The cardiovascular system may be one of the target organs of both immunoglobulin G4 related and non-related systemic multifocal fibrosclerosis. We present a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis on echocardiography. For a more detailed differential diagnosis, we used multimodal imaging techniques. After surgical biopsy around the abdominal aortic area in the retroperitoneum, histological examination revealed IgG4 non-related systemic multifocal fibrosclerosis. We describe the multimodal imaging used to diagnose IgG4 non-related systemic multifocal fibrosclerosis and a positive response to steroid treatment. There have been no previous case reports of IgG4 non-related systemic multifocal fibrosclerosis with intracardiac involvement. Here, we report a case of IgG4 non-related systemic multifocal fibrosclerosis mimicking mitral stenosis.
Aged ; Aorta, Abdominal/pathology ; Diagnosis, Differential ; Echocardiography ; Female ; Humans ; Immunoglobulin G/*blood/immunology ; Magnetic Resonance Imaging ; Mitral Valve Stenosis/diagnosis ; Myocardium/*pathology ; Peritoneum/surgery ; Positron-Emission Tomography ; Retroperitoneal Fibrosis/*congenital/diagnosis/drug therapy/ultrasonography ; Steroids/therapeutic use ; Tomography, X-Ray Computed

The ischemic heart disease has been endangering human health seriously. Although there are many kinds of anti-ischemic drugs, most of them are lacking in tissue specificity, which together with a remarkably reduced blood circulation in the ischemic zone often lead to a quite low drug distribution in the targets. Myocardial ischemia can cause a lot of pathophysiological changes, such as the enhanced permeability of the endothelial cell membrane, the up-regulated expression of various cell adhesion molecules on endothelium, the exposure of intracellular antigenic components, the decrease of pH within the ischemic zone, and so on. To date, some of these changes have been exploited with limited success to gain the passive, active and physicochemical targeting of diagnostic or therapeutic drugs to myocardial ischemic regions. However, more effective delivery strategies are still eagerly needed. Here, we reviewed and discussed the potential targeting-delivery mechanisms and strategies, used or may be used in the future, for myocardial ischemic regions.
Animals ; Antibodies, Monoclonal ; immunology ; Capillary Permeability ; Drug Carriers ; Drug Delivery Systems ; methods ; Genetic Therapy ; Humans ; Liposomes ; chemistry ; metabolism ; Myocardial Ischemia ; therapy ; Myocardium ; metabolism ; pathology ; Polyethylene Glycols ; metabolism ; Ultrasonics

OBJECTIVETo explore the action mechanism of the immune active components of sappon wood (SWE) for antagonizing reject reaction by observing the influence of its ethyl acetate extract on mRNA expression of myocardial GrB in rat model of allogenic ectopic cardiac transplantation.

METHODSAnimal model of abdominal cardiac ectopic transplantation was established taking Wistar rat as the donor and SD rat as the receptor. The successfully modeled rats were randomly divided into the model group, the SWE group and the CsA group. GrB mRNA expression was detected by RT-PCR method and myocardial pathomorphologic picture was observed in routine.

RESULTSThe pathologic changes in the SWE group (23 scores) and the CsA group (14 scores) were milder than in the model group (31 scores), the former two could markedly alleviate the myocardial pathologic injury (P<0.05, P<0.01). The GrB mRNA expression in the model group was 1.3000 +/- 0.1207, the SWE group 0. 7070 +/- 0.1215, and the CsA group 0.6700 +/- 0.0997, respectively; compared with the model group, the latter two could obviously down-regulate the expression of GrB mRNA (P<0.01) and no significant difference was found between the latter two groups (P>0.05).

CONCLUSIONSWE could alleviate the pathologic change, down-regulate the mRNA expression of myocardial GrB in allogenic ectopic transplanted myocardium of rats, it is possibly one of the factors for its antagonizing effect against reject reaction.

Acetates ; chemistry ; Animals ; Caesalpinia ; chemistry ; Gene Expression Regulation, Enzymologic ; drug effects ; Graft Rejection ; drug therapy ; Granzymes ; genetics ; Heart ; drug effects ; Heart Transplantation ; immunology ; Male ; Models, Animal ; Myocardium ; metabolism ; pathology ; Plant Extracts ; pharmacology ; therapeutic use ; RNA, Messenger ; genetics ; metabolism ; Rats ; Transplantation, Homologous

OBJECTIVETo investigate the role of immunodeficiency and intestinal mixed infection on inducing extraintestinal dissemination of rotavirus (RV).

METHODSImmunodeficiency was induced in healthy Kunming mice by introperitoneal injection of cyclophosphamide, and RV was administered either orally or via intraperitoneal injection. In another group, toxigenic E. coli and human RV were given sequentially by intragastric administration to induce mixed infection. Three days later the organs of the mice were taken for pathological examination, and RV was detected by in situ PCR and hybridization. In children with or without viremia of rotavirus, blood tests for levels of tumor necrosis factor alpha (TNF-alpha), interleukin-2 (IL-2) and 7 trace elements (zinc, iron, copper, lead, calcium, manganese, and magnesium) were performed.

RESULTSIn immunodeficient mice, pathological changes were found in the small intestinal villus, gastric lamina propria and the cardiac cells of mice taking RV orally, and the mice with intraperitoneal RV injection showed additional liver and kidney pathologies. In mice with mixed infections, pathological changes occurred in the intestines, livers and kidneys. In situ hybridization detected RV in the intestinal villus of immunodeficient mice with oral RV administration, and in the intestinal villus and kidneys of the mice with mixed infections. In situ PCR revealed the presence of RV in the intestinal villus, intestinal gland cells, epithelial cells of the proximal convoluted tubules and collecting tubes in the kidneys of immunodeficient mice taking RV orally, in the intestinal villus, kidneys, livers, hearts and pancreases of those with RV injection, and in the intestines, kidneys, and livers of the mice with mixed infection. Children with rotavirus viremia had TNF-alpha level in comparison with those free of rotavirus viremia, and the majority of the former children showed disorder in trace elements.

CONCLUSIONImmunodeficiency, mixed infection and malnutrition can be important factors contributing to or exacerbating RV infection and extraintestinal RV dissemination.

Animals ; Cyclophosphamide ; administration & dosage ; toxicity ; DNA, Viral ; genetics ; Enzyme-Linked Immunosorbent Assay ; Female ; Immunocompromised Host ; drug effects ; immunology ; Interleukin-2 ; blood ; Intestines ; pathology ; virology ; Kidney ; pathology ; virology ; Liver ; pathology ; virology ; Male ; Mice ; Myocardium ; pathology ; Polymerase Chain Reaction ; Rotavirus ; genetics ; immunology ; Rotavirus Infections ; blood ; immunology ; virology ; Trace Elements ; blood ; Tumor Necrosis Factor-alpha ; blood

The hypertension is one of chronic vascular diseases, which often implicates multiple tissues causing stroke, cardiac hypertrophy, and renal failure. A growing body of evidence suggests that inflammatory mechanisms are important participants in the pathophysiology of hypertension. In this study, the inflammatory status of these tissues (kidney, liver, heart, and brain) in spontaneously hypertensive rats (SHR) was analyzed and its molecular mechanism was explored. The tissues were dissected from SHR and age-matched control Wistar-Kyoto (WKY) rats to investigate the abundance of inflammation-related mediators (IL-1beta, TNFalpha, ICAM-1, iNOS, C/EBPdelta and PPARgamma). mRNA levels were determined by reverse transcription-polymerase chain reaction and protein expression was evaluated by Western blot. To evaluate the oxidative stress of tissues, carbonyl protein content and total antioxidant capacity of tissues were detected by spectrophotometry and ferric reduction ability power (FRAP) method. The results suggest that: (1) Expressions of inflammation-related mediators (IL-1beta, TNFalpha, ICAM-1, iNOS, C/EBPdelta and PPARgamma) in SHR were higher compared with those in WKY rats except no evident increase of IL-1beta mRNA in liver and brain in SHR. (2) Tissues in SHR contained obviously increased carbonyl protein (nmol/mg protein) compared to that in WKY rats (8.93+/-1.08 vs 2.27+/-0.43 for kidney, 2.23+/-0.23 vs 0.17+/-0.02 for heart, 13.42+/-1.10 vs 5.72+/-1.01 for brain, respectively, P<0.05). However, no evident difference in the amount of carbonyl protein in liver was detected between SHR and WKY rats. (3) Total antioxidant capacities of kidney, liver, heart and brain were markedly lower in SHR than that in WKY rats (P<0.05). Thus, the present data reveal a higher inflammatory status in the important tissues in SHR and indicate that inflammation might play a potential role in pathogenesis of hypertension and secondary organ complications.
Animals ; Brain ; metabolism ; pathology ; Cytokines ; genetics ; metabolism ; Hypertension ; pathology ; Inflammation ; pathology ; Interleukin-1beta ; genetics ; metabolism ; Kidney ; metabolism ; pathology ; Male ; Myocardium ; metabolism ; pathology ; Oxidative Stress ; immunology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Tumor Necrosis Factor-alpha ; genetics ; metabolism

OBJECTIVEViral myocarditis (VM) is one of the most common acquired myocardial diseases in children. However, its pathogenesis is not clear. Recent studies indicate that the cytotoxicity mediated by cytotoxic T lymphocyte (CTL) plays an important role in the development of myocardial injury involved in VM. Apoptosis mediated by Fas/FasL pathway is an essential mechanism of target cells damage by CTL. In this study, the authors investigated the regulatory effects of neutralizing anti-Fas ligand (anti-FasL) antibody on apoptosis and caspase-3 expression in experimental coxsackievirus B3 myocarditis and the role of the CTL mediated apoptosis in myocardium through Fas/FasL pathway in the development of VM.

METHODSA total of 80 BALB/c mice were used in the experiments. They were divided randomly into the following groups: normal control group (Gr1), CVB3 control group (Gr2), IgG control group (Gr3) and anti-FasL antibody therapy group (Gr4). The mice in Gr2, Gr3 and Gr4 were inoculated with 0.15 ml of TCID(50) 10(9)/ml coxsackie virus B3 (CVB3) and the mice in Gr1 with 0.15 ml of Eagle reagent. The mice in Gr3 and Gr4 were inoculated with IgG (0.1 mg/kg) and FasL antibody (0.1 mg/kg) on days 0 and days 3 after inoculation (p.i.), respectively. Eight mice in each group were sacrificed on day 10 p.i. Histopathological studies and terminal transferase-mediated dUTP-biotin nick end labeling (TUNEL) assays were used to quantify inflammation, necrosis and apoptosis in myocardium. The expression of active caspase-3 in myocardium was determined by immunohistochemistry. Caspase-3 mRNA and CVB3 mRNA were analyzed by reverse-transcription polymerase chain reaction (RT-PCR).

RESULTS(1) Caspase-3 activation and apoptosis were seen in the myocardium of mice with myocarditis. They had a significantly positive correlation with the changes of myocardial histopathologic scores (r = 0.81, P < 0.05; r = 0.73, P < 0.05). (2) The pathologic scores, average percentages of apoptotic cardiomyocytes, expression of active caspase-3 (protein and mRNA) and expression of CVB3 mRNA in myocardium of mice in Gr4, were significantly reduced compared to those in the myocardium of mice in Gr2 (P < 0.01, P < 0.01, P < 0.01, P < 0.01, and P < 0.05, respectively) and Gr3 (P < 0.01, P < 0.01, P < 0.05, P < 0.01, and P < 0.05, respectively).

CONCLUSIONMyocytic apoptosis is a key mechanism responsible for myocardial damage in viral myocarditis. Anti-FasL antibody can effectively reduce expression of active caspase-3 protein and mRNA, viral replication, cardiomyocytic apoptosis and myocardial injury in the experimental CVB3 myocarditis.

Animals ; Antibodies, Neutralizing ; therapeutic use ; Apoptosis ; Caspase 3 ; immunology ; Coxsackievirus Infections ; drug therapy ; immunology ; Enterovirus B, Human ; physiology ; Fas Ligand Protein ; immunology ; Mice ; Mice, Inbred BALB C ; Myocarditis ; drug therapy ; immunology ; virology ; Myocardium ; immunology ; pathology ; Virus Replication

Endomyocardial biopsy often fails to show myocardial inflammation for patients with clinically suspected myocarditis. The serum isoforms of troponin T (cTnT) level is a very sensitive marker of myocardial injury and it is elevated even in the absence of myocardial inflammation. We investigated the correlations for myocardial injury, virus titers and inflammation in acute viral infection. Using the murine coxsackievirus group B3 (CVB3) myocarditis model, the histopathologic findings and virus titers in mouse hearts were compared with the serum cTnT levels measured by ELISA at various time points. Viable virus titers in the hearts peaked at 3 days after infection (8.22+/-0.13 log10 PFU/100 mg of heart); they decreased at day 7 and no viable virus was detected from day 14. Myocardial inflammation was minimal at day 3, peaked at day 7 and markedly decreased at day 14. The individual serum TnT levels were significantly increased at day 3 (7.37+/-1.46 ng/ml), persisted to day 7 (0.73+/-0.08 ng/ml), and normalized at day 14. Serum cTnT levels were correlatable with virus titers in the heart (r=0.744, P <0.01), but the serum cTnT levels were not correlated with the degrees of inflammation. Using the less myocarditic strain of CVB3, similar relationships were observed between the changes for the serum cTnT levels and the heart virus titers. During the course of viral infection, myocardial injury precedes the pathologic evidence of inflammation, and the elevated cTnT levels provide evidence of myocardial injury even in the absence of any histologic findings of myocarditis.
Acute Disease ; Animals ; Coxsackievirus Infections/*pathology ; Enterovirus B, Human/isolation & purification/pathogenicity/*physiology ; Female ; Heart/*virology ; Hela Cells ; Humans ; Inflammation/*immunology ; Mice ; Mice, Inbred BALB C ; Myocardial Infarction/immunology/*pathology ; Myocarditis/immunology/pathology/*virology ; *Myocardium/immunology/pathology ; Research Support, Non-U.S. Gov't ; Troponin T/blood ; Virus Replication

OBJECTIVETo explore the operational mechanisms and potential approach to inducing transplantation immune tolerance of FTY720.

METHODSMouse splenocytes were incubated with FTY720, then the DNA was extracted and analyzed using gel electrophoresis. Hearts of inbred BALB/c (H-2(d)) mice were transplanted heterotopically in C57BL/6 (H-2b) mice. Recipients were randomly divided into six groups. Group-1 (n = 6) was the nil-treated control. Groups-2, 3 and 4 were given FTY720 at the dose of 3 mg.kg(-1) by oral gavage once a day with different time courses. Group-2 (n = 14) were administrated from 3 days before transplantation (day-3) to the 11th day after the transplantation (day 11); Group-3 (n = 6) from day 0 to day 14; Group-4 (n = 6) from day-3 to day 0. Group-5 (n = 5) and 6 (n = 5) were treated with Cyclosporine A (10 mg.kg(-1)) and 40-O-(2-hydroxyethyl)-rapamycin (RAD) (3 mg.kg(-1)) respectively by daily gavage from day 3 to day 11. The long survivors (> 100 d) in Group-2 were detected with their IL-4 and IFN-gamma levels and their tolerant state was challenged with second graft: the donor type skin.

RESULTSApoptosis changes of the mouse splenocytes incubated with FTY720 was showed by typical DNA ladders. The median survival time (MST) of Group-1 was 8 d. MST of Group-2 was 55 d and grafts in six mice survived more than 100 d. MST of Group-3 was 16.5 d. Group-4 has a MST of 14 d with one case exceeded 100 d. MST of Group-5 and 6 were 10 d and 13 d respectively. Long survivors of Group-2 can accept donor-type skin graft and the level of IL-4 in their serum is up-regulated while IFN-gamma remained stable.

CONCLUSIONSPretreatment of FTY720 bring about effect on the early events of transplantation immune responses. This effect might be mediated by apoptosis induction in lymphocytes using this drug. We originally designed the regime of FTY720 monotherapy, which started pre-operationally and maintained for a short period of time, and induced stable tolerance the allo-graft in mouse.

Adjuvants, Immunologic ; pharmacology ; Animals ; Apoptosis ; Fingolimod Hydrochloride ; Heart Transplantation ; immunology ; Immune Tolerance ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Myocardium ; pathology ; Propylene Glycols ; pharmacology ; Sphingosine ; analogs & derivatives ; Transplantation Immunology

OBJECTIVEIn order to explore the possible roles played by the autoimmune mechanism in the progression of myocarditis into dilated cardiomyopathy (DCM) using an animal model, we investigated whether autoimmune myocarditis might develop into DCM.

METHODSExperimental Balb/C mice (n = 20) were immunized with cardiac myosin with Freund's complete adjuvant at days 0, 7 and 30. The control Balb/C mice (n = 10) were immunized with Freund's complete adjuvant in the same mannere. Serum and myocardium samples were collected after the first immunization at days 15, 21 and 120. The anti-myosin antibody was examined by enzyme-linked immunosorbent assay and immunoblotting.

RESULTSPathological findings demonstrated that there was myocardial necrosis or inflammatory infiltration during acute stages and fibrosis mainly in the late phase of experimental group, but the myocardial lesions were not found in the control group. Autoimmunity could induce myocarditis and DCM in the absence of viral infection. High titer anti-myosin IgG antibodies were found in the experimental group, but not in the control group. Furthermore, the anti-myosin heavy chain (200 KD) antibody was positive in 21 of 48 patients with DCM and viral myocarditis, but only 4 of 20 patients with coronary heart disease, including 1 case and 3 cases that reacted with heavy and light chains (27.5 KD), respectively. The antibodies were not detected in healthy donors.

CONCLUSIONCardiac myosin might be an autoantigen that provokes autoimmunity and leads to the transformation of myocarditis into DCM. Detection of anti-myosin heavy chain antibody might contribute to diagnosis for DCM and viral myocarditis.

Adult ; Aged ; Animals ; Autoantibodies ; blood ; Autoimmune Diseases ; complications ; Cardiac Myosins ; immunology ; Cardiomyopathy, Dilated ; etiology ; immunology ; Female ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Middle Aged ; Myocarditis ; complications ; Myocardium ; pathology

This study was designed to investigate the increase in the number of circulating CD34+ cells after acute myocardial infarction (MI) and the differentiation of these cells to cardiomyocytes after transplantation into infarcted myocardium. The study involved five donor groups: MI (n=27), sham (n=26), granulocyte-colony stimulating factor (GCSF) (n=26), MI+GCSF (n=25), and control (n=25). Acute MI was induced by ligating the left anterior descending coronary arteries (LAD) of donor rats, and LAD of recipient rats were ligated on the same day. Seven days after ligation, CD34+ cells in donor rats were counted and then were directly injected into the infarcted myocardium of recipient rats. Eight weeks after the transplantation, significant differences (p<0.001) were observed in the CD34+cell counts among the 5 donor groups with the greatest increase in the MI+GCSF donor group. In rats receiving CD34+ cells, the size of the scar area smaller (p<0.001) and the thickness of the scar was greater (p=0.001) than in CD34- and saline-transplanted rats. The transplanted CD34+ cells differentiated into cardiomyocytes in the scar. This study suggests that CD34+ cells may be a potential source of stem cells and that they may be useful in strategies aimed at the regeneration of infarcted myocardium.
Animals ; Antigens, CD34/*analysis ; Body Weight ; Cell Differentiation ; Heart/*physiology ; Myocardial Infarction ; Myocardium/*cytology/pathology ; Myocytes, Cardiac/*physiology ; Rats ; *Regeneration ; *Stem Cell Transplantation ; Stem Cells/*immunology/metabolism ; Support, Non-U.S. Gov't