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Biomedical subjects

D H Adams

Publications and source records attributed to D H Adams.

At least 145 records · Page 8Linked to original sources
PubMed1994

Mechanisms involved in living systems organisation, especially the programming necessary to enable the construction of individuals in three dimensions.

The complexity of the organization of living systems escalates by orders of magnitude in the development, from single precursor cells, not only of the three-dimensional structures characterizing each species but also in the variations necessary to accommodate the 1 million or more separate and identifiable species on this planet. Although the genetic information controlling such information is currently considered to reside in cellular DNA, it is also held that such information is restricted to a linear form encoding specifically for protein. However, this not only fails to explain the co-ordination of the vast number of processes occurring in simple, single cell, organisms, but also the integration of cellular activities to serve the interest of the total system. In particular how can a homeobox containing only genes encoding specifically for proteins organize and implement the mechanisms necessary for three-dimensional development? This, and the organization and implementation of the massive amount of information necessary to execute the construction of such a wide range of species, each in its own unique and exquisite detail, calls for internal programming of a highly complex and sophisticated nature. It is proposed here that such a central computer-analog program does exist, housed in the molecular electronic structure of cellular nucleic acid, primarily in DNA: its possible nature is discussed. Since precursor cells contain only of the order of 10(-10) g of DNA, this proposal involves an increase in information storage efficiency comparable with that already achieved by silicon microprocessors over mechanical calculators.

Animals↗
PubMed1994

Leucocyte adhesion molecules and alcoholic liver disease.

The causative agent of alcoholic liver disease is self-evident although the pathogenesis of the liver damage is not well understood. There is increasing evidence from both animal experiments and human studies that inflammation triggered in response to alcohol or its metabolites is important in the tissue damage and fibrosis of alcoholic liver disease. Both alcoholic hepatitis and alcoholic cirrhosis are characterized by inflammation of the liver, although the nature of the inflammatory infiltrate differs between the two diseases. The activation of leucocytes, their migration into tissue and subsequent interaction with target cells are all dependent on regulated adhesion. Therefore, leucocyte adhesion molecules and their counter-receptors will play a crucial role in determining the nature and activity of leucocytes infiltrating the liver in alcoholic liver disease. Evidence is now emerging that suggests roles for particular adhesion pathways in two aspects of the inflammatory response in alcoholic liver disease, (1) leucocyte recruitment to the liver, and (2) cell-mediated hepatocyte damage. It is important that these pathways are defined since therapy aimed at blocking leucocyte adhesion molecules might provide an effective future therapy for selected patients with alcoholic liver disease.

Animals↗
PubMed1994

Aortic valve endocarditis. Determinants of early survival and late morbidity.

BACKGROUND: Aortic valve surgery for endocarditis remains a high-risk procedure. The objective of this study was to analyze the interaction between the various subsets of endocarditis (native, prosthetic, healed, and active), timing of surgery, and their influence on early and late outcomes. METHODS AND RESULTS: During a 20-year period starting January 1972, 200 patients underwent aortic valve replacement for infective endocarditis (age range, 13 to 88 years; median, 53 years). There were 51 (26%) females, and 109 (55%) were in New York Heart Association functional class IV before surgery. Native valve endocarditis (NVE) and prosthetic valve endocarditis (PVE) were present in 132 (66%) and 68 (34%) patients, respectively. Surgery was required in 120 (60%) during the active phase (AE) and 80 (40%) during the healed phase (HE) of endocarditis. The main indication for surgery in the healed group was progressive congestive heart failure. The indications for the active group were congestive heart failure (68%), continuing active sepsis (70%), echocardiographic vegetation (28%), peripheral emboli (30%), and arrhythmias (13%). Streptococcal infections predominated in NVE, staphylococcal in PVE and AE; culture-negative endocarditis predominated in the healed group. Isolated aortic valve surgery was performed in 68% of the patients, and concomitant procedures (32%) included mitral valve and coronary bypass procedures. The overall operative mortality (OM) was 12.5%. The OM was 7.5% and 22% for NVE and PVE, respectively (P = .004), and 7% for HE versus 15% for AE (P = .06). The OM for early PVE was 33% versus 18% for late PVE (P < .05). Multivariate logistic regression analysis identified PVE and New York Heart Association functional class IV to be independent predictors for early death. Recurrent endocarditis occurred 26 times in 24 patients (11 early, 13 late), with three operative deaths in the early group, all due to residual staphylococcal infections. Freedom from recurrent endocarditis was significantly different between HE (96 +/- 3% and 86 +/- 6% at 5 and 10 years, respectively) and AE (89 +/- 3% and 83 +/- 4%, respectively (P = .02). Long-term survival for discharged patients was 81 +/- 3% and 63 +/- 5% at 5 and 10 years, respectively, with no significant difference between NVE, PVE, AE, and HE. CONCLUSIONS: These data suggest that for active endocarditis, surgery should be delayed to achieve a healed status provided there is no pressing need for immediate surgery. Patients with staphylococcal endocarditis, particularly on a prosthesis, should be operated on sooner and should be covered with antibiotics for an extended period to prevent recurrent PVE. This study stresses the need for aggressive antibiotic prophylaxis, particularly in the presence of a prosthesis.

Aortic Valve↗
PubMed1994

CD4+ mononuclear cells induce cytokine expression, vascular smooth muscle cell proliferation, and arterial occlusion after endothelial injury.

Studies of T cell-deficient or immunosuppressed animals undergoing arterial endothelial denudation have yielded conflicting results as to the contribution of the immune system to neointimal vascular smooth muscle cell accumulation and proliferation. We investigated the cell types and cytokine expression associated with intimal hyperplasia occurring 14 days after balloon angioplasty of the carotid artery in Sprague-Dawley rats. Immunohistological studies using monoclonal antibodies showed that the carotid luminal occlusion observed was associated with smooth muscle cell proliferation and neointimal accumulation of large numbers of CD4+, ED1+ mononuclear cells but no T cells. There was also wide-spread staining for the inflammatory cytokine interleukin-1B (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and IL-8, as well as dense expression of the potent smooth muscle mitogens platelet-derived growth factor (PDGF), transforming growth factor-beta (TGF-beta), and protein S. The relationship of smooth muscle cell proliferation to monocyte/macrophage accumulation and cytokine expression was tested by daily intraperitoneal administration for 14 days of a rat CD4-specific monoclonal antibody, BWH-4 (500 micrograms/day). Morphometric analysis at day 14 showed that the intimal area of animals treated with CD4 monoclonal antibody comprised 7% +/- 4% of the arterial wall compared with 50% +/- 6% in control animals (n = 6/group, P < 0.001). In addition, immunohistological studies showed that CD4 monoclonal antibody treatment markedly reduced the intimal accumulation of mononuclear and smooth muscle cells and essentially abrogated expression of the cytokines PDGF-BB, TGF-beta, IL-1 beta, TNF-alpha, and IL-8, plus the anticoagulant molecule, protein S. Our results document the extensive expression in vivo of cytokines that in vitro promote vascular smooth muscle cell proliferation, and suggest that CD4+ mononuclear cells or their secreted products play a key role in the pathogenesis of intimal hyperplasia after endothelial injury. Furthermore, these observations may have clinical relevance in the development of novel strategies to prevent arteriosclerosis.

Angioplasty, Balloon↗
PubMed1994

Chronic rejection in experimental cardiac transplantation in a rat model.

The most significant pathologic finding in chronically rejected organ grafts is diffuse concentric intimal proliferation in the arterial system. To develop a reproducible model of chronic vascular rejection in cardiac grafts which we could then use to study the pathogenesis and therapy of this disease process, we exchanged heterotopic cardiac allografts across minor histocompatibility barriers using commercially available Lewis rats as donors and F-344 rats as recipients. We found that all long-term surviving allografts developed diffuse graft arteriosclerotic lesions which were virtually identical in appearance to those seen in chronically rejected human cardiac grafts. Immunohistochemical studies confirm that end-stage lesions are similar in composition to human lesions and are made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of continuous series of rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM-1 probably underlies early mononuclear cell adherence to the endothelium. Analysis using quantitative RT-PCR and immunocytochemistry confirms MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF and IL-1 beta in vascular lesions suggests these factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts, as they, along with protein S, were closely associated with sites of intimal hyperplasia and smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Rapid noninvasive diagnosis and surgical repair of acute ascending aortic dissection. Improved survival with less angiography.

Angiography has been considered the gold standard for the diagnosis of acute dissection of the ascending aorta, but it may increase mortality by imposing an unnecessary delay before surgical repair. In addition, coronary angiography has often been considered essential as well. From 1988 to 1993, 37 patients (median age 61 years, 30 men and 7 women) had acute dissection of the ascending aorta. All of the initial 15 patients (group I) had angiography, even through the diagnosis of aortic dissection had already been made noninvasively in 14; six (40%) of 15 died, three of aortic rupture and none of complications of coronary artery disease. Among the next 22 patients (group II), 21 had a noninvasive diagnosis of acute dissection of the ascending aorta (eight by echocardiography; 13 by computed tomography), and 19 (86%) were operated on without angiography; two died (9%, p = 0.03 versus group I) and neither death was due to aortic rupture or coronary artery disease. Overall, either root or selective coronary angiography was attempted in 18 of 37 patients, but it documented coronary artery disease in only two patients (11%). Coronary artery disease was found in four other patents at autopsy; three of them, including two that died of aortic rupture, had angiography that failed to reveal the coronary artery disease. Noninvasive diagnosis of acute dissection of the ascending aorta is reliable and avoids the risks and delays inherent in invasive angiography. Rapid noninvasive diagnosis of aortic dissection and avoidance of routine angiography appear to improve survival by expediting surgical intervention and thus decreasing the risk of aortic rupture.

Acute Disease↗
PubMed1994

The long-term results of mitral valve reconstruction for the "floppy" valve.

The myxomatous degenerated, prolapsed, or floppy mitral valve is the most common etiology of mitral regurgitation in North American populations. We performed mitral valve reconstruction for this diagnosis in 252 patients from 1984 to 1993. There were 165 males and 87 females ranging in age from 23 to 84 years (mean 64 years); 93 (37%) were > or = 70 years. One hundred eighty-six were New York Heart Association Functional Class III or IV and 29% (72) underwent concomitant coronary bypass operation. Operations included posterior leaflet resection, anterior leaflet resection treatment of chordal pathology by shortening or Gore-Tex replacement, and ring annuloplasty. There were five operative deaths for an operative mortality of 2%. The operative risk in patients under 70 years was 1 of 159 (0.6%) and 4 of 93 (4%) in patients older than 70 years. Ninety percent of patients are asymptomatic in a follow-up period extending 10 years, while structural valve degeneration requiring reoperation at 5 years was 85%. From 1990 to 1993 there has been a less than 5% absolute incidence of structural valve degeneration. Mitral valve reconstruction for complicated floppy mitral valve is feasible and offers excellent early and medium-term results.

Adult↗
PubMed1994

Retransplantation in heart-lung recipients with obliterative bronchiolitis.

Obliterative bronchiolitis remains the leading cause of morbidity and mortality in long-term survivors after heart-lung transplantation. Despite enhanced immunosuppressive therapy, a significant number of patients progress to end-stage respiratory failure, leaving retransplantation as the only potential therapeutic option. Between October 1986 and August 1990, 25 heart-lung recipients (mean age 22 +/- 2 years) underwent repeat heart-lung transplantation at an average of 21 months after their first procedure. Twenty-one patients (83%) were ventilator dependent at the time of retransplantation. The Kaplan-Meier survival at 1, 6, 12, and 24 months was 52%, 33%, 25%, and 25%, respectively. Postoperative complications included bleeding, multisystem organ failure, and infection. Obliterative bronchiolitis resulted in death or graft failure in three patients between 12 and 36 months after the second transplantation. Five patients were currently alive at the time this article was written, with a median follow-up of 54 months. Three were in New York Heart Association class I, and two had obliterative bronchiolitis with class III symptoms. Recently, we investigated the role of single lung retransplantation in nine heart-lung recipients (mean age 23 +/- 3 years). The mean interval between procedures was 36 months, and eight patients (88%) were ventilator dependent. The Kaplan-Meier survival at 1, 6, 12, and 24 months was 89%, 67%, 67%, and 50%, respectively. We observed significantly less perioperative morbidity in this group. Five patients were alive (median follow-up 20 months); four were in New York Heart Association class I or II, and one was in New York Heart Association class III with recurrent obliterative bronchiolitis. We did not have enough patients to perform multivariate survival analysis. Survival curve comparisons with the use of the Wilcoxon test did show that the absence of performed antibodies in the recipient (panel reactive antibody frequency less than 10%) was associated with significantly improved survival after retransplantation. We also noted trends for improved survival in patients who had retransplantation at least 18 months after their original transplantation and in patients with negative preoperative sputum cultures. Retransplantation is a high-risk procedure that can result in rehabilitation in otherwise incapacitated patients. Single lung retransplantation appears to be the preferred option in carefully selected patients.

Adolescent↗
PubMed1993

Protease inhibitors selectively block T cell receptor-triggered programmed cell death in a murine T cell hybridoma and activated peripheral T cells.

The hypothesis that cytoplasmic proteases play a functional role in programmed cell death was tested by examining the effect of protease inhibitors on the T cell receptor-mediated death of the 2B4 murine T cell hybridoma and activated T cells. The cysteine protease inhibitors trans-epoxysuccininyl-L-leucylamido-(4-guanidino) butane (E-64) and leupeptin, the calpain selective inhibitor acetyl-leucyl-leucyl-normethional, and the serine protease inhibitors diisopropyl fluorophosphate and phenylmethylsulfonyl fluoride, all showed dose-dependent blocking of the 2B4 death response triggered by the T cell receptor complex and by anti-Thy-1. These protease inhibitors enhanced rather than inhibited IL-2 secretion triggered by T cell receptor cross-linking, showing that they did not act by preventing signal transduction. Growth inhibition induced by cross-linking the 2B4 T cell receptor, measured by inhibition of thymidine incorporation, was not generally blocked by these protease inhibitors. All five of these protease inhibitors enhanced rather than blocked 2B4 cell death triggered by dexamethasone, an agent previously shown to have a death pathway antagonistic with that of the TCR. 2B4 cytolysis by the cytotoxic agents staphylococcal alpha-toxin and dodecyl imidazole, and that caused by hypotonic conditions, was not significantly affected by the five protease inhibitors tested. The selected protease inhibitors blocked both the apoptotic nuclear morphology changes and DNA fragmentation induced by T cell receptor cross-linking, and enhanced both these properties induced by dexamethasone in 2B4 cells. The T cell receptor-induced death of activated murine lymph node T cells and human peripheral blood CD4+ T cells was blocked by both cysteine and serine protease inhibitors, showing that the protease-dependent death pathway also operates in these systems.

Animals↗
PubMed1993

Early and persistent induction of monocyte chemoattractant protein 1 in rat cardiac allografts.

The early response gene for monocyte chemoattractant protein 1 (MCP-1) encodes a potent chemotactic factor that is specific for monocytes. To determine whether MCP-1 is involved in macrophage recruitment in cardiac allografts, we studied time-dependent MCP-1 gene and protein expression patterns in the heterotopic, Lewis to F-344 rat transplantation model (by reverse transcription-PCR and immunohistochemistry). There was a significant increase (8- to 12-fold) in MCP-1 gene transcripts in cardiac allografts compared with host hearts at 7, 14, and 28 days after transplantation. This induction was not observed with syngeneic transplants or hosts exposed to the same circulating cells and blood products. The MCP-1 gene product was expressed predominantly by mononuclear cells that double-stained with antimacrophage antibody (ED1) and localized to the interstitial and vascular spaces of the allografts. Immunocytochemical cell counting revealed significant increases in both MCP-1- and ED1-immunopositive cells in 7-, 14-, and 28-day allografts (in comparison with day 0 hearts). The absolute number of MCP-1-positive cells (5-7%) was lower than that of ED1-positive cells (25-34%) at all time points, suggesting that MCP-1-positive cells represent a subpopulation of activated macrophages. The persistent expression of MCP-1 in association with increased macrophage localization suggests that this inducible mediator contributes to the chronic inflammatory response following cardiac transplantation and that it may play a role in the pathogenesis of transplant arteriosclerosis.

Animals↗
PubMed1993

T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta.

Lymphocyte migration from blood into tissue depends on integrin-mediated adhesion to endothelium. Adhesion requires not only integrin ligands on the endothelium, but also activation signals because T-cell integrins cannot bind well until they are activated. The physiological 'triggers' for T-cell adhesion are unknown, but cytokines may be good candidates as they are released during inflammation and trigger adhesion in neutrophils and monocytes. We have identified a cytokine, macrophage inflammatory protein-1 beta (MIP-1 beta), that induces both chemotaxis and adhesion of T cells; MIP-1 beta is most effective at augmenting adhesion of CD8+ T cells to the vascular cell adhesion molecule VCAM-1. We reasoned that, as cytokines in vivo will be rapidly washed away, MIP-1 beta might be bound to endothelial surfaces and so induce adhesion in its immobilized form. Here we show that: (1) MIP-1 beta is present on lymph node endothelium; (2) immobilized MIP-1 beta induces binding of T cells to VCAM-1 in vitro. MIP-1 beta was immobilized by binding to proteoglycan: a conjugate of heparin with bovine serum albumin and cellular proteoglycan CD44 were both effective. We propose that MIP-1 beta and other cytokines with glycosaminoglycan-binding sites will bind to and be presented by endothelial proteoglycans to trigger adhesion selectively not only of lymphocyte subsets, but also of other cell types.

Cell Adhesion↗
PubMed1993

Decrease in operative risk of reoperative valve surgery.

We analyzed the risk of valve re-replacement in 640 patients reoperated on between 1980 and 1992. This represented 17% of total valve operations (640/3,764) during that period. A univariate and logistic multivariate analysis was carried out for four sequential periods for the 640 re-replacement patients to determine if changing methods of perfusion and myocardial protection affected recent results. There were 323 female and 317 male patients with a mean age of 58 years (range, 17 to 84 years). Ninety-seven (15%) had coronary artery bypass grafting, 135 (21%) were 70 years old or older, 377 (59%) were in New York Heart Association functional class III or less, and 263 (41%) were in functional class IV. The aortic valve was re-replaced in 245, the mitral valve in 289, and both aortic and mitral synchronously in 106. Four periods were analyzed: 1980 through 1982, 1983 through 1985, 1986 through 1988, and 1989 through 1992. The overall operative mortality was 65 of 640 patients (10%), falling from 12/73 (16%) in 1980 through 1982 to 23/268 (8%) in 1989 through 1992 (p = 0.05). Univariate and multivariate logistic analysis documented that New York Heart Association functional class was highly significant for operative mortality; operative mortality was 4% for functional classes I through III, and 19% for functional class IV (p < or = 0.001). The requirement for coronary bypass was of borderline significance (p = 0.05), and year of operation was also significant. Mortality for re-replacement of aortic valve fell from 15% to 10%, double valve from 20% to 9%, and mitral valve from 16% to 6%.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1993

Femoral veno-arterial extracorporeal life support with minimal or no heparin.

Recent technological advances in cardiopulmonary bypass circuits achieving surface bonding with heparin have permitted prolonged extracorporeal life support (ECLS) in experimental studies without the use of systemic anticoagulation. Excessive bleeding and the need for massive transfusions after extended ECLS with systemic heparinization have often led to the development of sepsis and multisystem organ failure. The Carmeda bioactive surface circuit, along with a Bio-Medicus centrifugal pump (Bio-Pump) and the femoral veno-arterial route, were used successfully in 3 patients requiring ECLS between April 1992 and December 1992. In 2 patients the need for ECLS was acute allograft dysfunction after orthotopic cardiac transplantation with no evidence of cellular rejection. Both patients were receiving multiple inotropes and intraaortic balloon counter-pulsation; their condition continued to deteriorate rapidly before the initiation of ECLS. The third patient failed to be weaned from cardiopulmonary bypass after myocardial revascularization for ischemic cardiomyopathy. Time on ECLS ranged from 57 to 128 hours. No systemic anticoagulation was used. One patient received no heparin, and the other 2 patients received intermittent heparin infusion to maintain an average activated clotting time of 195 and 214 seconds. Multisystem organ dysfunction present before initiation of ECLS was rapidly reversed, and all patients were weaned successfully without any immediate major complications. The ability to conduct prolonged ECLS without systemic anticoagulation and without repeat sternotomy opens new avenues for the use of this procedure in profound heart failure.

Blood Coagulation↗
PubMed1993

Proteoglycans on endothelial cells present adhesion-inducing cytokines to leukocytes.

Leukocyte recruitment from the blood circulation into tissue is essential for effective immune responses, and is, consequently, carefully regulated. In this article Yoshiya Tanaka and co-workers describe a model in which proteoglycans on the luminal surface of endothelium capture pro-adhesive cytokines. These cytokines provide the adhesion-inducing signal to particular leukocyte subsets which initiates their transmigration.

Animals↗
PubMed1993

Detection of circulating intercellular adhesion molecule-1 after liver transplantation--evidence of local release within the liver during graft rejection.

The adhesion molecule ICAM-1 mediates leucocyte adhesion to target structures and other immune cells by binding with the leucocyte adhesion receptors LFA-1 and MAC-1. During rejection of human liver transplants there is increased expression of ICAM-1 on target structures such as bile ducts and venous endothelium and also on lymphocytes infiltrating the graft. Recent reports suggest that a soluble, functionally active form of ICAM-1 designated circulating ICAM-1 (cICAM-1) is released by activated lymphocytes and might be an important mechanism for modulating lymphocyte adhesion and the inflammatory process. We detected cICAM-1 in bile and serum after liver transplantation using an enzyme-linked immunosorbent assay. Serum cICAM-1 was elevated early in the course of acute rejection and appeared at the same time as the soluble interleukin-2 receptor, a marker of lymphocyte activation. Serum levels, however, were not specific for rejection since they were also elevated in infective complications. In contradistinction, biliary levels of cICAM-1 were only elevated in rejection and appeared to be due to local release/secretion within the liver. These data demonstrate that cICAM-1 is released within the liver during graft rejection, probably from activated lymphocytes, and support previous studies that suggested that factors in bile reflect immunological activity within the liver graft more closely than serum factors.

Bile↗
PubMed1993

Experimental graft arteriosclerosis. II. Immunocytochemical analysis of lesion development.

The development of progressive graft arteriosclerosis causes the majority of late deaths occurring in cardiac transplant recipients. The pathogenesis of this process remains unclear. In order to characterize the cellular composition of lesions progressively, we employed a model of graft arteriosclerosis in the rat involving untreated heterotopic cardiac allografts transplanted across minor histocompatibility barriers. Immunocytochemical studies were performed on arterial lesions in allografts removed at 15, 45, 75, and 120 days posttransplantation, using monoclonal antibodies specific for smooth muscle cells (HHF35, CGA7), monocytes/macrophages (ED1), T cells (W313), and endothelial cells (anti-vWf). We found areas of coronary intimal thickening demonstrated marked cellular heterogeneity. The earliest lesions involved the adherence of monocytes and T cells to the coronary endothelial surface. At later time points, we noted marked subendothelial accumulations of macrophages and occasional T cells in areas of intimal thickening. In contrast, smooth muscle cells were the major cell type identified in intimal lesions in 120-day-old allografts. Intimal macrophages are frequently seen in spontaneous human arteriosclerotic lesions; our findings suggest that macrophages, perhaps interacting with T cells, play an important role in the pathogenesis of graft arteriosclerosis.

Animals↗
PubMed1993

Chronic rejection in experimental cardiac transplantation: studies in the Lewis-F344 model.

Despite recognition of chronic vascular injection by numerous investigators since the beginning of experimental and solid organ transplantation, the pathogenesis of graft arteriosclerosis remains poorly understood. We have defined a reproducible model of this disease by transplanting heterotopic cardiac grafts across minor histocompatibility barriers using inbred strains of rat. We found that long-term surviving Lewis grafts in untreated F344 recipients are subjected to a chronic rejection process which results in the development of diffuse graft arteriosclerotic lesions, indistinguishable in appearance from those seen in human cardiac grafts. Immunohistochemical studies confirm that end-stage lesions are similar in composition to human lesions, made up predominantly of vascular smooth muscle cells with occasional monocytes and T cells. Analysis of serial rejecting allografts demonstrates that a distinct inflammatory stage precedes smooth muscle cell accumulation in areas of intimal thickening, suggesting that mononuclear cells play a role in the developing lesion. Endothelial expression of class II and ICAM-1 appears to lead to early mononuclear cell adherence to the endothelium. Analysis using quantitative RT-PCR confirms that MCP-1 is expressed by ED1-positive monocyte/macrophages in rejecting cardiac grafts, suggesting that this chemoattractant may help drive mononuclear cell accumulation in the expanding intima. Immunohistochemical labelling of PDGF, TNF, and IL-1 in vascular lesions suggests that these growth factors may trigger intimal vascular smooth muscle cell proliferation in chronically rejecting allografts. Hypercholesterolemia did not enhance the severity of lesion development in long-term surviving allografts, suggesting that lipid levels are not a major etiologic factor in graft arteriosclerotic lesion formation in the Lewis-F344 model. Finally, the dietary manipulation of EFAD reduced graft infiltration by mononuclear cells and markedly diminished arterial lesion development in chronically rejecting grafts. Heparin anologues have previously been shown to inhibit proliferative vascular smooth muscle cell lesions in rats following endothelial injury (Clowes & Karnovsky 1977), and we are currently assessing the role of heparin in the therapy of graft arteriosclerosis in the Lewis-F344 model. We are also investigating the role of CD4-positive mononuclear cells in the pathogenesis of lesion development, using the anti-CD4 monoclonal antibody BWH-4 to deplete recipients of CD4-positive cells (Sayegh et al. 1991). In summary, our studies in the Lewis-F344 model suggest that monocyte/macrophages play an important role in the pathogenesis of cardiac graft arteriosclerosis. Future studies utilizing this model should help further elucidate the mechanisms resulting in--and help define potential therapies for--chronic rejection in cardiac transplantation.

Animals↗