Chronic Vascular Lesions Research Articles

Obliterative Endophlebitis in Mute Swans (Cygnus olor) Caused by Trichobilharzia sp. (Digenea: Schistosomatidae) Infection

Schistosome infections in mammals cause chronic proliferative vascular lesions associated with the presence of adult parasites in the lumen of mesenteric and portal veins. In birds, however, this has never been reported. In this study, we found obliterative endophlebitis associated with the presence of adult schistosomes (Trichobilharzia sp., probably Trichobilharzia filiformis) as the main pathologic finding in five of eight mute swans (Cygnus olor). On histologic examination, the intestinal and portal veins of these swans showed moderate to severe, diffuse, hyperplastic endophlebitis, characterized by myointimal hyperplasia, often with obliteration of the vascular lumen. In addition, moderate to severe lymphocytic and granulocytic enteritis occurred in all eight swans associated with the presence of schistosome eggs in the intestinal mucosa. Other findings included hepatic and splenic hemosiderosis and high hepatic copper levels. The vascular lesions associated with Trichobilharzia sp. infection may have contributed to the emaciation and death of those mute swans by obstruction of venous return in the intestinal and portal veins.

Differences in Cell Activation byChlamydophila pneumoniaeandChlamydia trachomatisInfection in Human Endothelial Cells

Seroepidemiological studies and demonstration of viable bacteria in atherosclerotic plaques have linked Chlamydophila pneumoniae infection to the development of chronic vascular lesions and coronary heart disease. In this study, we characterized C. pneumoniae-mediated effects on human endothelial cells and demonstrated enhanced phosphorylation and activation of the endothelial mitogen-activated protein kinase (MAPK) family members extracellular receptor kinase (ERK1/2), p38-MAPK, and c-Jun-NH2 kinase (JNK). Subsequent interleukin-8 (IL-8) expression was dependent on p38-MAPK and ERK1/2 activation as demonstrated by preincubation of endothelial cells with specific inhibitors for the p38-MAPK (SB202190) or ERK (U0126) pathway. Inhibition of either MAPK had almost no effect on intercellular cell adhesion molecule 1 (ICAM-1) expression. While Chlamydia trachomatis was also able to infect endothelial cells, it did not induce the expression of endothelial IL-8 or ICAM-1. These effects were specific for a direct stimulation with viable C. pneumoniae and independent of paracrine release of endothelial cell-derived mediators like platelet-activating factor, NO, prostaglandins, or leukotrienes. Thus, C. pneumoniae triggers an early signal transduction cascade in target cells that could lead to endothelial cell activation, inflammation, and thrombosis, which in turn may result in or promote atherosclerosis.

ANGIOTENSING CONVERTING ENZIME (ACE) MRNA EXPRESSION IN PROTOCOL BIOPSIES WITH CHRONIC ALLOGRAFT NEPHROPATY (CAN)

P291 Although chronic allograft nephropathy (CAN) is a multifactorial disease, it has been suggested that the renine-angiotensin system (RAS) could have a critical role in its development. The key reaction in the RAS pathway is catalysed by the angiotensing-converting enzime (ACE), and their blockade has been shown to improve the prognosis of several chronic nephropathies. Aims: The main aim of this study was to analyse the association among kidney allograft lesions and ACE renal levels. Moreover, since the DD polymorphism of the ACE gene has been associated with a poor kidney survival, we also studied the role of DD genotype in ACE mRNA expression. Methods: ACE genotype and ACE mRNA levels were determined in 64 protocol biopsies from the same number of transplanted patients. Results: ACE mRNA levels were not related to the ACE genotype, and did not depend on the severity of the allograft lesions, as classified according to the Banff squema. In patients displaying the DD genotype ACE mRNA levels were correlated with proteinuria (R=0.51, p=0.012), and were higher in allografts with chronic vascular lesions than in patients without vascular involvement (vasculopathy: n=4, 1.38 ± 0.97, no vasculopathy: n=19, 0.36±0.65, p=0.016). In patients with non-DD genotypes, ACE levels were correlated with mean arterial pressure (R=0.3, p=0.055). Finally, we observed an association among ACE levels in DD-patients and the immunossupressive treatment used. Thus, DD patients displayed higher ACE levels than non-DD patients only when treated with Csa (DD: n=11, 0.89±1.04 vs no-DD: n=16, 0.064 ±0.68, p=0.019), and not when treated with tacrolimus. Conclusions: In DD-patients, renal ACE levels correlated with proteinuria, and increased with Csa treatment and with chronic vascular lesions. Treating patients displaying CAN and vasculopathy with ACEI or ARAII should improve their prognosis.

Efficacy and safety of ABI793, a novel human anti-human CD154 monoclonal antibody, in cynomolgus monkey renal allotransplantation.

Anti-CD154 monoclonal antibodies (mAbs) cause long-term graft survival in preclinical allotransplantation experiments. This is the first report on the efficacy and safety of ABI793, a novel human anti-human CD154 mAb, in Cynomolgus renal transplant recipients. ABI793 (human immunoglobulin-G1:kappa) was derived from a hybridoma generated after immunization of human immunoglobulin transgenic mice (HuMAb-Mouse, Medarex Inc., Annandale, NJ). Cynomolgus monkey recipients of major histocompatibility complex-mismatched, life-supporting renal allografts were treated repeatedly with intravenous ABI793 for a 3-month period posttransplantation. Graft function was monitored by serum creatinine, and rejection was confirmed histologically. ABI793 binds to human, Cynomolgus and Rhesus monkey CD154; it inhibits dose dependently in vitro CD154:CD40 binding and human mixed lymphocyte reaction. ABI793 is comparable to the mouse anti-human CD154 mAbs 5c8 and 24-31 with respect to affinity, inhibitory capacity, and species specificity; however, ABI793 binds to a different CD154 epitope. With 20 mg/kg of ABI793, five of nine recipients showed substantially prolonged graft survival after cessation of treatment, whereas four of nine recipients were killed because of high serum creatinine while still receiving treatment. ABI793 treatment was associated with episodes of severe acute tubular necrosis (which was unrelated to rejection and responded to fluid and diuretic treatment) and a decrease in platelet numbers. Chronic and acute thromboembolic vascular lesions with hemorrhages were observed in the lung and brain of two allograft recipients. None of these side effects were observed in animals that underwent autotransplantation, thus excluding direct toxicity of ABI793. ABI793 treatment effectively prevents graft rejection in Cynomolgus monkeys. Evidence for rare thromboembolic events, as also previously observed with different anti-human CD154 mAbs, suggests that thromboembolic complications may be a class effect of anti-CD154 mAbs, unrelated to their epitope specificity.

Induction of tolerance to heart transplants by simultaneous cotransplantation of donor kidneys may depend on a radiation-sensitive renal-cell population.

To determine the mechanism by which cotransplantation of a donor kidney and heart allograft induces tolerance to both organs in miniature swine, we examined the renal elements responsible for tolerance induction. Recipients received 12 days of cyclosporine, and transplants were performed across a major histocompatibility complex (MHC) class I mismatch. Group 1 animals received heart transplants (n=5); group 2 animals received heart and kidney allografts with no other manipulation (n=4); group 3 animals received heart transplants and donor-specific renal parenchymal cells (n=4); group 4 animals received heart and kidney allografts from lethally irradiated donors (n=7); group 5 animals received irradiated hearts and nonirradiated kidneys (n=2); group 6 animals received nonirradiated hearts and peripheral blood leukocytes from swine MHC matched to recipients and becoming tolerant to donor antigen (n=2); group 7 animals received nonirradiated hearts and donor-specific peripheral blood monocyte cells (PBMC) (n=2). Animals in group 1 developed vasculopathy and fulminant rejection by day 55. Animals in group 2 never developed vascular lesions. Parenchymal kidney cell infusion (group 3) did not prolong cardiac survival. Animals in group 4 developed arteriopathy by postoperative day (POD) 28. Group 5 recipients accepted allografts without vascular lesions. Adoptive transfer of leukocytes from tolerant swine (group 6) prolonged cardiac graft survival as much as 123 days, whereas donor PBMC infusion (group 7) did not affect cardiac survival or development of arteriopathy. Radiosensitive elements in kidney allograft may be responsible for tolerance induction and prevention of chronic vascular lesions in recipients of simultaneous heart and kidney allografts.

Histologic and immunohistologic study and clinical presentation of ANCA-associated glomerulonephritis with correlation to ANCA antigen specificity

Background: The major antigen specificities of antineutrophil cytoplasmic antibodies (ANCA) are for proteinase 3 (PR3) and myeloperoxidase (MPO). Only a limited number of studies have systematically assessed renal pathology with respect to ANCA antigen specificity. Methods: The authors evaluated renal biopsy light microscopy and immunofluorescence findings, clinical presentation, and outcome in 135 patients with ANCA-associated vasculitides. Results: Patients were divided into 3 groups: PR3-ANCA (n = 55), MPO-ANCA (n = 74), and ANCA of other specificities (n = 6). The mean duration of renal disease at biopsy was significantly longer in patients with MPO-ANCA than in those with PR3-ANCA (6.9 v 3.0 months). Immunofluorescence results showed mostly pauci-immune glomerulonephritis (n = 129) and rarely diffuse granular glomerular immune deposits suggesting immune complex deposition (n = 6). A focal form of crescentic glomerulonephritis was more frequent (P < 0.001), and glomerular necrosis was more prominent (P = 0.013) in the PR3-ANCA group, whereas diffuse crescentic glomerulonephritis, glomerulosclerosis, and interstitial fibrosis predominated in the MPO-ANCA group (P < 0.001). Extraglomerular vasculitis, present in 22.2%, and chronic vascular lesions indicative of previous vasculitis, present in 11.9% of patients, correlated with systemic involvement. Conclusion: The evolution of the pathologic lesions of PR3-ANCA and MPO-ANCA-associated glomerulonephritis seems to be similar. Differences in histopathology could be explained by the observation that in patients with PR3-ANCA, kidney biopsy was performed soon after renal involvement appeared, and focal active lesions were prevalent, whereas in patients with MPO-ANCA, kidney biopsy was done late in the course of the disease, and diffuse chronic sclerotic lesions predominated. Renal extraglomerular small vessel vasculitis appeared to be predictive of systemic involvement. Am J Kidney Dis 41:539-549. © 2003 by the National Kidney Foundation, Inc.

Suppression of Akt signaling induces Fas ligand expression: involvement of caspase and Jun kinase activation in Akt-mediated Fas ligand regulation.

Fas and Fas ligand (FasL) expression has been detected in chronic vascular lesions, and Fas-mediated apoptosis of vascular smooth muscle cells (VSMC) may influence the integrity of the atherosclerotic plaque. Here we report that FasL is not expressed by normal VSMC, but its expression is upregulated by stresses that induce apoptosis, including serum deprivation, exposure to the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor wortmannin, and ablation of Akt signaling. Conversely, constitutive activation of Akt signaling diminished FasL expression in VSMC cultures exposed to low-mitogen media or wortmannin. Under conditions of suppressed PI 3-kinase/Akt signaling, VSMC apoptosis was partially inhibited by treatment with neutralizing antibody against FasL. Suppression of Akt signaling increased the activity of c-Jun N-terminal kinase, and transduction of dominant-negative c-Jun inhibited FasL induction under these conditions. Diminished Akt signaling promoted the cleavage of caspase 3, and both caspase 3 cleavage and FasL induction were inhibited by transduction of dominant-negative caspase 9 or the caspase 8 inhibitor CrmA. Similarly, induction of FasL by the Akt-regulated forkhead transcription factor FKHRL1 was dependent upon caspase and c-Jun activation. Taken together, these results indicate that the sequential activation of caspase 3 and c-Jun participates in the induction of FasL under conditions of suppressed Akt signaling or FKHRL1 activation and that FasL participates in a positive-feedback loop to promote cell death under conditions of cellular stress.

Acute inflammatory intestinal vascular lesions and in situ abnormalities of the plasminogen activation system in Crohn's disease.

The distribution of the intestinal vascular lesions and their relation with the fibrinolysis process are poorly known in Crohn's disease (CD). The mediators of the plasminogen activator system, namely urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor type-1 (PAI-1), are a key complex involved in fibrinolysis. The aims of this study were: (1) to further define vascular lesions and their distribution in the intestine; and (2) to study concomitantly the qualitative in situ expression and the levels of u-PA, t-PA and PAI-1 in the ileum of patients with CD. Histological, immunohistochemical and ultrastructural studies of vascular lesions in the resected ileum of 27 patients with CD were performed and compared with 36 control patients. Levels of u-PA, t-PA and PAI-1 measured by ELISA methods were compared in healthy and inflamed ileal tissues of 17 patients with CD. Acute vascular lesions involving mainly serosal venules and capillaries were present in 63% of patients with CD vs 3/36 controls and were associated with PAI-1 expression. They were prominent on the mesenteric border beneath macroscopically normal mucosa. In contrast, chronic vascular lesions were present in all layers beneath mucosal ulcerations, where a significant increase of PAI-1 levels was found. These results suggest that vascular involvement associated with abnormalities of PAI-1 expression is an early and widespread event in CD. Their prominence on the mesenteric border might explain the characteristic location of CD ulceration along the mesenteric margin.

Malignant catarrhal fever in bison, acute and chronic cases.

Acute malignant catarrhal fever (MCF) was diagnosed in 10 bison from 6 herds and ranging from 1 to 6 years of age. The pattern of clinical signs and morphologic lesions differed among bison. Combinations of corneal opacity, lacrimation, nasal discharge, depression, excess salivation, anorexia, diarrhea, melena, and hematuria were observed. Vasculitis characterized by lymphoid infiltrates in the adventia with variable extension into media and intima was found in multiple tissues in each animal. Fibrinoid vascular necrosis was rare. Ulceration in the alimentary tract was found in 9/10 bison, and ulceration or hemorrhage in the urinary bladder was found in 8/10 bison. Lymphoid infiltrates were present in 7 of 9 livers and 9 of 9 kidneys examined histologically. Hyperplasia of lymph nodes was observed in 5 bison. Chronic MCF was diagnosed in 1 bison with an 80-day course of illness that began with lacrimation, corneal opacity, mucoid nasal discharge, depression, and anorexia. These signs ceased after 15 days but circling and blindness developed on day 76. Chronic vascular lesions characterized by endothelial cell hypertrophy, intimal thickening, fragmentation of the internal elastic membrane, smooth muscle hypertrophy, and adventitial infiltrates of lymphocytes and plasma cells were found in many organs. The retinal arteries had chronic inflammation and acute transmural fibrinoid necrosis. The retinas were infarcted. Polymerase chain reaction technique for amplification of ovine herpesvirus 2 sequences was performed on formalin-fixed tissues, and viral sequences were detected in 1-7 tissues from each animal. These viral sequences were not found in tissues of 4 bison not affected by MCF.

CHRONIC CARDIAC ALLOGRAFT REJECTION IS INDEPENDENT OF DONOR MHC CLASS II ANTIGENS

381 Donor MHC class II antigens are expressed on the vascular endothelium during chronic rejection. However, whether expression of donor MHC class II antigens is required for chronic rejection is not known. The purpose of this study was to determine whether allografted MHC II-/- hearts which do not reject acutely in the presence of only CD4 T cells would develop chronic vascular lesions. To test this proposition, heterotopic cardiac allografts from C57BL/6 (H-2b) MHC II +/+ or MHC II-/- mice were transplanted into immune-deficient C.B-17scid (H-2d, SCID) mice. SCID mice bearing established cardiac grafts were: (1) left unreconstituted, (2) reconstituted by adoptive transfer with unfractionated lymph node cells from BALB/c (H-2d) donors (10 ×106 cells), or (3) reconstituted with purified CD4 BALB/c T cells (10× 106 cells). Hearts were monitored for rejection by daily palpation. CD4 T cells isolated by antibody column purification (Biotex) and had undetectable numbers (<0.5%) of contaminating CD8 T cells or B220 B cells by flow cytometry.RESULTS: Unreconstituted SCID mice did not reject either cardiac MHC II +/+ or MHC -/- allografts (n=10, n=6, graft survival >60 days). Adoptive transfer of unfractionated cells to SCID recipients triggered acute rejection of both MHC II+/+ allografts (n=7, days 8,9,10, 10, 11, 19, 19) and MHC-/- allografts (n=6, days 8,10,10,10,10,11). MHC II+/+ allografts in SCID mice reconstituted with purified CD4 cells rejected in a time course similar to control mice (n=10, days 8, 9, 9, 10, 10, 10, 11, 11, 16, 22). MHC II-/- allografts in SCID mice reconstituted with purified CD4 cells did not reject acutely (n=7, 4/5 grafts >60 days, p<0.005), but all developed intimal thickening and evidence of chronic rejection. Unreconstituted long term (>60 days) allografts from either MHC class II+/+ or -/- donors did not develop evidence of chronic rejection. Acutely rejecting allografts demonstrated a typical lymphocytic infiltrate but did show evidence of chronic rejection. CONCLUSIONS: 1) Donor MHC class II antigens are not required for chronic rejection of cardiac allografts. 2) CD4 T cells are sufficient for chronic rejection of allografts, independently from either CD8 T cells or B cells. 3) Furthermore, we propose that CD4-dependent chronic graft rejection can be mediated through the indirect (host APC) dependent pathway.

Experimental piglet lung transplantation: histological bioptic changes and autopsy findings.

To investigate difficulties in diagnosing pulmonary rejection and to create a new model to observe long-term histological consequences, 21 piglets were subjected to left single lung transplantation. Five of these transplants served as targets for unmodified rejection in piglets without immunosuppression (Group I), 13 recipients were treated with cyclosporin A, azathioprine and methylprednisolone (Group II), and in 3 cases reimplantation of an autograft was performed (Group III). In the course of postoperative graft monitoring, transthoracic/bronchial biopsies were obtained on days 3, 5, 7, 10, 14, and 20, and thereafter less frequently up to 134 days. In the unmodified rejection group, grafts consolidated in one week and histologically presented perivascular mononuclear cell infiltrates, except for one case which showed vasculitis. Lymphocytic bronchiolitis and or peribronchiolar infiltrate was present in three of the four autopsied grafts. In Group II acute rejection was detected six times in three piglets, and all except one of these specimens had a peribronchiolar component. Although no incontestable bronchiolitis obliterans developed, mild to moderate chronic obliterative vascular lesions were detected in all immunosuppressed piglets (n = 3) surviving more than 80 days. Contralateral lungs and Group III autografts showed mild changes related to the operation itself and interstitial swine endemic pneumonia (SEP). Chronic changes related to rejection were limited to the vascular wall. The mainly inflammatory bronchiolar changes are thought to present an incipient phase leading to obliterative lesions.

Clinico-mr-tomographic characteristics of different kinds of chronic vascular multiple brain lesions

21 patient with different clinical patterns of non-insult course of developing vascular brain disturbance were included into investigation. Standard neurological examination was fol lowed by MR-tomography. Different degress of intellectualmnestic disorders and various locomotor disturbances correspond to the depicted in tomograms multiple brain lesions with cortical and subcortical foci. Comparison of clinical and MRT-data didnt reveal in full measure correlations between them.

Cavitating mycotic pulmonary infection in a German shepherd dog

ABSTRACTA four‐year‐old German shepherd dog had a chronic cough unresponsive to antibacterial and anti‐inflammatory therapy. Radiography revealed consolidation and cavitation in the anterior left lung field. Histological examination of the lung showed extensive necrosis, cavitation and chronic vascular lesions. Fungal infection of the lung was identified histologically and appeared to be an Aspergillus species. Necropsy confirmed extensive consolidation of the affected lung, but no other gross evidence of mycotic infection outside the lung.

Transient and sustained recovery from renal shutdown in accelerated hypertension

Ten black patients (eight men) with renal shutdown from accelerated hypertension were treated with hemodialysis. Renal function improved, and dialysis was discontinued after 6 ± 2 months. Five patients (Group I) have maintained good renal function at 25 ± 3 months of follow-up, whereas the other five (Group II) had deterioration again to advanced azotemia over 16 ± 6 months. On admission, Group I patients had lower levels of serum creatinine(9 ± 1.2 mg/dl [mean ± SE] versus 13.6 ± 1.7 mg/dl, p = 0.04) and urinary protein (0.98 ± 0.78 g per day versus 2.17 ± 1.5 g per day) and were more oliguric (451 ± 145 ml per day versus 1,122 ± 494 ml per day) than Group II. In Group I, renal shutdown was faster (8 ± 4 days versus (38 ± 28 days), recovery earlier (4 ± 1.5 months versus 8 ± 4 months) and greater (lowest serum creatinine level 1.9 ± 0.3 mg/dl versus 5.7 ± 1.7 mg/dl, p <0.05), and compliance better than in Group III. Two patients in the former group but none in the latter had peripheral schistocytes. It is concluded that the sustained recovery in Group I resulted from the resolution not only of the acute vascular lesions but also of tubular necrosis and microangiopathy, and the postrecovery deterioration in Group II is attributed to the more severe renal damage initially, the progression of the chronic vascular lesions in uncompliant patients, and possibly hyperfiltration damage in the remaining nephrons.

実験的高血圧における血漿レニン活性と血管障害

In order to clarify the roll of intrinsic renin in the development of hypertensive vascular lesions, plasma renin activity (PRA) and pathological findings were studied in two types of renovascular hypertension in rabbits.I. Short-term experiment.Hypertension was produced by constriction of left renal artery with an intact right kidney (two-kidney hypertension, Group A, 33 animals), and with right previous nephrectomy (one-kidney hypertension, Group B, 33 animals). Seven days after renal artery clipping, colloidal carbon was injected intravenously, and after one hour animals were sacrificed and examined light microscopically. PRA, serum Na, serum K, urea-N and hematocrit were determined before and after the operation.Hypertension developed in both A and B groups similarly. Increased PRA, hypokalemia and increased hematocrit value were observed in animals of group A only. PRA was increased in about half of animals of group A, but it remained unchanged or rather reduced in animals of group B. Acute vascular lesions were defined as fibrinoid necrosis of the small arteries and arterioles, insudation of carbon particles into the arterial wall, or lesions resembling periarteritis. The vascular lesions were found in 19 (57.6%) of 33 animals of gloup A and in 17 (51.5%) of 33 animals of group B. There was no difference in incidence and histological features of the vascular lesions between the two groups. The presence or absence of the vascular lesions did not depend upon the level of blood pressure in both groups. Within the group A, there was no significant correlation between PRA and development of the vascular lesions.II. Long-term experiment.Twenty animals of two-kidney hypertension (Group A) and twenty-one of one-kidney hypertension (Group B) were observed for twenty weeks after the renal artery costriction. Hypertension developed similarly in both groups. In animals of group A, increased PRA, hypokalemia and increased hematocrit values were seen. But in animals of group B, PRA was not increased.Eight (38%) out of twenty-one animals of group B died, and all these eight animals had cerebral haemorrhage. None of group A animals died. Histologically fibrinoid necrosis was seen in all animals that died and had cerebral heamorrhage, but in another animals it was seen in only one of group A animals. Another chronic vascular lesions were seen frequently in both groups. There was no significant difference in blood pressure and in another parameters between animals that died and survived.It is concluded that the vascular lesions and cerebral haemorrhage can develop independently of PRA or level of blood pressure.

The effect of heparin and dipyridamole on chronic vascular lesions in monkey cardiac allografts

The effect of heparin and dipyridamole on chronic vascular lesions in monkey cardiac allografts