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Biomedical subjects

K Lemström

Publications and source records attributed to K Lemström.

At least 19 recordsLinked to original sources
PubMed1999

Prevention of cardiac allograft arteriosclerosis by protein tyrosine kinase inhibitor selective for platelet-derived growth factor receptor.

BACKGROUND: Increased immunoreactivity of platelet-derived growth factor (PDGF)-AA, -Ralpha, and -Rbeta in intimal cells correlates with the development of cardiac allograft arteriosclerosis, a condition for which there is little or no current therapy. Therefore, we hypothesized that PDGF may have a rate-limiting role in the development of this disease. METHODS AND RESULTS: The hypothesis was tested in a rat model of heterotopic cardiac and aortic allografts using dark agouti (AG-B4, RT1(a)) donors and Wistar-Furth (AG-B2, RT1(u)) recipients. The recipients received CGP 53716, a selective PDGF-R protein tyrosine kinase inhibitor, 50 mg. kg-1. d-1, or vehicle for 60 days. Cardiac allograft recipients also received background cyclosporin A immunosuppression. Our results demonstrate that CGP 53716 significantly reduced the incidence and intensity of arteriosclerotic lesions in rat cardiac and aortic allograft recipients. When rat coronary smooth muscle cells were stimulated in vitro with PDGF-AA or -BB in the presence of interleukin-1beta or tumor necrosis factor-alpha, CGP 53716 significantly inhibited only AA-ligand-induced but not BB-ligand-induced replication. Concomitantly, in quantitative reverse transcriptase-polymerase chain reaction, interleukin-1beta or tumor necrosis factor-alpha stimulation specifically upregulated the expression of PDGF-Ralpha mRNA but not of other ligand or receptor genes in cultured smooth muscle cells. CONCLUSIONS: We conclude that a PDGF-AA/Ralpha-dependent cycle is induced in the generation of allograft arteriosclerosis that may be inhibited by blocking of signaling downstream of PDGF-R.

Animals↗
PubMed1999

Selective tyrosine kinase inhibitor for the platelet-derived growth factor receptor in vitro inhibits smooth muscle cell proliferation after reinjury of arterial intima in vivo.

The long-term success of coronary angioplasty is limited by restonosis. This study was undertaken to investigate whether and to what extent the enhanced proliferative response observed in a balloon reinjury model of rat aorta is regulated by the PDGF receptor (PDGF-R). Balloon injury was performed to 14-day-old pre-existing neointimal lesion in rat aorta. PDGF receptor and ligand immunoreactivity were measured at several time points after the first and second injury, and PDGF-R signaling was blocked with a selective inhibitor of PDGF-R tyrosine kinase. In the neointima, after repeated injury, upregulation of PDGF-AA was seen to coincide with a prompt proliferative response of smooth muscle cells (SMC). Administration of the PDGF-R tyrosine kinase inhibitor in vivo, tested and found to inhibit the proliferation of SMC induced by PDGF-AA and PDGF-BB, but not by IGF-1, EGF, or bFGF, resulted in a 60% reduction in the absolute number and percentage of BrdU + cells after the second balloon injury to pre-existing neointima, but had no significant effect on proliferation after the first injury. Endpoint lesion area was reduced by 50% in the treated group at 14 days after the second injury. The results suggest that systemic administration of a tyrosine kinase inhibitor specific for the PDGF-R can be useful in the prevention of restenosis.

Angioplasty, Balloon, Coronary↗
PubMed1997

Cytomegalovirus infection-enhanced cardiac allograft vasculopathy is abolished by DHPG prophylaxis in the rat.

BACKGROUND: A wealth of clinical and experimental evidence exists for cytomegalovirus (CMV) infection as an accelerating factor in the development of cardiac allograft vasculopathy. In this study, the impact of 9-(1,3-dihydroxy-2-propoxymethyl) guanine (DHPG) on rat CMV infection-enhanced cardiac allograft vasculopathy is investigated. METHODS AND RESULTS: Heterotopic rat cardiac allografts were performed from the DA to the WF rat strain, and the recipients were immunosuppressed with cyclosporine A 2 mg.kg-1.d-1 s.c. for a period of 90 days until the end of experiment. Two groups of recipients were infected intraperitoneally with 10(5) plaque-forming units of rat CMV, whereas one group was left noninfected and used as controls. One group of rat CMV-infected rats was treated with DHPG with an initial dose of 20 mg/kg i.p. and a maintenance dose of 10 mg/kg i.p. twice a day from 1 day before transplantation to 30 days after transplantation. Compared with noninfected rats, rat CMV infection was associated with a significant increase in intimal thickening, from 0.68 +/- 0.10 to 1.30 +/- 0.12 score units (P < .01), and double the number of vessels affected (P < .01). DHPG treatment significantly reduced intimal thickening in rat CMV-infected rats, from 1.30 +/- 0.12 to 0.68 +/- 0.13 score units (P < .01), and halved the number of vessels affected (P < .01). CONCLUSIONS: The present results demonstrate that DHPG prophylaxis entirely abolishes the accelerating effect of rat CMV infection on cardiac allograft vasculopathy in immunosuppressed rat recipients, which is consistent with our earlier findings demonstrating a similar effect in nonimmunosuppressed rat aortic allografts. Taken together, these results suggest that DHPG might be useful in the prevention of CMV-accelerated cardiac allograft vasculopathy among heart transplant recipients.

Animals↗
PubMed1997

Inhibition of platelet-derived growth factor receptor tyrosine kinase inhibits vascular smooth muscle cell migration and proliferation.

Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) have been linked to vascular smooth muscle cell (SMC) migration and proliferation leading to atherosclerosis, restenosis, and chronic allograft rejection. This study describes the effect of CGP 53716, a specific PDGFR tyrosine kinase inhibitor on SMC proliferation and migration in vitro and in neointimal formation in vivo. CGP 53716 inhibited dose dependently tyrosine phosphorylation of both the known PDGFRs: the PDGFR-alpha and PDGFR-beta. In primary rat SMC cultures, a dose-dependent inhibition of PDGF-AA and PDGF-BB induced migration, and tritiated thymidine incorporation of SMC was seen at nontoxic concentrations. After rat carotid artery ballooning injury in vivo, the migration of alpha-actin-positive cells on the luminal side of internal elastic lamina was decreased with 50 mg x kg(-1) x day(-1) of CGP 53716 from 38 +/- 10 (control group) to 4 +/- 2 (P<0.0001, Mann-Whitney U test, N=18). CGP 53716 did not inhibit the number of replicating bromodeoxyuridine (BrdU)-incorporating cells in the intima, media, or adventitia during BrdU labeling at 0-96 postoperative h, though it inhibited significantly (P<0.01) the replication of medial and intimal cells from 93 h onward. Intima/media ratio was inhibited by 40% after 14 days in the CGP 53716-treated group (P=0.028) after rat aortic denudation. The results indicate that inhibition of the PDGFR tyrosine kinase inhibits SMC migration and proliferation in vitro, SMC migration, and, to a lesser extent, proliferation after ballooning injury in vivo, confirming a causal role for activation of the PDGFR and the formation of neointimal lesions.

3T3 Cells↗
PubMed1996

Rat cytomegalovirus infection and chronic kidney allograft rejection.

To investigate the effect of cytomegalovirus (CMV) infection on the development of experimental chronic kidney allograft rejection, orthotopic kidney allografts from DA donors (Ag-B4, RT1a1) to WF (Ag-B2, RT1u) recipients were used. The rats received cyclosporine A (CsA) for 12 weeks. A group of recipients was infected with 10(5) plaque-forming units of rat CMV (RCMV), and another group was left non-infected and used as controls. The grafts were removed 12 weeks after transplantation. RCMV infection significantly enhanced the development of chronic kidney allograft rejection as follows: the intensity of interstitial inflammation (P < 0.025), particularly the degree of pyroninophilic cells in the inflammatory infiltrate (P < 0.025); the glomeruli mesangial matrix increase (P < 0.05) and capillary basement membrane thickening (P < 0.01); the extent of endothelial cell swelling (P < 0.025) and intimal proliferation (P < 0.025) in the graft vasculature; and the extent of tubular epithelial atrophy (P < 0.025). The chronic allograft damage index (CADI) was significantly increased to 4.2 +/- 0.9 in RCMV-infected allografts, compared with 0.8 +/- 0.4 in non-infected (P < 0.02). At the molecular level, RCMV infection significantly increased vascular endothelial (P < 0.05) and tubular epithelial (P < 0.01) ICAM-1 expression. Viral antigens were detected in tubular epithelial cells and in some inflammatory cells.

Animals↗
PubMed1996

Cytomegalovirus infection accelerates obliterative bronchiolitis of rat tracheal allografts.

A cascade of inflammation and injury of the airway wall followed by a fibroproliferative process that results in airway obstruction has been suggested as the explanation of the process of obliterative bronchiolitis (OB) in lung allograft recipients. To determine the impact of rat cytomegalovirus (RCMV) infection on the development of OB, heterotopic rat tracheal allografts were transplanted from DA donors to WF recipients immunosuppressed with 2 mg/kg per day cyclosporine A. Chronic RCMV infection was similarly established 8 weeks before transplantation in donors alone (D+/R-), recipients alone (D-/R+), and both donors and recipients (D+/R+). The control rats were left non-infected, but were similarly immunosuppressed. The results of this study demonstrate that both acute and chronic recipient RCMV infection, but not donor infection, amplify the development of experimental OB in the rat and suggest that RCMV infection-associated immune response, rather than the viral load in the graft, is essential for the development of the accelerated form of OB.

Animals↗
PubMed1996

Chronic rejection.

The pathogenesis of chronic rejection is a complex network of immunological, metabolic and haemodynamic events leading to a cascade of cellular and molecular events with a subsequent remodelling of the graft. Evidence suggests that the frequency and intensity of acute rejection episodes strongly correlate with graft loss as a result of chronic rejection. The most characteristic feature of chronic rejection, shared by all organs, is concentric generalized arteriosclerosis with low-grade perivasculitis affecting all intragraft arteries of the transplant. In-vitro studies have demonstrated that a variety of cells and molecules may regulate smooth muscle cell replication in the vascular wall, the migration of smooth muscle cells from the media into the intima, and the development of arteriosclerotic lesions throughout the entire length of the vessel wall. These molecules include peptide growth factors, cytokines, vasoactive hormones, and lipid mediators of inflammation (eicosanoids), and they are secreted in situ by inflammatory, endothelial and smooth muscle cells in the vascular wall. In order to prevent chronic rejection it is necessary to optimize immunosuppression, possibly by the use of new immunosuppressive drugs that also seem to have direct inhibitory effect on smooth muscle cells and on transplant arteriosclerosis. The scope of this review is to highlight our current understanding of the risk factors, pathogenesis and prevention of chronic renal allograft rejection. This review will also briefly discuss present animal models used to investigate chronic rejection at the cellular and molecular level.

Animals↗
PubMed1995

Cytomegalovirus antigen expression, endothelial cell proliferation, and intimal thickening in rat cardiac allografts after cytomegalovirus infection.

BACKGROUND: Cardiac allograft arteriosclerosis is the primary cause of late death in heart transplant recipients. Clinical studies have suggested that humoral and cellular immune response, hyperlipidemia, and cytomegalovirus (CMV) infection may amplify the disease. In this study, the role of CMV infection in the development of rat cardiac allograft arteriosclerosis is investigated. METHODS AND RESULTS: Heterotopic rat cardiac allografts were performed from the DA to the WF rat strains. To prevent rejection, the recipients received triple-drug (cyclosporine A 20 mg.kg-1.d-1, azathioprine 2 mg.kg-1.d-1, and methylprednisolone 0.5 mg.kg-1.d-1) immunosuppression postoperatively. Recipient rats were infected intraperitoneally (n = 21) with 10(5) plaque-forming units of rat CMV (RCMV) 1 day after transplantation or were left uninfected and used as controls (n = 18). The grafts were removed 7 and 14 days and 1 and 3 months after transplantation. In 42% (9 of 21) of cardiac allografts in RCMV-infected rats, an intramural, mononuclear cell inflammation of small intramyocardial arterioles was observed compared with none in uninfected rats (P = .005). Acute RCMV infection was associated with an early perivascular inflammatory cell response of helper T (W3/25), cytotoxic T (OX8), and NK (3.2.3) cells, macrophages (OX42), and major histocompatibility complex class II expression around small intramyocardial arterioles and capillaries. No upregulation of interleukin-2 receptor expression was seen. In arteries and small intramyocardial arterioles, RCMV infection was associated with a significant endothelial cell proliferation and a clear increase in intimal thickening. Significant endothelial cell proliferation was also observed in the capillaries after RCMV infection. Immunohistochemistry revealed specific focal RCMV early and late antigen expression in epicardial and interstitial ED1-immunoreactive mononuclear cell infiltrates and around small arterioles of RCMV-infected cardiac allografts. Occasionally, media cells of stenosed small intramyocardial arterioles also showed strong focal RCMV antigen expression. In addition, infectious RCMV could be recovered by plaque assay in cardiac allografts expressing RCMV antigens. CONCLUSIONS: These results demonstrate a productive RCMV infection in cardiac allograft structures and suggest that RCMV infection accelerates cardiac allograft arteriosclerosis, particularly in small intramyocardial arterioles mediated by inflammatory responses in the vascular wall and perivascular space.

Animals↗
PubMed1995

De novo expression of endothelial sialyl Lewis(a) and sialyl Lewis(x) during cardiac transplant rejection: superior capacity of a tetravalent sialyl Lewis(x) oligosaccharide in inhibiting L-selectin-dependent lymphocyte adhesion.

Acute organ transplant rejection is characterized by a heavy lymphocyte infiltration. We have previously shown that alterations in the graft endothelium lead to increased lymphocyte traffic into the graft. Here, we demonstrate that lymphocytes adhere to the endothelium of rejecting cardiac transplants, but not to the endothelium of syngeneic grafts or normal hearts analyzed with the in vitro Stamper-Woodruff binding assay. Concomitant with the enhanced lymphocyte adhesion, the cardiac endothelium begins to de novo express sialyl Lewis(a) and sialyl Lewis(x) (sLea and sLex) epitopes, which have been shown to be sequences of L-selectin counterreceptors. The endothelium of allografts, but not that of syngeneic grafts or normal controls, also reacted with the L-selectin-immunoglobulin G fusion protein, giving further proof of inducible L-selectin counterreceptors. The lymphocyte adhesion to endothelium could be significantly decreased either by treating the lymphocytes with anti-L-selectin antibody HRL-1, or by treating the tissue sections with sialidase or anti-sLea or anti-sLex monoclonal antibodies. Finally, we synthetized enzymatically several members of the sLex family oligosaccharides and analyzed their ability to block lymphocyte adhesion to cardiac endothelium. The monovalent sLex (a tetramer), divalent sLex (a decamer), and tetravalent sLex (a 22-mer) could all significantly reduce lymphocyte binding, but the inhibition by the tetravalent sLex-construct was clearly superior to other members of the sLex family. The crucial control oligosaccharides, sialyl lactosamines lacking fucose but being otherwise similar to the members of sLex family, had no effect on lymphocyte binding.

Animals↗
PubMed1995

Molecular mechanisms of chronic renal allograft rejection.

The etiology of chronic rejection is most likely multifactorial. Taking into account the two major histological manifestations of chronic rejection--inflammation and arteriosclerosis--we have formulated the following working hypothesis: the immune response characterized by the perivascular inflammation induces a persistent low-grade damage to vascular endothelium, which in turn begins to secrete growth factors to repair the damage. This results in smooth muscle cell replication in the vascular wall and the influx of myocytes from the media into the intima and generation of an arteriosclerotic lesion, and in glomeruli mesangial cell proliferation and glomerular sclerosis. Both nonimmunological and immunological factors contribute to the development of chronic rejection. It seems that acute inflammation (acute rejection) is on most occasions a prerequisite for chronic changes. In addition, increased glomerular capillary pressure may have an additional role in chronic rejection of kidney transplants. Several different molecular cascades seem to participate in the generation of allograft arteriosclerosis. Most likely the final effector molecules may be growth factors that are synthesized, in response to injury, by the parenchymal and endothelial cells of the transplant. If this hypothetical sequence of events is true, there will be no single therapy or treatment of this disorder. Thus, prophylaxis may be more applicable than therapy to a pre-existing lesion. Most likely several different parameters have to be encountered simultaneously in order to counteract these alterations. However, if the current half-life of the renal transplants, seven to eight years, could be doubled, chronic rejection would be overcome.

Animals↗
PubMed1994

Frequency of infections and their relation to episodes of acute rejection among heart allograft recipients.

OBJECTIVES: Infections and episodes of acute rejections are major factors affecting allograft survival during the first year after transplantation. The frequency of infections, and the relation of injections to rejection episodes were studied among heart allograft recipients with the follow-up time one year. METHODS: The study population consisted of 58 patients receiving a heart allograft through 1985 to 1990. Low-dose triple-drug therapy was used for immunosuppression, and rejections were treated either with methylprednisolone, antithymocyte globulin, or the combination of methylprednisolone and antithymocyte globulin. The patients received 2 g of vancomycin i.v. 2 days postoperatively, and no further antibacterial prophylaxis was used. The diagnosis of infection was based on clinical symptoms and on microbiological or serological demonstration of an infection. When the correlations between severe infections and rejections were examined, only infections occurring within 1 month from the onset of the rejection were included. Chi-square test was used for statistical analysis. RESULTS: Seventy-nine infections were registered (1.6 +/- 1.4 episodes/patients); 74% of the patients underwent at least one infection episode. Most infections, 61% (49), occurred during the first three posttransplant months, cytomegalovirus and bacterial agents accounting for the most important aetiology. No difference in the overall infection frequency existed between the patients with or without rejections. Twenty seven infection episodes were recorded in 18/50 patients with rejections (p = NS), 11 of them in relation to rejection in 5/18 patients. The frequency of infections after antirejection therapy either with antithymocyte globulin or the combination of methylprednisolone and antithymocyte globulin (7/11) was higher than with methylprednisolone alone (4/20) (p < 0.05). Infections were the primary cause of death in 50%. The rest of deaths were caused by acute rejections. CONCLUSION: There was a typical pattern of infections occurring mainly during the first three months after transplantation, and a significant tendency towards severe infections after intense antirejection therapy with antithymocyte globulin.

Acute Disease↗