. Results:, Hyperinsulinemic-euglycemic clamp studies revealed that chronic ethanol feeding to rats decreased whole-body glucose utilization and decreased insulin-mediated suppression of hepatic glucose production. Chronic ethanol feeding decreased glucose uptake in epididymal, subcutaneous, and omental adipose tissue during the hyperinsulinemic-euglycemic clamp, but had no effect on glucose disposal in skeletal muscle. Chronic ethanol feeding increased the infiltration of macrophages into epididymal adipose tissue and changed the expression of mRNA for adipocytokines: expression of mRNA for monocyte chemoattractant protein 1, tumor necrosis factor ,, and interleukin-6 were increased, while expression of mRNA for retinol binding protein 4 and adiponectin were decreased in epididymal adipose tissue. Conclusions:, These data demonstrate that chronic ethanol feeding results in the development of insulin resistance, associated with impaired insulin-mediated suppression of hepatic glucose production and decreased insulin-stimulated glucose uptake into adipose tissue. Chronic ethanol-induced insulin resistance was associated with increased macrophage infiltration into adipose tissue, as well as changes in the expression of adipocytokines by adipose tissue. [source] Heparin Coating of Small-Caliber Decellularized Xenografts Reduces Macrophage Infiltration and Intimal HyperplasiaARTIFICIAL ORGANS, Issue 6 2009Wei-Wei Cai Abstract Small-caliber decellularized xenografts with surface heparin coating are known to reduce in vivo thrombogenicity. This study was performed to examine whether heparin coating on the small-caliber decellularized xenografts would reduce macrophage infiltration and intimal hyperplasia. In a rabbit model of bilateral carotid implantation, each of the animals (n = 18) received a heparin-coated decellularized xenograft from a canine carotid artery on one side and a nonheparin-coated one on the other side. These experiments were terminated respectively at 1 week (n = 6), 3 weeks (n = 6), and 12 weeks (n = 6). Results showed that, compared with the nonheparin-coated grafts, the heparin-coated grafts had significantly less macrophage infiltration 1 week after implantation, identified by the mouse antirabbit macrophage antibody (RAM11)-positive cells on the vascular wall, covering all the proximal, middle, and distal parts of the grafts (P < 0.01). Moreover, the heparin-coated grafts also showed less deposition of proliferation cell nuclear antigen (PCNA)-positive cells on the vascular wall, indicating less cell proliferation, which was significant not only at 1 week (P < 0.01) but also at 12 weeks (P < 0.01). Intimal hyperplasia, measured by the intimal : media (I : M) ratio, was found similar in both groups at 1 and 3 weeks. However, the I : M ratio was significantly lower in the heparin-coated group than in the nonheparin-coated group at 12 weeks, especially in the proximal anastomosis area (0.76 ± 0.12 vs. 0.345 ± 0.06, P < 0.01). Heparin coating of small-caliber decellularized xenografts is associated with an early reduction of macrophage infiltration and intimal hyperplasia in a rabbit model of bilateral carotid artery implantation for 12 weeks. Thus, heparin coating appears to deliver not only the antithrombogeneity but also the antiproliferative property for small-caliber decellularized xenografts. [source] Anti-VEGF-A therapy reduces lymphatic vessel density and expression of VEGFR-3 in an orthotopic breast tumor modelINTERNATIONAL JOURNAL OF CANCER, Issue 10 2007Brandt Whitehurst Abstract Because metastasis contributes significantly to cancer mortality, understanding its mechanisms is crucial to developing effective therapy. Metastasis is facilitated by lymphangiogenesis, the growth of new intratumoral or peritumoral lymphatic vessels from pre-existing vessels. Vascular endothelial growth factor A (VEGF-A) is a well-known angiogenic factor. Increasing evidence implicates VEGF-A in lymphangiogenesis, although the mechanism of its pro-lymphangiogenic effect is poorly understood. We examined the effect of the anti-VEGF-A neutralizing antibody 2C3 on tumor lymphangiogenesis and metastasis in an orthotopic breast carcinoma model using MDA-MB-231 cells and its luciferase-tagged derivative, 231-Luc+ cells. Anti-VEGF-A antibody therapy reduced blood and lymphatic vessel densities by 70% and 80%, respectively, compared with the control antibody. Treatment with 2C3 antibody also decreased incidence of lymphatic and pulmonary metastases by 3.2- and 4.5-fold, respectively. Macrophage infiltration was reduced in 2C3-treated tumors by 32%, but VEGF-C expression was unchanged. In contrast, neoplastic cells and blood vessels in tumors from 2C3-treated mice expressed significantly less angiopoietin-2 (Ang-2) than tumors from control mice. The reduction in Ang-2 was associated with inhibition of VEGFR-3 expression in intratumoral lymphatic endothelial cells. Both VEGF-A and Ang-2 upregulated the expression of VEGFR-3 in cultured lymphatic endothelial cells. VEGF-A induced proliferation of lymphatic endothelial cells was reduced by 50% by soluble Tie-2, suggesting that Ang-2 is an intermediary of the pro-lymphangiogenic VEGF-A effect. These results suggest a novel mechanism by which anti-VEGF-A therapy may suppress tumor lymphangiogenesis and subsequent metastasis supporting the use of anti-VEGF-A therapy to control metastasis clinically. © 2007 Wiley-Liss, Inc. [source] C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinasesTHE JOURNAL OF PATHOLOGY, Issue 5 2004Toshiyuki Okuma Abstract Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2,/,) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 ,/, mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2,/, and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2,/, mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2,/, mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2,/, mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2,/, mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2,/, mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Serum interleukin-6 is elevated in symptomatic carotid bifurcation diseaseACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009M. Koutouzis Introduction,,, The levels of circulating proinflammatory cytokines may express the extent of the inflammatory response and their participation in plaque progression and rupture needs to be evaluated. We aimed to investigate differences in circulating levels of proinflammatory cytokines and in plaque infiltration by macrophages between patients undergoing carotid endarterectomy for symptomatic and asymptomatic carotid atherosclerotic disease. Methods,,, One hundred nineteen patients (91 men and 28 women; mean age 66 ± 8 years; range 42,83 years) who underwent carotid endarterectomy for significant (>70%) carotid bifurcation stenosis were enrolled in this study. Patients were characterized as symptomatic (n = 62) or asymptomatic (n = 57) after neurological examination. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-, (TNF-,), IL-1,, serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP) were evaluated. Macrophage infiltration of the plaque was assessed quantitatively from endarterectomy specimens using the monoclonal antibody CD68. Results,,, Serum IL-6 levels were significantly higher in patients with symptomatic compared with those with asymptomatic carotid disease (3.3 [2.0,6.5] pg/ml vs 2.5 [1.9,4.1] pg/ml, P = 0.02). TNF-,, IL-1,, SAA, and hs-CRP levels did not differ significantly between the two groups. Symptomatic patients had also more intense macrophage accumulation in the carotid plaque compared with asymptomatic patients (0.6 ± 0.1% vs 0.4 ± 0.1%, P < 0.001). Although there were correlations between the levels of the different inflammatory markers, there were no correlation between any of them and the extent of plaque macrophage infiltration. Conclusion,,, Patients with symptomatic carotid atherosclerotic disease have elevated serum IL-6 levels compared with asymptomatic patients. Symptomatic patients have also more intense macrophage infiltration of the atherosclerotic plaque suggesting that inflammatory process may contribute to the destabilization of the carotid plaque. [source] MACROPHAGE INFILTRATION AND INDUCTION OF P75 NTR AND IL-1B IN THE NERVE OF DIABETIC RATSJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2000G. Conti Recently, inflammation has been involved in the pathogenesis of diabetic neuropathy, and activated macrophages have been found in the peripheral nervous system of diabetic rats, with a possible role in chemotaxis and regeneration. In this study, we obtained sciatic nerve specimens from diabetic rats at different time points following STZ administration. Macrophages infiltration, IL-1b and p75NTR induction were analyzed by immunocytochemistry on frozen sections and on teased nerve fibers. Apoptosis was detected on teased nerve fibers by TUNEL and DAPI staining. Cell phenotype was characterized by double-staining with antibodies specific for Schwann cells and macrophages. The nerves obtained from STZ-diabetic rats showed macrophages infiltration by day 14 following STZ administration, with complete clearance by day 35. Fifteen percent of these cells were TUNEL positive. IL-1B induction was concomitant with macrophages infiltration and not detectable by day 35. p75NTR expression began by day 21, peaking by day 35, and dropping to barely detectable levels by day 105. These findings seem to indicate that the concomitance of these processes may be crucial in the regulation of nerve damage and in promoting an attempt of regeneration at the early stages of STZ diabetic neuropathy. [source] SARS-coronavirus modulation of myocardial ACE2 expression and inflammation in patients with SARSEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2009G. Y. Oudit Abstract Background, Angiotensin converting enzyme 2 (ACE2), a monocarboxylase that degrades angiotensin II to angiotensin 1,7, is also the functional receptor for severe acute respiratory syndrome (SARS) coronavirus (SARS-CoV) and is highly expressed in the lungs and heart. Patients with SARS also suffered from cardiac disease including arrhythmias, sudden cardiac death, and systolic and diastolic dysfunction. Materials and methods, We studied mice infected with the human strain of the SARS-CoV and encephalomyocarditis virus and examined ACE2 mRNA and protein expression. Autopsy heart samples from patients who succumbed to the SARS crisis in Toronto (Canada) were used to investigate the impact of SARS on myocardial structure, inflammation and ACE2 protein expression. Results, Pulmonary infection with the human SARS-CoV in mice led to an ACE2-dependent myocardial infection with a marked decrease in ACE2 expression confirming a critical role of ACE2 in mediating SARS-CoV infection in the heart. The SARS-CoV viral RNA was detected in 35% (7/20) of autopsied human heart samples obtained from patients who succumbed to the SARS crisis during the Toronto SARS outbreak. Macrophage-specific staining showed a marked increase in macrophage infiltration with evidence of myocardial damage in patients who had SARS-CoV in their hearts. The presence of SARS-CoV in the heart was also associated with marked reductions in ACE2 protein expression. Conclusions, Our data show that SARS-CoV can mediate myocardial inflammation and damage associated with down-regulation of myocardial ACE2 system, which may be responsible for the myocardial dysfunction and adverse cardiac outcomes in patients with SARS. [source] Fc, receptor I activation induces leukocyte recruitment and promotes aggravation of glomerulonephritis through the FcR, adaptorEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 4 2007Yutaka Kanamaru Abstract Myeloid cells bear Fc receptors (FcR) that mediate inflammatory signaling through the ITAM-containing FcR, adaptor. They express FcR,-associated Fc,RI, which modulate either activating or inhibitory signaling depending on the type of ligand interaction. The role of Fc,RI, in disease progression remains unknown, notably in IgA nephropathy (IgAN), one of major causes of end-stage renal disease, in which large amounts of circulating IgA-immune complexes (IC) may mediate receptor activation. To analyze the involvement of Fc,RI activation in glomerulonephritis (GN), we generated Tg mice expressing a mutated, signaling-incompetent, human Fc,RIR209L that cannot associate with FcR,. Like Fc,RIwt -Tg mice, they developed mesangial IgA deposits but not macrophage infiltration. Fc,RI activation in Fc,RIwt, but not in Fc,RIR209L, Tg mice resulted in marked inflammation with severe proteinuria and leukocyte infiltration in spontaneous IgAN or anti-glomerular basement membrane Ab-induced GN models. Receptor triggering of syngenically transferred Fc,RIwt Tg macrophages into non-Tg animals induced their recruitment into injured kidneys during GN development. Fc,RIwt cross-linking on macrophages activated MAP kinases and production of TNF-, and MCP-1. Moreover, IgA-IC from IgAN patients activated Fc,RI and induced TNF-, production. Thus, Fc,RI activation mediates GN progression by initiating a cytokine/chemokine cascade that promotes leukocyte recruitment and kidney damage. [source] Expression of VCAM-1, ICAM-1, E- and P-selectin and tumour-associated macrophages in renal cell carcinomaHISTOPATHOLOGY, Issue 1 2000B Hemmerlein Aims Neoangiogenesis is accompanied by an increase in endothelial surface, which can support infiltration by immune cells depending on adhesion molecule expression. Therefore, the expression of cell adhesion molecules on microvessels and epithelial cells was analysed in renal cell carcinomas as compared to tumour-free tissue. Methods and results PECAM-1, CD34, ICAM-1, VCAM-1, VLA-4, P- and E-selectin, the macrophage antigens Ki-M1P and Mac-1, and lymphocyte function antigen LFA-1 were identified immunohistochemically. VCAM-1, ICAM-1, and E-selectin were equally or less expressed, whereas P-selectin was increased on microvessels in tumour tissue. The density of VCAM-1-positive tumour microvessels correlated positively with an advanced tumour stage and E- and P-selectin-positive tumour microvessels with the amount of associated macrophages. The expression of ICAM-1 and VCAM-1 on neoplastic epithelia correlated with an increased density of macrophages and a minor degree of tumour differentiation. Conclusions The positive correlation of macrophage infiltration and expression of cell adhesion molecules on tumour microvessels and epithelia with minor tumour differentiation and an advanced stage indicates that adhesion molecule expression is not associated with an effective antitumour function of macrophages [source] Stromal MCP-1 in mammary tumors induces tumor-associated macrophage infiltration and contributes to tumor progressionINTERNATIONAL JOURNAL OF CANCER, Issue 6 2009Hiroshi Fujimoto Abstract There is growing evidence that tumor-associated macrophages (TAMs) promote tumor growth and dissemination. Many individual reports have focused on the protumor function of molecules linked to the recruitment of macrophages, but little is known about which factor has the strongest impact on recruitment of macrophages in breast cancer. To elucidate this question, we performed RT-PCR using species-specific primers and evaluated tumoral and stromal mRNA expression of macrophage chemoattractants separately in human breast tumor xenografts. The correlation between the tumoral or stromal chemoattractant mRNA expression including monocyte chemoattractant protein-1 (MCP-1) (CCL2), MIP-1, (CCL3), RANTES (CCL5), colony-stimulating factor 1, tumor necrosis factor ,, platelet-derived growth factor (PDGF)-BB and macrophage infiltration were compared. There was significant positive correlation between stromal MCP-1 expression and macrophage number (r = 0.63), and negative correlation between tumoral RANTES expression and macrophage number (r = ,0.75). However, no significant correlation was found for the other tumoral and stromal factors. The interaction between the tumor cells and macrophages was also investigated. Tumor cell,macrophage interactions augmented macrophage-derived MCP-1 mRNA expression and macrophage chemotactic activity in vitro. Treatment of immunodeficient mice bearing human breast cancer cells with a neutralizing antibody to MCP-1 resulted in significant decrease of macrophage infiltration, angiogenetic activity and tumor growth. Furthermore, immunohistochemical analysis of human breast cancer tissue showed stromal MCP-1 had a significant correlation with relapse free survival (p = 0.029), but tumoral MCP-1 did not (p = 0.105). These findings indicate that stromal MCP-1 produced as a result of tumor,stromal interactions may be important for the progression of human breast cancer and macrophages may play an important role in this tumor,stroma interaction. © 2009 UICC. [source] A study to assess inducible nitric oxide synthase expression in oral lichen planusJOURNAL OF ORAL PATHOLOGY & MEDICINE, Issue 6 2000Peter A. Brennan Abstract: Nitric oxide (NO) has been implicated in a variety of diseases but has not been previously studied in oral lichen planus (OLP). Since OLP has a complex immunogenesis with abundant macrophage infiltration, this study determined by immunohistochemistry whether or not the expression of the inducible form of nitric oxide synthase (iNOS) was increased in this condition relative to normal mucosa. Thirty cases of OLP and 10 normal buccal mucosa biopsies were studied utilising primary antibodies to iNOS and CD68, a myelomonocytic marker. iNOS activity was additionally assessed using a [14,C]-labelled arginine to citrulline assay. CD68 expression was significantly increased in the cellular infiltrate of all 30 cases of OLP compared with normal mucosa (P<0.009). Although iNOS staining was seen in a minority of cells in nine cases, this was not statistically significant when compared with the absent staining in normal oral mucosa (P=0.26). Furthermore, the minimal iNOS activity found in OLP was similar to that in normal mucosa. We conclude that expression of iNOS by macrophages is downregulated in OLP and discuss the possible reasons for this finding. [source] Chronic Ethanol-Induced Insulin Resistance Is Associated With Macrophage Infiltration Into Adipose Tissue and Altered Expression of AdipocytokinesALCOHOLISM, Issue 9 2007Li Kang Background:, Chronic ethanol consumption disrupts glucose homeostasis and is associated with the development of insulin resistance. While adipose tissue and skeletal muscle are the two major organs utilizing glucose in response to insulin, the relative contribution of these two tissues to impaired glucose homeostasis during chronic ethanol feeding is not known. As other models of insulin resistance, such as obesity, are characterized by an infiltration of macrophages into adipose tissue, as well as changes in the expression of adipocytokines that play a central role in the regulation of insulin sensitivity, we hypothesized that chronic ethanol-induced insulin resistance would be associated with increased macrophage infiltration into adipose tissue and changes in the expression of adipocytokines by adipose tissue. Methods:, Male Wistar rats were fed a liquid diet containing ethanol as 36% of calories or pair-fed a control diet for 4 weeks. The effects of chronic ethanol feeding on insulin-stimulated glucose utilization were studied using the hyperinsulinemic-euglycemic clamp technique, coupled with the use of isotopic tracers. Further, macrophage infiltration into adipose tissue and expression of adipocytokines were also assessed after chronic ethanol feeding. Results:, Hyperinsulinemic-euglycemic clamp studies revealed that chronic ethanol feeding to rats decreased whole-body glucose utilization and decreased insulin-mediated suppression of hepatic glucose production. Chronic ethanol feeding decreased glucose uptake in epididymal, subcutaneous, and omental adipose tissue during the hyperinsulinemic-euglycemic clamp, but had no effect on glucose disposal in skeletal muscle. Chronic ethanol feeding increased the infiltration of macrophages into epididymal adipose tissue and changed the expression of mRNA for adipocytokines: expression of mRNA for monocyte chemoattractant protein 1, tumor necrosis factor ,, and interleukin-6 were increased, while expression of mRNA for retinol binding protein 4 and adiponectin were decreased in epididymal adipose tissue. Conclusions:, These data demonstrate that chronic ethanol feeding results in the development of insulin resistance, associated with impaired insulin-mediated suppression of hepatic glucose production and decreased insulin-stimulated glucose uptake into adipose tissue. Chronic ethanol-induced insulin resistance was associated with increased macrophage infiltration into adipose tissue, as well as changes in the expression of adipocytokines by adipose tissue. [source] The membrane attack complex (C5b-9) in liver cold ischemia and reperfusion injuryLIVER TRANSPLANTATION, Issue 8 2008Constantino Fondevila Activation of the complement cascade represents an important event during ischemia/reperfusion injury (IRI). This work was designed to investigate the role of the membrane attack complex (MAC; C5b-9) in the pathogenesis of hepatic IRI. Livers from B&W/Stahl/rC6(+) and C6(,) rats were harvested, stored for 24 hours at 4°C, and then transplanted [orthotopic liver transplantation (OLT)] to syngeneic recipients. There were 4 experimental groups: (1) C6(+),C6(+), (2) C6(+),C6(,), (3) C6(,),C6(+), and (4) C6(,),C6(,). At day +1, C6(,) OLTs showed decreased vascular congestion/necrosis, contrasting with extensive necrosis in C6(+) livers, that was independent of the recipient C6 status (Suzuki score: 7.2 ± 0.9, 7.3 ± 1.3, 4.5 ± 0.6, and 4.8 ± 0.4 for groups 1-4, respectively, P < 0.05). The liver function improved in recipients of C6(,) grafts (serum glutamic oxaloacetic transaminase: 2573 ± 488, 1808 ± 302, 1170 ± 111, and 1188 ± 184 in groups 1-4, respectively, P < 0.05). Intragraft macrophage infiltration (ED-1 immunostaining) and neutrophil infiltration (myeloperoxidase activity) were reduced in C6(,) grafts versus C6(+) grafts (P = 0.001); these data were confirmed by esterase staining (naphthol). The expression of proinflammatory interferon-,, interleukin-1,, and tumor necrosis factor messenger RNA/protein was also reduced in C6(,) OLTs in comparison with C6(+) OLTs. Western blot,assisted expression of proapoptotic caspase-3 was decreased in C6(,) OLTs versus C6(+) OLTs (P = 0.006), whereas antiapoptotic Bcl-2/Bag-1 was enhanced in C6(,) OLTs compared with C6(+) OLTs (P = 0.001). Terminal deoxynucleotidyl transferase,mediated dUTP nick end-labeling staining of apoptotic cells was enhanced (P < 0.05) in C6(+) OLTs compared with C6(,) OLTs. Thus, the terminal products of the complement system are essential in the mechanism of hepatic IRI. This is the first report using a clinically relevant liver cold ischemia model to show that local MAC inhibition attenuates IRI cascade in OLT recipients. Liver Transpl 14:1133,1141, 2008. © 2008 AASLD. [source] Rosiglitazone treatment attenuates renal tissue inflammation generated by urinary tract obstructionNEPHROLOGY, Issue 2 2009SHAI EFRATI SUMMARY Aim: Peroxisome proliferator-activated receptor (PPAR)-, activation by rosiglitazone decreases manifestation of intrarenal inflammatory hallmarks. Inflammation significantly aggravates renal injury following urinary tract obstruction. The effect of rosiglitazone on renal inflammation following unilateral ureteral obstruction was investigated. Methods: Ninety-six Srague,Dawley rats were subjected to unilateral ureteral ligation, or to sham operation. Half of each group received rosiglitazone, 5 mg/kg bodyweight per day. The animals were killed and their kidneys allocated following 1 h, 24 h or 2 weeks, for pathological examination or for intrarenal transforming growth factor (TGF)-,, interleukin (IL)-4, IL-6, IL-10 and nitric oxide (NO) assessment by specific enzyme-linked immunosorbent assays. Apoptosis rates, extracellular matrix deposition, PPAR-,, ,-smooth muscle actin (,-SMA) expression and macrophage infiltration were assessed by specific immunohistological stainings. Results: PPAR-, receptor expression was downregulated, and infiltration of macrophages decreased, in all rosiglitazone-treated kidneys. Rosiglitazone significantly decreased apoptosis, TGF-,, IL-6, ,-SMA expression and NO availability in obstructed kidneys. Synthesis of IL-10 was unaltered, while IL-4 augmented by Rosiglitazone. Rosiglitazone also affected NO and IL-4 production in sham-operated controls. Conclusion: (i) Rosiglitazone attenuates profibrotic and pro-inflammatory responses in a rat model of ureteral obstruction-induced renal inflammation; (ii) rosiglitazone stimulates counteractive anti-inflammatory responses in the damaged kidneys; (iii) in part, rosiglitazone exerts comparable anti-inflammatory effects on obstructed kidneys and unobstructed healthy controls. Taken together, this ascertains the importance of the anti-inflammatory role of rosiglitazone treatment in amelioration of ureteral obstruction-induced renal damage. [source] Partial depletion of macrophages by ED7 reduces renal injury in Adriamycin nephropathyNEPHROLOGY, Issue 5 2005YIPING WANG SUMMARY: Background: Because macrophages are considered to be possible effectors of disease in Adriamycin (ADR) nephrosis, we hypothesized that depletion of macrophages might protect against the initiation of renal injury. In the present study, a monoclonal antibody (ED7) directed against CD11b/CD18 integrin, which is expressed by macrophages, was used to investigate the pathogenetic effects of macrophages in ADR nephropathy. Methods: Male Wistar rats were treated with ED7 antibody, starting 1 day prior to ADR (7.5 mg/kg) treatment, or 7 days post-ADR when overt proteinuria was established. Results: Circulating ED7-positive cells were reduced by approximately 30% in rats with ADR nephrosis by the ED7 antibody, while the number of macrophages in the renal cortex of ADR rats was reduced by nearly 50% with the ED7 treatment, whether administered before or after ADR. Creatinine clearance was significantly ameliorated by ED7 when commenced pre-ADR (P < 0.05), but not when commenced post-ADR (P = NS) in comparison to untreated ADR rats. However, proteinuria was not alleviated by either ED7 treatment. Morphometric analysis showed less glomerular sclerosis when ED7 was commenced pre-ADR compared with ADR alone (P < 0.01), but not when commenced post-ADR (P = NS). Tubular atrophy was reduced by ED7 when it was commenced pre-ADR (tubular cell height and tubular diameter: P < 0.01 and P < 0.001, respectively), as was interstitial expansion (P < 0.01) compared with ADR alone. Cortical macrophage infiltration was reduced by 50% compared with ADR alone by the ED7 commenced before or after ADR. The number of cortical CD4+ T cells fell with ED7 starting pre-ADR, but not with the ED7 treatment commencing after ADR. Conclusion: Partial macrophage depletion starting before but not after ADR protected both renal function and structure in this model of chronic proteinuric renal disease. [source] Autopsy case of neuro-Behçet's disease with multifocal neutrophilic perivascular inflammationNEUROPATHOLOGY, Issue 6 2006Yoshifumi Arai We report here an autopsy case of neuro-Behçet's disease. The patient was a 28-year-old man, who developed a slight fever, right uveitis, and right sensory neural hearing loss at the age of 25. These symptoms relapsed repeatedly despite treatment. Eventually he was admitted to hospital because of progressing neurological deficits such as pyramidal symptoms, somatic sensorial and autonomic disorders, and bulbar palsy. The patient's condition deteriorated and he died of heart failure. Total clinical course was about three years. In postmortem examination, various-sized necrotic foci, often accompanied by gliosis and foamy macrophage infiltration, were scattered in the diencephalic region and brain stem. Meningitis was observed on the ventral side of the brain stem as well as inferior cerebral surface. Non-bacterial or non-fungal acute perivascular inflammatory foci were also present in the brain stem and cerebellar parenchyma. These histopathological findings suggest that a destructive multifocal neutrophilic inflammation might have caused the neurological deficits. Perivascular inflammation might be important to understanding the pathogenesis of neuro-Behçet's disease. [source] Fas-mediated upregulation of vascular endothelial growth factor and monocyte chemoattractant protein-1 expression in cultured dermal fibroblasts: Role in the inflammatory responseTHE JOURNAL OF DERMATOLOGY, Issue 2 2007Masao FUJIWARA ABSTRACT The Fas,Fas ligand interaction is the most important pathway in starting apoptosis. In addition, several recent reports have emerged documenting non-apoptotic roles for Fas. However, a non-apoptotic role of Fas in dermal fibroblasts remains unknown. The present study investigated whether Fas stimulation not only promotes apoptosis but also stimulates elements of the inflammatory response such as angiogenesis and macrophage infiltration. Fas stimulation was performed by treating cultured human dermal fibroblasts with an agonistic anti-Fas monoclonal antibody (mAb). Anti-Fas mAb-treated fibroblasts showed a significantly greater increase of caspase-3 and caspase-8 activity compared with control fibroblasts. Addition of the anti-Fas mAb induced DNA fragmentation, as confirmed by the DNA ladder assay. Terminal deoxynucleotidyl transferase-mediated 2,-deoxyuridine 5,-triphosphate nick end labeling (TUNEL) staining showed that treatment with the anti-Fas mAb induced an increase of apoptotic fibroblasts in a time-dependent manner. At both mRNA and protein levels, anti-Fas mAb-treated fibroblasts showed significantly higher expression of vascular endothelial growth factor (VEGF) and monocyte chemoattractant protein (MCP)-1 compared with control fibroblasts. A pan-caspase inhibitor (Z-VAD-FMK) significantly inhibited VEGF and MCP-1 expression. After transplantation of fibroblasts into mice with severe combined immunodeficiency, the nodules derived from anti-Fas mAb-treated fibroblasts showed more abundant neovascularization, increased macrophage infiltration, and more apoptotic cells in comparison with nodules derived from control fibroblasts. The results of both in vitro and in vivo studies confirmed significantly higher angiogenic activity and macrophage chemotactic activity of anti-Fas mAb-treated fibroblasts compared with control fibroblasts. [source] C-C chemokine receptor 2 (CCR2) deficiency improves bleomycin-induced pulmonary fibrosis by attenuation of both macrophage infiltration and production of macrophage-derived matrix metalloproteinasesTHE JOURNAL OF PATHOLOGY, Issue 5 2004Toshiyuki Okuma Abstract Macrophage infiltration is implicated in various types of pulmonary fibrosis. One important pathogenetic process associated with pulmonary fibrosis is injury to basement membranes by matrix metalloproteinases (MMPs) that are produced mainly by macrophages. In this study, C-C chemokine receptor 2-deficient (CCR2,/,) mice were used to explore the relationship between macrophage infiltration and MMP activity in the pathogenesis of pulmonary fibrosis, using the bleomycin-induced model of this disease process. CCR2 is the main (if not only) receptor for monocyte chemoattractant protein-1/C-C chemokine ligand 2 (MCP-1/CCL2), which is a critical mediator of macrophage trafficking, and CCR2 ,/, mice demonstrate defective macrophage migration. Pulmonary fibrosis was induced in CCR2,/, and wild-type (CCR2+/+) mice by intratracheal instillation of bleomycin. No significant differences in the total protein concentration in bronchoalveolar lavage (BAL) fluid, or in the degree of histological lung inflammation, were observed in the two groups until day 7. Between days 3 and 21, however, BAL fluid from CCR2,/, mice contained fewer macrophages than BAL fluid from CCR2+/+ mice. Gelatin zymography of BAL fluid and in situ zymography revealed reduced gelatinolytic activity in CCR2,/, mice. Immunocytochemical staining showed weaker expression of MMP-2 and MMP-9 in macrophages in BAL fluid from CCR2,/, mice at day 3. Gelatin zymography of protein extracted from alveolar macrophages showed reduced gelatinolytic activity of MMP-2 and MMP-9 in CCR2,/, mice. At days 14 and 21, lung remodelling and the hydroxyproline content of lung tissues were significantly reduced in CCR2,/, mice. These results suggest that the CCL2/CCR2 functional pathway is involved in the pathogenesis of bleomycin-induced pulmonary fibrosis and that CCR2 deficiency may improve the outcome of this disease by regulating macrophage infiltration and macrophage-derived MMP-2 and MMP-9 production. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] The Molecular Phenotype of Heart Transplant Biopsies: Relationship to Histopathological and Clinical VariablesAMERICAN JOURNAL OF TRANSPLANTATION, Issue 9 2010M. Mengel Histopathology of endomyocardial biopsies (EMB) is the standard rejection surveillance for heart transplants. However, ISHLT consensus criteria for interpreting biopsies are arbitrarily defined. Gene expression offers an independent re-evaluation of existing diagnostic systems. We performed histologic and microarray analysis on 105 EMB from 45 heart allograft recipients. Histologic lesions, diagnosis and transcripts were compared to one another, time posttransplantation, indication for biopsy and left ventricular ejection fraction (LVEF). Histologic lesions presented in two groups: myocyte,interstitial and microcirculation lesions. Expression of transcript sets reflecting T cell and macrophage infiltration, and ,-interferon effects correlated strongly with each other and with transcripts indicating tissue/myocardium injury. This molecular phenotype correlated with Quilty (p < 0.005), microcirculation lesions (p < 0.05) and decreased LVEF (p < 0.007), but not with the histologic diagnosis of rejection. In multivariate analysis, LVEF was associated (p < 0.03) with ,-interferon inducible transcripts, time posttransplantation, ischemic injury and clinically indicated biopsies, but not the diagnosis of rejection. The results indicate that (a) the current ISHLT system for diagnosing rejection does not reflect the molecular phenotype in EMB and lacks clinical relevance; (b) the interpretation of Quilty lesions has to be revisited; (c) the assessment of molecules in heart biopsy can guide improvements of current diagnostics. [source] Composite Tissue Vasculopathy and Degeneration Following Multiple Episodes of Acute Rejection in Reconstructive TransplantationAMERICAN JOURNAL OF TRANSPLANTATION, Issue 2 2010J. V. Unadkat Transplant vasculopathy has not been systematically investigated in composite tissue allotransplantation (CTA). The impact of multiple acute rejections (ARs) on long-term graft outcomes in reconstructive transplantation remains unknown. This study in a rat hind-limb allotransplantation model systematically analyzes vasculopathy and tissue-specific pathological changes secondary to multiple AR episodes. LEW rats were transplanted with BN rat hind limbs and treated as follows: Group 1 (Iso): isografts. Group 2 (CsA): Cyclosporine (CsA) qd; Group 3 (mult AR): CsA and dexamethasone only when AR was observed. No AR was observed in Groups 1 and 2. Multiple AR were observed in Group 3, and each episode was completely reversed (clinically) with pulsed CsA + dexamethasone treatment. Group 3 animals demonstrated significant vascular lesions along with skin and muscle atrophy, upregulation of profibrotic gene expression and fibrosis when compared to Groups 1 and 2. In addition, allograft bone was sclerotic, weak and prone to malunion and nonunion. Interestingly, vasculopathy was a late finding, whereas muscle atrophy with macrophage infiltration was seen early, after only a few AR episodes. Taken together, multiple AR episodes lead to vasculopathy and tissue-specific pathology in CTA. This is the first evidence of ,composite tissue vasculopathy and degeneration (CTVD)' in CTA. [source] Overexpression of cyclooxygenase-2 in urothelial carcinoma in conjunction with tumor-associated-macrophage infiltration, hypoxia-inducible factor-1, expression, and tumor angiogenesisAPMIS, Issue 3 2009WAN-TZU CHEN This study examines whether the expression of cyclooxgenase-2 (COX-2) in urothelial carcinoma (UC) is associated with macrophage infiltration, hypoxia-inducible factor-1, (HIF-1,) expression and angiogenesis. We investigated the expression of COX-2 associated with HIF-1, and performed double immunohistochemical analysis of 216 UCs for COX-2 expression and the correlation with tumor-associated-macrophage (TAM) density and microvessel density (MVD) in situ. A high expression of COX-2 was positively correlated with tumor invasiveness, histologic grade and HIF-1, expression in UC (p<0.0001, p=0.003, p<0.0001, respectively). Quantification of double staining of COX-2/CD34 and COX-2/CD68 showed that a higher MVD and TAM density was found in COX-2 high-expression than in COX-2 low-expression tumor fields (p<0.0001). Adjacent to the principal of COX-2 expression areas, MVD value and TAM density were significantly increased in HIF-1, high-expression specimens compared with HIF-1, low-expression ones (p<0.0001). Interestingly, our data revealed that high COX-2 expression (p=0.002), high HIF-1, expression (p<0.0001) and TAM density (p<0.0001) were all associated with high MVD value. Our results suggest that COX-2 may produce a cooperative effect in promoting tumor progression and may be involved in the process of angiogenesis through increasing TAM infiltration or HIF-1, regulation by hypoxia. [source] Epigallocatechin-3-gallate diminishes CCL2 expression in human osteoblastic cells via up-regulation of phosphatidylinositol 3-Kinase/Akt/Raf-1 interaction: A potential therapeutic benefit for arthritisARTHRITIS & RHEUMATISM, Issue 10 2008Sze-Kwan Lin Objective To assess the effects of epigallocatechin-3-gallate (EGCG) on oncostatin M (OSM),induced CCL2 synthesis and the associated signaling pathways in human osteoblastic cells. The therapeutic effect of EGCG on collagen-induced arthritis (CIA) in rats was also studied. Methods CCL2 and c-Fos messenger RNA expression was analyzed by Northern blotting. The modulating effects of EGCG on the activation of Raf-1, Akt, and phosphatidylinositol 3-kinase (PI 3-kinase) were examined by coimmunoprecipitation, Western blotting, and PI 3-kinase activity assay. Interactions between c-Fos and CCL2 promoter were evaluated by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay. The effect of EGCG on CIA in rats was examined clinically and immunohistochemically. Results EGCG inhibited OSM-stimulated CCL2 expression in primary human osteoblasts and MG-63 cells. In MG-63 cells, EGCG alleviated the OSM-induced phosphorylation of Raf-1 at Ser338 but restored the dephosphorylation of Raf-1 at Ser259. EGCG increased the activity of PI 3-kinase, the level of phosphorylated Akt (Ser473), and binding between Raf-1 and active Akt. EMSA and ChIP assay revealed that EGCG attenuated activator protein 1 (AP-1),CCL2 promoter interaction, possibly by reducing c-Fos synthesis. Codistribution of CD68+ macrophages and CCL2+ osteoblasts in osteolytic areas was obvious in the CIA model. Administration of EGCG markedly diminished the severity of CIA, macrophage infiltration, and the amount of CCL2-synthesizing osteoblasts. Conclusion By stimulating PI 3-kinase activity, EGCG promoted Akt/Raf-1 crosstalk, resulting in decreased AP-1 binding to CCL2 promoter, and finally reduced CCL2 production in osteoblasts. EGCG alleviated the severity of CIA, probably by suppressing CCL2 synthesis in osteoblasts to diminish macrophage infiltration. Our data support the therapeutic potential of EGCG on arthritis. [source] Chronic arthritis aggravates vascular lesions in rabbits with atherosclerosis: A novel model of atherosclerosis associated with chronic inflammationARTHRITIS & RHEUMATISM, Issue 9 2008Raquel Largo Objective To determine whether systemic inflammation induced by chronic antigen-induced arthritis (AIA) accelerates vascular lesions in rabbits with atherosclerosis. Methods Two models of atherosclerosis and chronic AIA were combined. Atherosclerosis was induced by coupling a hyperlipemic diet with an endothelial lesion at the femoral arteries, while chronic AIA was induced by ovalbumin injection. Markers in sera and peripheral blood mononuclear cells (PBMCs) as well as vessels and synovial membranes from the rabbits with the double phenotype (both chronic AIA and atherosclerosis) were compared with those from rabbits with each disease alone. Results Serum levels of interleukin-6, C-reactive protein, and prostaglandin E2 increased in rabbits with both chronic AIA and atherosclerosis as compared with healthy animals or animals with either chronic AIA alone or atherosclerosis alone. NF-,B binding and CCL2 and cyclooxygenase 2 (COX-2) expression were higher in PBMCs from rabbits with both chronic AIA and atherosclerosis than in PBMCs from healthy rabbits. The intima-media thickness ratio of femoral arteries was equally increased in rabbits with atherosclerosis alone and in rabbits with both chronic AIA and atherosclerosis, but the latter group showed a higher level of macrophage infiltration. Femoral CCL2 and COX-2 expression was increased in rabbits with both chronic AIA and atherosclerosis as compared with rabbits with atherosclerosis alone. In the aortas, vascular lesions were found in 27% of rabbits with atherosclerosis alone and in 60% of rabbits with both chronic AIA and atherosclerosis. Rabbits with both chronic AIA and atherosclerosis exhibited more severe synovitis and higher synovial expression of CCL2 than did rabbits with chronic AIA alone. Conclusion The onset of chronic AIA in animals with atherosclerosis resulted in the local and systemic up-regulation of mediators of tissue inflammation and plaque instability associated with a higher incidence of aortic lesions. This model could represent a novel approach to the study of inflammation-associated atherosclerosis. [source] Association of interleukin-18 expression with enhanced levels of both interleukin-1, and tumor necrosis factor , in knee synovial tissue of patients with rheumatoid arthritisARTHRITIS & RHEUMATISM, Issue 2 2003Leo A. B. Joosten Objective To examine the expression patterns of interkeukin-18 (IL-18) in synovial biopsy tissue of patients with rheumatoid arthritis (RA), and to determine whether expression of this primary cytokine is related to the expression of other cytokines and adhesion molecules and related to the degree of joint inflammation. Methods Biopsy specimens of knee synovial tissue either without synovitis (n = 6) or with moderate or severe synovitis (n = 11 and n = 12, respectively) were obtained from 29 patients with active RA. Paraffin-embedded, snap-frozen sections were used for immunohistochemical detection of IL-18, tumor necrosis factor , (TNF,), IL-1,, IL-12, and IL-17. Furthermore, adhesion molecules, such as intercellular adhesion molecule 1, vascular cell adhesion molecule 1, and E-selectin, and cell markers CD3, CD14, and CD68 were stained. Results IL-18 staining was detectable in 80% of the RA patients, in both the lining and sublining of the knee synovial tissue. IL-18 expression in the synovial tissue was strongly correlated with the expression of IL-1, (in the sublining r = 0.72, in the lining r = 0.71; both P < 0.0001) and TNF, (in the sublining r = 0.59, P < 0.0007, and in the lining r = 0.68, P < 0.0001). In addition, IL-18 expression in the sublining correlated with macrophage infiltration (r = 0.64, P < 0.0007) and microscopic inflammation scores (r = 0.78, P < 0.0001), and with the acute-phase reaction as measured by the erythrocyte sedimentation rate (r = 0.61, P < 0.0004). Interestingly, RA synovial tissue that coexpressed IL-18 and IL-12 demonstrated enhanced levels of the Th1-associated cytokine IL-17. Conclusion Our results show that expression of IL-18 is associated with that of IL-1, and TNF, and with local inflammation in the synovial tissue of patients with RA. In addition, synovial IL-18 expression correlates with the acute-phase response. These data indicate that IL-18 is a primary proinflammatory cytokine in RA that drives the local production of IL-1, and TNF,. [source] Heparin Coating of Small-Caliber Decellularized Xenografts Reduces Macrophage Infiltration and Intimal HyperplasiaARTIFICIAL ORGANS, Issue 6 2009Wei-Wei Cai Abstract Small-caliber decellularized xenografts with surface heparin coating are known to reduce in vivo thrombogenicity. This study was performed to examine whether heparin coating on the small-caliber decellularized xenografts would reduce macrophage infiltration and intimal hyperplasia. In a rabbit model of bilateral carotid implantation, each of the animals (n = 18) received a heparin-coated decellularized xenograft from a canine carotid artery on one side and a nonheparin-coated one on the other side. These experiments were terminated respectively at 1 week (n = 6), 3 weeks (n = 6), and 12 weeks (n = 6). Results showed that, compared with the nonheparin-coated grafts, the heparin-coated grafts had significantly less macrophage infiltration 1 week after implantation, identified by the mouse antirabbit macrophage antibody (RAM11)-positive cells on the vascular wall, covering all the proximal, middle, and distal parts of the grafts (P < 0.01). Moreover, the heparin-coated grafts also showed less deposition of proliferation cell nuclear antigen (PCNA)-positive cells on the vascular wall, indicating less cell proliferation, which was significant not only at 1 week (P < 0.01) but also at 12 weeks (P < 0.01). Intimal hyperplasia, measured by the intimal : media (I : M) ratio, was found similar in both groups at 1 and 3 weeks. However, the I : M ratio was significantly lower in the heparin-coated group than in the nonheparin-coated group at 12 weeks, especially in the proximal anastomosis area (0.76 ± 0.12 vs. 0.345 ± 0.06, P < 0.01). Heparin coating of small-caliber decellularized xenografts is associated with an early reduction of macrophage infiltration and intimal hyperplasia in a rabbit model of bilateral carotid artery implantation for 12 weeks. Thus, heparin coating appears to deliver not only the antithrombogeneity but also the antiproliferative property for small-caliber decellularized xenografts. [source] Review article: Is obesity an inflammatory illness?BJOG : AN INTERNATIONAL JOURNAL OF OBSTETRICS & GYNAECOLOGY, Issue 10 2006Role of low-grade inflammation, macrophage infiltration in human white adipose tissue There are at least two scientific evidences of human obesity as a chronic inflammatory illness: first, the well-described moderate increase of inflammatory factors in the circulation in obese subjects, and second, the recent identification of macrophage cells infiltrating the white adipose tissue (WAT). These observations led to a revision of the physiopathology of obesity and its co-morbidities. It has been suggested that the ,low-grade' inflammatory state associates with metabolic and cardiovascular complications of obesity. Weight loss is able to improve this inflammatory state by both significantly decreasing circulating inflammatory molecules and macrophage cell infiltration in WAT depots. However, the mechanisms of WAT macrophage recruitment into the adipose tissue and their role in obesity complications have not been defined. This review aims to point out the knowledge on inflammatory cytokines associated with obesity and focuses on macrophage infiltration in human WAT, discussing their recruitment and role. The interactions of macrophages with adipocytes will certainly be the subject of intense investigations in the future. [source] Serum interleukin-6 is elevated in symptomatic carotid bifurcation diseaseACTA NEUROLOGICA SCANDINAVICA, Issue 2 2009M. Koutouzis Introduction,,, The levels of circulating proinflammatory cytokines may express the extent of the inflammatory response and their participation in plaque progression and rupture needs to be evaluated. We aimed to investigate differences in circulating levels of proinflammatory cytokines and in plaque infiltration by macrophages between patients undergoing carotid endarterectomy for symptomatic and asymptomatic carotid atherosclerotic disease. Methods,,, One hundred nineteen patients (91 men and 28 women; mean age 66 ± 8 years; range 42,83 years) who underwent carotid endarterectomy for significant (>70%) carotid bifurcation stenosis were enrolled in this study. Patients were characterized as symptomatic (n = 62) or asymptomatic (n = 57) after neurological examination. Serum levels of interleukin-6 (IL-6), tumor necrosis factor-, (TNF-,), IL-1,, serum amyloid A (SAA), and high-sensitivity C-reactive protein (hs-CRP) were evaluated. Macrophage infiltration of the plaque was assessed quantitatively from endarterectomy specimens using the monoclonal antibody CD68. Results,,, Serum IL-6 levels were significantly higher in patients with symptomatic compared with those with asymptomatic carotid disease (3.3 [2.0,6.5] pg/ml vs 2.5 [1.9,4.1] pg/ml, P = 0.02). TNF-,, IL-1,, SAA, and hs-CRP levels did not differ significantly between the two groups. Symptomatic patients had also more intense macrophage accumulation in the carotid plaque compared with asymptomatic patients (0.6 ± 0.1% vs 0.4 ± 0.1%, P < 0.001). Although there were correlations between the levels of the different inflammatory markers, there were no correlation between any of them and the extent of plaque macrophage infiltration. Conclusion,,, Patients with symptomatic carotid atherosclerotic disease have elevated serum IL-6 levels compared with asymptomatic patients. Symptomatic patients have also more intense macrophage infiltration of the atherosclerotic plaque suggesting that inflammatory process may contribute to the destabilization of the carotid plaque. [source] Immunosuppression with mycophenolate mofetil attenuates the development of hypertension and albuminuria in deoxycorticosterone acetate-salt hypertensive ratsCLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 10 2010Erika I Boesen Summary 1. The interplay between the immune and renin,angiotensin systems is emerging as a crucial factor in the development and progression of hypertension. The aim of the present study was to determine the involvement of immune cells in the hypertension and renal injury produced by a non-angiotensin II-dependent form of hypertension, namely deoxycorticosterone acetate (DOCA)-salt-induced hypertension, in rats. 2. Male Sprague-Dawley rats underwent uninephrectomy and received either a sustained-release pellet of DOCA s.c. and 0.9% NaCl (saline) to drink for 21 days or a placebo pellet and water to drink for 21 days. Additional groups of DOCA-salt- and placebo-treated rats were treated concurrently with the immune suppressant mycophenolate mofetil (MMF; 30 mg/kg per day). Rats were placed in metabolic cages for 24 h urine collection prior to and at weekly intervals during the 21 day experimental period. 3. Mycophenolate mofetil significantly attenuated the development of hypertension in DOCA-salt rats compared with untreated DOCA-salt hypertensive rats (mean arterial pressure by telemetry on Day 18 146 ± 7 vs 180 ± 3 mmHg, respectively; P < 0.001), as well as proteinuria (87 ± 27 vs 305 ± 63 mg/day, respectively, on Day 21) and albuminuria (51 ± 15 vs 247 ± 73 mg/day, respectively, on Day 21). Creatinine clearance was better preserved in MMF-treated DOCA-salt rats compared with untreated DOCA-salt rats (0.74 ± 0.07 vs 0.49 ± 0.09 mL/min, respectively; P < 0.05), but was still significantly reduced compared with that in the placebo group (1.15 ± 0.12 mL/min; P < 0.05). Finally, MMF treatment significantly attenuated the DOCA-salt-induced rise in renal cortical T-lymphocyte and macrophage infiltration (P < 0.05). 4. These data indicate that immune cells play a deleterious role in both the hypertension and renal injury associated with DOCA-salt hypertension. [source] MACROPHAGE INFILTRATION AND INDUCTION OF P75 NTR AND IL-1B IN THE NERVE OF DIABETIC RATSJOURNAL OF THE PERIPHERAL NERVOUS SYSTEM, Issue 1 2000G. Conti Recently, inflammation has been involved in the pathogenesis of diabetic neuropathy, and activated macrophages have been found in the peripheral nervous system of diabetic rats, with a possible role in chemotaxis and regeneration. In this study, we obtained sciatic nerve specimens from diabetic rats at different time points following STZ administration. Macrophages infiltration, IL-1b and p75NTR induction were analyzed by immunocytochemistry on frozen sections and on teased nerve fibers. Apoptosis was detected on teased nerve fibers by TUNEL and DAPI staining. Cell phenotype was characterized by double-staining with antibodies specific for Schwann cells and macrophages. The nerves obtained from STZ-diabetic rats showed macrophages infiltration by day 14 following STZ administration, with complete clearance by day 35. Fifteen percent of these cells were TUNEL positive. IL-1B induction was concomitant with macrophages infiltration and not detectable by day 35. p75NTR expression began by day 21, peaking by day 35, and dropping to barely detectable levels by day 105. These findings seem to indicate that the concomitance of these processes may be crucial in the regulation of nerve damage and in promoting an attempt of regeneration at the early stages of STZ diabetic neuropathy. [source] | ||||||||||||||||||||||||||||