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Biomedical subjects

M Rabinovitch

Publications and source records attributed to M Rabinovitch.

At least 73 records · Page 4Linked to original sources
PubMed1995

Lymphocyte transendothelial migration toward smooth muscle cells in interleukin-1 beta-stimulated co-cultures is related to fibronectin interactions with alpha 4 beta 1 and alpha 5 beta 1 integrins.

We previously reported infiltration of immune-inflammatory cells in coronary arteries from cardiac allografts, associated with increased endothelial and smooth muscle cell fibronectin synthesis regulated by interleukin (IL)-1 beta. We now investigate, using a porcine endothelial-smooth muscle cell co-culture system, whether IL-1 beta-stimulated fibronectin production is functionally important in lymphocyte transendothelial migration. Lymphocytes were harvested from porcine peripheral blood and, in the unactivated state or following activation with phorbol myristic acetate (PMA) and IL-2, were characterized by fluorescence-activated cell sorter (FACS) analysis and added to a confluent endothelial monolayer on the upper chamber of a transwell system. Endothelial cells, as well as smooth muscle cells (in the bottom of the chamber), were stimulated with IL-1 beta. Then transendothelial lymphocyte migration was determined in the presence of CS1 and RGD (fibronectin) peptides, blocking alpha 4 beta 1 and alpha 5 beta 1 integrin receptors on lymphocyte surfaces, respectively. A 55-70% inhibition of lymphocyte migration was observed when compared to control peptides. The combination of CS1 and RGD peptides did not significantly enhance the inhibitory effect of either peptide alone. A similar decrease in lymphocyte transendothelial migration toward smooth muscle cells was documented using a monoclonal antibody to cellular fibronectin. Furthermore, using smooth muscle cell conditioned medium, we reproduced the enhanced transendothelial lymphocyte migration as well as the inhibition with blocking peptides or fibronectin antibodies. Our data suggest that cytokine-mediated fibronectin synthesis in vascular cells recruits inflammatory cells through interactions of specific peptides with cell surface alpha 4 beta 1 and alpha 5 beta 1 integrins.

Amino Acid Sequence↗
PubMed1995

ICAM-1 and VCAM-1 expression in accelerated cardiac allograft arteriopathy and myocardial rejection are influenced differently by cyclosporine A and tumour necrosis factor-alpha blockade.

Expression of the vascular cell adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) occurs in allograft myocardium and in coronary arteries, promoting adhesion and transendothelial migration of inflammatory cells. We therefore investigated, in cholesterol-fed rabbits 9-10 days following heterotopic cardiac transplantation, whether the reduction of both myocardial rejection and graft arteriopathy with cyclosporine A (CsA) or graft arteriopathy alone with tumour necrosis factor-alpha soluble receptor (TNFsr) was associated with suppression of ICAM-1 and VCAM-1 expression. Host hearts showed negative immunostaining for these adhesion molecules, whereas donor specimens from untreated (control) rabbits showed moderate immunostaining for ICAM-1 and weaker immunostaining for VCAM-1 in the coronary arteries, myocardium (cardiac myocytes), and perivenular regions. The selective reduction of the coronary arteriopathy with TNFsr was associated with somewhat reduced expression of these adhesion molecules in the arteries, whereas CsA also suppressed myocardial rejection and markedly decreased both vascular and myocyte expression of ICAM-1 and VCAM-1.

Animals↗
PubMed1995

Abnormalities in intramyocardial arteries detected in cardiac transplant biopsy specimens and lack of correlation with abnormal intracoronary ultrasound or endothelial dysfunction in large epicardial coronary arteries.

OBJECTIVES: We sought to determine whether abnormalities in small intramyocardial vessels could be detected on routine cardiac transplant biopsy specimens and whether these features correlate with intimal thickening by intracoronary ultrasound and endothelial dysfunction in large epicardial vessels. BACKGROUND: Variability in clinical presentation of allograft vasculopathy suggests differential involvement of large and small vessels. Intracoronary ultrasound and endothelial function studies detect large-vessel abnormalities but may not reflect changes in small intramyocardial arteries. The latter could be detected in routine cardiac biopsy specimens by histologic and immunohistochemical studies. METHODS: Thirty-nine cardiac transplant recipients underwent intracoronary ultrasound and acetylcholine studies 5 to 7 days after endomyocardial biopsy. Biopsy tissue was evaluated for coronary artery endothelial plumping and intimal thickening and increased immunostaining for fibronectin, tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility. Large-vessel disease was assessed by calculating an average intimal index from intracoronary ultrasound of the left anterior descending coronary artery. Endothelial function was determined by quantitative coronary analysis after acetylcholine challenge. RESULTS: Coronary arteries were found in the biopsy tissue of 30 (76%) of the 39 patients who formed the study group. Fourteen of 30 patients had abnormal histologic findings. Immunohistochemical analysis for fibronectin, possible in 20 of 30 patients, was positive in 14 (70%) of 20 and correlated with abnormal histologic findings (p = 0.01). Immunostaining was positive for tumor necrosis factor-alpha and receptor for hyaluronan-mediated motility in 12 (40%) and 13 (43%) of 30 patients, respectively. All patients had intimal thickening by intracoronary ultrasound, but intimal index did not correlate significantly with small-artery disease by histologic or immunohistochemical analysis. Large-vessel endothelial dysfunction in 13 patients (43%) did not correlate with either abnormal ultrasound findings or small-vessel disease. CONCLUSIONS: Intramyocardial arteries are readily observed in biopsy specimens from cardiac transplant recipients and provide useful information about allograft vasculopathy. Lack of correlation between intramyocardial and epicardial vessel disease suggests discordant progression of allograft vasculopathy.

Adult↗
PubMed1995

Experience with repair of congenital heart defects using adjunctive endovascular devices.

The use of endovascular devices as an adjunct to repair of congenital heart anomalies represents a novel but unproven therapeutic approach. Intraoperative implantation of pulmonary arterial stents (5 to 15 mm diameter) was done in 11 patients with pulmonary atresia with ventricular septal defect (n = 4), classic tetralogy of Fallot (n = 2), truncus arteriosus (n = 1), hypoplastic left heart syndrome (stage II [n = 1] and stage III [n = 1] Norwood procedure), and miscellaneous pulmonary arterial stenoses (n = 3), as well as in patients with congenital (n = 1) and postoperative (n = 3) pulmonary venous obstruction and in 1 patient with combined pulmonary arterial and venous obstruction. The stents were effective at achieving immediate patency in all patients. There were two early deaths, one related to acute thrombosis of a small-diameter left pulmonary artery stent. Reintervention because of stent-related pulmonary arterial stenosis was frequently necessary. In five of seven patients who survived more than 1 month after implantation of stent size 8 mm or smaller severe stent-related pulmonary arterial obstruction developed. In four of the five patients with pulmonary vein stent implantation intractable obstruction developed, resulting in death in all three patients who had bilateral pulmonary vein stent implantation. Intraoperative occlusion of apical muscular ventricular septal defect with use of a clamshell device inserted from the right atrial approach was accomplished in four patients. One patient who underwent associated aortic arch reconstruction died as a result of left ventricular hypoplasia. The results in the remaining three patients were favorable on the basis of absence of significant late residual intraventricular shunting, left ventricular dysfunction, or arrhythmia. We conclude that recurrent intraluminal obstruction as a result of neointimal hyperplasia appears to be an eventual certainty in currently designed small-diameter endovascular stents. For this reason, we would recommend standard surgical techniques for repair of obstructive lesions of the pulmonary arterial confluence to maximize growth potential. Device occlusion of muscular ventricular septal defects is feasible but probably only indicated for complex cases of ventricular septal deficiency that otherwise necessitate a left ventriculotomy.

Adolescent↗
PubMed1995

Elastase and cell matrix interactions in the pathobiology of vascular disease.

Ultrastructural observations in lung tissue implicated an endogenous vascular elastase (EVE), in the pathobiology of pulmonary vascular disease. In experimental rats, increased activity of a 20 kDa serine proteinase related to adipsin precedes the development of sustained pulmonary hypertension and vascular abnormalities. A further increase in activity is related to malignant progression of the disease. A cause and effect relationship was suggested by studies in which elastase inhibitors successfully prevented or retarded progression of pulmonary hypertension. In vitro studies have shown that both serum and endothelial factors induce EVE via tyrosine kinase intracellular signalling. Induction of EVE can release basic fibroblast growth factor from the extracellular matrix in an active form stimulating smooth muscle cell proliferation. Elastase activity was also observed in the process of smooth muscle cell migration and neointimal formation in coronary arteries following experimental cardiac transplantation. An immune/inflammatory response is observed with increased production of cytokines, tumor necrosis factor-alpha and interleukin (IL)-1 beta, reciprocally up-regulating production of fibronectin, a glycoprotein which mediated smooth muscle cell migration. The action of IL-1 beta in inducing fibronectin is facilitated by the production of elastin peptides generated by increased activity of an elastase in the coronary arteries. Our studies suggest that ligation of the elastin binding protein by elastin peptides unmasks IL-1 receptors. Fibronectin also stimulates transendothelial migration of lymphocytes which perpetuates the inflammatory response leading to neointimal formation in this model. Masking integrins on T cells with a decoy synthetic CS-1 (fibronectin) peptide largely prevented transendothelial migration and coronary neointimal formation following cardiac transplant.

Animals↗
PubMed1995

Entry and survival of Leishmania amazonensis amastigotes within phagolysosome-like vacuoles that shelter Coxiella burnetii in Chinese hamster ovary cells.

Coxiella burnetii, a rickettsia, and Leishmania amazonensis, a protozoan flagellate, lodge in their host cells within large phagolysosome-like vacuoles. In the present study, C. burnetii-infected Vero or CHO cells were superinfected with L. amazonensis amastigotes to determine if these parasites can home to and survive within heterologous vacuoles. Six hours after superinfection, Leishmania amastigotes were located almost exclusively within large Coxiella-containing vacuoles. Thereafter, the numbers of parasites in the vacuoles increased at the same rate as those in cells infected with L. amazonensis alone. Furthermore, in cultures shifted to 25 degrees C, some of the amastigotes transformed into promastigote-like forms that moved their flagella within the adoptive vacuoles. Thus, L. amazonensis amastigotes not only entered Coxiella vacuoles, most likely by fusion of donor and recipient vacuoles, but temporarily survived, differentiated, and replicated therein. This appears to be the first account of the temporary cohabitation of two living pathogens within the same vacuole in a mammalian cell.

Animals↗
PubMed1995

Expression of tumour necrosis factor alpha and accumulation of fibronectin in coronary artery restenotic lesions retrieved by atherectomy.

BACKGROUND: The formation of coronary artery neointima experimentally induced in piglets after cardiac transplantation is related to an immune-inflammatory reaction associated with increased expression of T cells and inflammatory mediators (tumour necrosis factor alpha and interleukin 1 beta) and upregulation of fibronectin. In vivo blockade of tumour necrosis factor alpha in rabbits after cardiac transplantation results in reduced neointimal formation. The objective of this study was to investigate the hypothesis that coronary restenosis after atherectomy or percutaneous balloon angioplasty is associated with a similar inflammatory cascade initiated by mechanical injury. METHODS: Specimens taken at coronary atherectomy were analysed from 16 patients. Nine had had the procedure performed twice, firstly, to remove a primary lesion, and secondly, to remove a restenotic lesion. Seven had percutaneous balloon angioplasty after removal of restenotic tissue. Coronary atherectomy specimens were analysed by immunohistochemistry for the presence of T cells, macrophages, major histocompatibility complex II, interleukin 1 beta, tumour necrosis factor alpha, fibronectin, and the receptor for hyaluronan mediated motility. RESULTS: The groups were clinically and angiographically similar with equivalent lumens before and after atherectomy. Restenotic lesions had increased expression of tumour necrosis factor alpha and fibronectin compared with the primary lesions (P < 0.05 for both). There was also a trend towards a greater number of T cells and increased expression of interleukin 1 beta. CONCLUSIONS: Restenosis is associated with increased expression of tumour necrosis factor alpha and fibronectin, suggesting that an immune-inflammatory reaction probably contributes to neointimal formation and may represent a form of wound healing and repair secondary to mechanical injury.

Angioplasty, Balloon, Coronary↗
PubMed1995

Increased elastin-degrading activity and neointimal formation in porcine aortic organ culture. Reduction of both features with a serine proteinase inhibitor.

We investigated the association between tissue elastolytic activity and the development of neointimal formation using a previously described porcine aortic organ culture. Neointimal formation is associated with the presence of intact endothelium (nondenuded cultures) but is markedly reduced if endothelial cells are removed (denuded cultures). In nondenuded organ cultures, elastolytic activity assessed by using [3H]elastin increased sixfold at day 3 after initiation of the culture (P < .01), a time earlier than the previously published increase in intimal smooth muscle cells (ISMCs). Elastolytic activity did not increase from day 3 to day 7 despite doubling of ISMCs but did double by day 14 (P < .01) and remained elevated to day 28, correlating with increases in ISMCs. In denuded organ cultures, elastolytic activity was much lower than in nondenuded organ cultures at day 3 (P < .05) but increased fivefold in the presence of nondenuded organ culture conditioned medium (P < .01). Addition of alpha 1-proteinase inhibitor for 14 days caused a 60% decrease in elastolytic activity in nondenuded organ cultures and a 27% reduction in ISMCs compared with untreated controls (P < .05 for both). The elastolytic activity, resolved as lytic bands on an elastin substrate gel, reflected candidate enzymes, one at 76 kD and perhaps a doublet at 43 and 50 kD. Our study suggests that endothelial cells release a soluble agent that enhances elastin-degrading activity in the aorta and may at least partially account for the initiation of neointimal formation.

Animals↗
PubMed1995

Increased respiratory system resistance and bronchial smooth muscle hypertrophy in children with acute postoperative pulmonary hypertension.

Following surgery for congenital heart disease, there is often an increased reactivity of the pulmonary vasculature to stimuli, resulting in rapid increases in pulmonary artery pressure and a clinical impression of stiff lungs. Lung mechanics were measured in 30 children, mean age 6.7 +/- 4.1 mo, who were ventilated and had pulmonary artery pressure monitoring following surgery for congenital heart disease. A group of 15 patients developed postoperative pulmonary hypertension. In these patients, respiratory system resistance was 43% higher (p = 0.001) and compliance 11% lower (p = 0.004) during acute pulmonary hypertension compared with baseline pulmonary artery pressure. No changes in resistance or compliance were seen in the 15 patients who did not develop pulmonary hypertension. The changes in lung mechanics interfered with mechanical ventilation, resulting in a 9.4% rise in PaCO2 during pulmonary hypertension. The bronchial smooth muscle was found to be increased by 68%, and the vascular smooth muscle was more than twice normal in lung biopsies from 9 pulmonary hypertension patients compared with 6 age-matched postmortem controls patients who had no cardiac or pulmonary disease. The bombesin-immunoreactive pulmonary neuroendocrine cells (PNEC) were also increased in the pulmonary hypertension patients. These findings suggest a coconstriction and cohypertrophy of bronchial and vascular smooth muscle during pulmonary hypertension. Mediators, such as bombesin, endothelin-1, and serotonin, are known to be produced by PNEC and may be involved in the observed vasoconstriction, increased respiratory system resistance, and smooth muscle hypertrophy.

Acute Disease↗
PubMed1995

Blockade of very late antigen-4 integrin binding to fibronectin with connecting segment-1 peptide reduces accelerated coronary arteriopathy in rabbit cardiac allografts.

Graft arteriopathy, a leading cause of cardiac allograft failure, is associated with increased intimal smooth muscle cells, inflammatory cells, and accumulation of extracellular matrix. We hypothesized that cellular fibronectin plays a pivotal role in the progression of the allograft arteriopathy by directing the transendothelial trafficking of inflammatory cells through interaction of the connecting segment-1 (CS1) motif with the very late antigen-4 (VLA-4) integrin, and tested this in vivo using a blocking peptide. Cholesterol-fed rabbits underwent heterotopic cardiac transplantation without immunosuppression. The treatment group (n = 7) received a synthetic CS1 peptide (1 mg/kg per d, subcutaneously), and the controls (n = 7) received an inactive peptide (1 mg/kg per d, subcutaneously). At 7-8 d after transplantation, hearts were harvested and sectioned for morphometric analysis and immunohistochemical studies. We observed a > 50% decrease in the incidence (P < 0.001) and severity (P < 0.001) of donor coronary artery intimal thickening in the CS1-treated compared with the control group. These findings correlated with reduced infiltration of T cells (P < 0.05), a trend toward decreased expression of adhesion molecules (P < 0.06), and less accumulation of fibronectin (P < 0.03). Our data suggest that the VLA-4-fibronectin interaction is critical to the progression of the allograft arteriopathy by perpetuating the immune-inflammatory response in the vessel wall.

Amino Acid Sequence↗
PubMed1994

Serum-induced vascular smooth muscle cell elastolytic activity through tyrosine kinase intracellular signalling.

In previous studies, we related increased elastolytic activity in pulmonary arteries (PA) with endothelial injury to the later development of PA hypertension in rats. As the mechanism causing the increased PA elastase was unknown, we hypothesized that serum factors which are accessible to vascular smooth muscle cells (SMC) following endothelial injury stimulate their elastolytic activity. To test this, we developed an in vitro assay in which we added [3H]-elastin to cultured vascular SMC after 24 h serum starvation and monitored elastolysis following a further 24 h incubation with fetal bovine serum (FBS). We observed that serum induced increased elastolytic activity in both PA and aorta-derived SMC but not in endothelial cells or SMC with low basal levels of elastolytic activity. Maximum stimulation of SMC elastolytic activity occurred with a concentration as low as 1% FBS and despite elastase inhibitors in serum, suggesting that the activity is confined to the immediate pericellular region where enzyme concentration is high. Serum-stimulated elastolytic activity was not reproduced by growth factors or cytokines known to be associated with vascular disease or to induce release of elastases in other cells. The serum inducing elastolytic activity was heat and acid labile. It was associated with increased elastin adhesion to the 67 kD elastin binding protein on SMC surfaces and was prevented by tyrosine kinase inhibitors but not protein kinase C or A inhibitors. Our studies therefore suggest a mechanism whereby serum induction of SMC elastase requires signalling through the elastin binding protein and activation of tyrosine kinase.

Animals↗
PubMed1994

Prevalence of hepatitis B virus markers among hospital personnel in Israel: correlation with some risk factors.

During 1986-1987, 480 employees of the Tel-Aviv Medical Center were screened for hepatitis B virus (HBV) markers as a preliminary step in a vaccination campaign. One hundred and seventeen (24.4%) had evidence of previous infection, including nine (1.9%) carriers. The effect of potential risk factors on seropositivity was evaluated by multiple logistic regression analysis, which enabled assessment of the individual contribution of each risk factor under the specific environmental conditions. The following risk factors were found to influence seropositivity: origin from Third World countries as opposed to the Western World, employment as sanitary workers, age over 40 years, and history of accidental needle punctures. In the heterogeneous Israeli population, hospital workers had a relatively high prevalence of HBV markers, probably resulting from occupational exposure.

Adult↗
PubMed1994

67-kD elastin-binding protein is a protective "companion" of extracellular insoluble elastin and intracellular tropoelastin.

The 67-kD elastin-binding protein (EBP) mediates cell adhesion to elastin and elastin fiber assembly, and it is similar, if not identical, to the 67-kD enzymatically inactive, alternatively spliced beta-galactosidase. The latter contains an elastin binding domain (S-GAL) homologous both to the aorta EBP and to NH2-terminal sequences of serine proteinases (Hinek, A., M. Rabinovitch, F. W. Keeley, and J. Callahan. 1993. J. Clin. Invest. 91:1198-1205). We now confirm the functional importance of this homology by showing that elastolytic activity of a representative serine elastase, porcine pancreatic elastase, was prevented by an antibody (anti-S-GAL) and by competing with purified EBP or S-GAL peptide. Immunohistochemistry of adult aorta indicates that the EBP exists as a permanent component of mature elastic fibers. This observation, together with the in vitro studies, suggests that the EBP could protect insoluble elastin from extracellular proteolysis and contribute to the extraordinary stability of this protein. Double immunolabeling of fetal lamb aorta with anti-S-GAL and antitropoelastin antibodies demonstrated, under light and electron microscopy, intracellular colocalization of the proteins in smooth muscle cells (SMC). Incubation of SMC with galactosugars to dissociate tropoelastin from EBP caused intracellular aggregation of tropoelastin. A tropoelastin/EBP complex was extracted from SMC lysates by coimmunoprecipitation and cross-linking, and its functional significance was addressed by showing that its dissociation by galactosugars caused degradation of tropoelastin by endogenous serine proteinase(s). This suggests that the EBP may also serve as a "companion" to intracellular tropoelastin, protecting this highly hydrophobic protein from self-aggregation and proteolytic degradation.

Alternative Splicing↗
PubMed1994

Cytochrome P450 during ontogenic development: occurrence in the ductus arteriosus and other tissues.

Our previous investigations have implicated a cytochrome P450 mechanism in the oxygen contraction of the ductus arteriosus and, by extension, in the closure of the vessel at birth. This study was undertaken in fetal and newborn sheep to characterize the ductal cytochrome and gather insight into its operation. Other tissues, vascular and extravascular, were used as a reference. Benzo[a]pyrene hydroxylation (a marker for the 3-methylcholanthrene-inducible isozyme) and aminopyrine N-demethylation (a marker for the glucocorticoid-inducible isozyme) had insignificant activity in the ductus and aorta from fetal sheep, and no increase was noted after exposing the animal in utero to beta-naphthoflavone or dexamethasone, both alone and in combination with phenobarbital. However, dexamethasone and, particularly, dexamethasone plus phenobarbital produced a variable constriction of the fetal ductus. No monooxygenase activity was found in the naturally closing ductus of the newborn. Conversely, both enzyme reactions were measurable in the fetal liver, and they became more active after treatment with the inducers or at birth. Scanning immunoelectron microscopy of cultured endothelial and muscle cells from both ductus and aorta showed specific gold labelling for the glucocorticoid-inducible cytochrome P450 only in ductal muscle. By transmission electron microscopy, this immunoreactivity was located along the sarcolemma and in the sarcoplasmic reticulum. These findings indicate the presence in the ductus arteriosus of a cytochrome P450 belonging to the 3A subfamily. However, considering the uneven action of the inducers on enzyme activity in ductal tissue and muscle tone, the role of this cytochrome in closure of the vessel at birth remains to be ascertained.

Aging↗
PubMed1994

Pulmonary hypertension and vascular remodeling in fetal sheep.

Vascular remodeling is commonly associated with pulmonary hypertension (PH) postnatally, but little is known about its presence in fetuses. In sixteen fetal sheep (126 wk gestation), the ductus arteriosus (DA) was ligated, and the animals were studied at 4, 8, and 14 days after surgery. The uninstrumented twins served as controls. Four days post-DA ligation PH resulted in an increase in the right and left ventricular free wall weight ratio (1.2 +/- 0.1 vs. 1.0 +/- 0.1 in the controls; P < 0.01), with a further progressive increase at 8 (1.4 +/- 0.1 vs. 1.0 +/- 0.1; P < 0.01) and 14 days (1.5 +/- 0.2 vs. 1.0 +/- 0.1; P < 0.01). An increase in vascular percent medial thickness was observed after 4 days of DA ligation and was restricted to small vessels. The large arteries collagen and elastin contents were 28.9 +/- 3.4 and 27.1 +/- 3.4 micrograms/micrograms of DNA, respectively, and were not significantly different from control values even after 14 days DA ligation. We further compared elastin synthesis in fetal and neonatal arteries in vitro. Synthesis in the fetus was greater than the newborn (10.6 +/- 1.4 vs. 4.6 +/- 0.7 cpm.mg wet wt-1.h-1; P < 0.01). Vessel endothelium denudation reduced synthesis to 60 +/- 8% of controls in the fetus, whereas no change was seen in the newborn. After an increase in wall stress, synthesis increased in the fetus (194 +/- 28% of control P < 0.01) and newborn (173 +/- 25%; P < 0.01). Removal of the endothelium abolished the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

In vivo blockade of tumor necrosis factor-alpha in cholesterol-fed rabbits after cardiac transplant inhibits acute coronary artery neointimal formation.

BACKGROUND: We previously identified in piglet cardiac allografts an immunoinflammatory response in coronary arteries in which increased fibronectin regulated by interleukin-1 beta was associated with early evidence of intimal thickening. In the present study, we used rabbits to assess whether acute neointimal formation after cardiac transplantation was reduced by blockade of tumor necrosis factor (TNF)-alpha, which modulates interleukin-1 beta, or by cyclosporine A. METHODS AND RESULTS: Sixteen rabbits underwent heterotopic cardiac transplantation and were given saline, TNF-soluble receptor (sr), or cyclosporine A. In host hearts from saline- or TNFsr-treated groups, few coronary arteries (approximately 13% to 16%) had intimal thickening, whereas values were higher in the cyclosporine A-treated group (approximately 30%). In donor hearts from the saline-treated group, however, approximately 68% of vessels had intimal thickening versus approximately 32% in TNFsr- and approximately 30% in cyclosporine A-treated groups (P < .01 for both). Severity of intimal thickening assessed quantitatively as percent vessel area was approximately 38% in the saline-treated group but reduced in TNFsr- and cyclosporine A-treated groups to approximately 22% and 18%, respectively (P < .01 for each). Immunohistochemistry revealed increased staining for major histocompatibility complex II, T cells, interleukin-1 beta, TNF-alpha, and fibronectin in donor coronary arteries from saline-treated animals when compared with TNFsr- and cyclosporine A-treated animals. Grade 3 myocardial rejection was observed in both saline- and TNFsr-treated groups, but only grade 1 was apparent in the cyclosporine A-treated group. CONCLUSIONS: In vivo blockade of TNF-alpha suppresses the acute development of neointimal formation by selectively reducing the vascular immunoinflammatory reaction and accumulation of fibronectin, whereas cyclosporine A suppresses both the myocardial and the vascular immune reaction.

Acute Disease↗