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Biomedical subjects

C M Ballantyne

Publications and source records attributed to C M Ballantyne.

At least 91 records · Page 5Linked to original sources
PubMed1996

Increased expression of ICAM-1 in a case of accelerated coronary artery disease after heart transplantation.

The development of accelerated coronary artery disease after heart transplantation remains the limiting factor for long-term survival. The most widely accepted hypothesis to explain the development of this vascular lesion is chronic immunologic injury to the vessel wall, which leads to recruitment of monocytes and lymphocytes into the intima and to subsequent neointimal proliferation. In this report, we describe a case of accelerated coronary artery disease that led to allograft failure and repeat heart transplantation 3 years after the initial procedure. Pathologic examination showed striking intimal proliferation with abundant expression of intercellular adhesion molecule-1 in both endothelial cells and cells deep within the intima. Cardiac myocytes also stained for intercellular adhesion molecule-1, with the most intense staining noted in intercalated disks, whereas staining for E-selectin was restricted to endothelial cells. These findings are similar to those we observed in a canine model of transplant arteriopathy and highlight the need for further studies to examine whether inhibitors of endothelial cell adhesion molecules or their leukocyte ligands can successfully ameliorate transplant vasculopathy.

Coronary Disease↗
PubMed1995

Cardiac allograft survival in mice deficient in intercellular adhesion molecule-1.

BACKGROUND: Intercellular adhesion molecule-1 (ICAM-1, CD54) is a cell adhesion molecule that interacts with the leukocyte beta 2 integrins, lymphocyte function-associated antigen-1, and macrophage antigen-1. ICAM-1 is postulated to play a key role in several cell-cell interactions that are important in allograft rejection, including antigen presentation, transendothelial migration of leukocytes, and leukocyte-medicated myocyte injury. METHODS AND RESULTS: Mice homozygous for a gene-targeted mutation of ICAM-1 were used in two different cardiac transplant models to further define the role of ICAM-1 in the process of allograft rejection. In the first model, hearts from newborn mice were implanted in the ear pinnae of H-2-incompatible recipients. In the second model, intra-abdominal transplantation by direct vascular anastomosis was performed. Time to rejection was defined by the loss of pulsatile activity assessed by visual inspection in the ear model or by cessation of palpable cardiac impulse in the abdominal model. Allograft survival did not differ significantly between control groups that express normal levels of ICAM-1 and those groups using ICAM-1-deficient mutants as either donors or recipients. Histological examination of rejection of both normal and mutant (ICAM-1-deficient) cardiac allografts revealed similar patterns of infiltration of mononuclear and granulocytic leukocytes and myocyte necrosis. Immunostaining with anti-ICAM-1 antibodies showed ICAM-1-positive infiltrating cells in both mutant (ICAM-1-deficient) and normal allografts, with the graft endothelium negative for ICAM-1 staining in the mutant allografts. CONCLUSIONS: The absence of surface expression of ICAM-1 in the donor allograft or recipient is insufficient to produce a significant impact on cardiac allograft survival. This study highlights the need to understand more precisely the mechanism of action whereby monoclonal antibodies to ICAM-1 prolong cardiac allograft survival before new therapeutic strategies based on gene transfer technology or small molecule inhibitors are developed. Mutant mice with targeted mutations in cell adhesion molecules provide powerful tools to study the complex role that cell adhesion molecules play in the cellular interactions between donor graft tissue and the recipient that culminate in graft rejection.

Animals↗
PubMed1995

Cloning and comparative sequence analysis of the gene encoding canine intercellular adhesion molecule-1 (ICAM-1).

Canine intercellular adhesion molecule-1 (ICAM-1) plays a primary role in the adherence of canine neutrophils to endothelial cells and in the cytotoxicity of canine neutrophils for adult cardiac myocytes. We have cloned the canine ICAM-1 gene and have analyzed the conservation of ICAM-1 amino acid (aa) sequences in man, chimpanzee, mouse, rat and dog. Canine ICAM-1 displays 61% identity with human ICAM-1. Cys residues critical to the immunoglobulin (Ig) fold structure and four sites of N-linked glycosylation are absolutely conserved in ICAM-1 from all species. Residues in the cytoplasmic tail associated with cytoskeletal alpha-actinin binding are highly conserved, supporting the hypothesis that intracellular attachment is indeed important for ICAM-1 function. Residues critical for human ICAM-1 binding to the beta 2-integrin leukocyte-function-associated antigen 1 (LFA-1) are highly conserved between all species, whereas those residues demonstrated to play an important role in interaction of human ICAM-1 with macrophage activation complex 1 (Mac-1) are not highly conserved. Residues critical for ICAM-1 binding to rhinovirus and malaria-infected red blood cells (IRBC) are not highly conserved.

Amino Acid Sequence↗
PubMed1995

Myocardial ischemia and reperfusion: a murine model.

Myocardial ischemia followed by reperfusion promotes a complex series of inflammatory reactions as noted in a variety of large animal studies. With development of genetically altered mice, there is intense interest in developing murine models to study mechanisms operative in cardiovascular disease. We developed a mouse model to study coronary artery occlusion and reperfusion effects and the method required to perform these studies both acutely and chronically. In mice, we applied a left anterior descending coronary artery occlusion either permanently or for 30 or 60 min followed by reperfusion allowing flow through the previously occluded coronary artery bed. Reperfusion was documented visually as well as by using Doppler ultrasound and histopathological techniques. The area at risk (AAR) and infarct size (IS) were assessed by EVans blue dye and triphenyltetrazolium chloride staining with computerized planimetry using an image analysis software program. The infarct as percentage of AAR and IS as percentage of the left ventricle in 13 mice with permanent occlusion was 68.6 +/- 4.4 and 28.0 +/- 2.8%, respectively. Reperfusion after occlusions of 60 and 30 min resulted in a significant decrease in IS as a percentage of the AAR compared with permanent occlusion. Histological examination of the ischemic and reperfused myocardium shows infiltration of leukocytes into the ischemic region as well as contraction bands classically associated with reperfusion. This new model allows assessment of AAR, IS, cardiac function, and pathophysiology in the mouse. With the current technology to develop genetically altered mice for overexpression or targeted mutations of various genes, this model is used to understand the complex pathophysiology of ischemia and reperfusion injury.

Animals↗
PubMed1994

Murine VCAM-1. Molecular cloning, mapping, and analysis of a truncated form.

Vascular cell adhesion molecule-1 (VCAM-1) is a member of the Ig superfamily that shows increased expression in a number of pathologic conditions. The role of VCAM-1 in human disease remains undefined and murine models are being extensively studied to help define the importance of VCAM-1 in inflammatory disorders. We have cloned and characterized the murine Vcam1 gene including 3 kb of 5'-flanking sequences and mapped the gene to chromosome 3 near Amy1. cDNA clones isolated from a stimulated hepatic library were found to encode a truncated form of VCAM-1 (T-VCAM-1) which contains Ig domains 1 through 3 and has a unique alternative carboxyl terminus. This form arises by alternative splicing. High level expression of T-VCAM-1 in transfected L cells was sufficient to support adhesion of lymphocytes, and this adhesion was blocked by Abs to VCAM-1. Treatment of transfected COS cells with phospholipase C led to reduced levels of T-VCAM-1 on the cell surface consistent with glycosylphosphatidylinositol linkage. Northern blot analysis showed that mRNA for T-VCAM-1 is inducible in multiple tissues after stimulation with endotoxin. Both forms of VCAM-1 were expressed in cultured endothelial, fibroblast, and aortic smooth muscle cells, whereas neither form was observed in monocyte- and lymphocyte-derived lines. Differential regulation of both forms of VCAM-1 was observed in the three different cell types that are present in the vessel wall. Thus, expression of VCAM-1 is restricted and controlled at the level of transcription and by alternative splicing.

3T3 Cells↗
PubMed1994

Molecular evidence for induction of intracellular adhesion molecule-1 in the viable border zone associated with ischemia-reperfusion injury of the dog heart.

BACKGROUND: Acute inflammation may play a role in injury during reperfusion following myocardial ischemia. Studies in vitro suggest that intracellular adhesion molecule-1 (ICAM-1) mediates neutrophil adherence to cardiac myocytes and neutrophil-mediated injury. We have shown cytokine activity in postischemic cardiac lymph sufficient to maximally express ICAM-1 on myocytes and that ICAM-1 mRNA is found in the previously ischemic myocardium early in reperfusion. METHODS AND RESULTS: In the present study, we used in situ hybridization techniques to detect ICAM-1 mRNA and examine the cells of origin, relation to cell injury, and relation to inflammatory infiltration after 1 hour of ischemia and varying times of reperfusion. By 1 hour of reperfusion, ICAM-1 mRNA was detected in much of the ischemic myocardium, except in areas of contraction band necrosis. At 2 and 3 hours, a clear demarcation of necrotic areas surrounding ischemic areas of viable myocardium with ICAM-1 mRNA staining was present, and ICAM-1 mRNA staining increased with time. Nonischemic areas had no visible ICAM-1 mRNA staining in the first 3 hours. By 24 hours of reperfusion, ICAM-1 mRNA was present in both control and ischemic segments (excluding the necrotic areas) compatible with a generalized circulation of cytokines persistent at 24 hours. In the absence of reperfusion, ICAM-1 mRNA staining was not seen in the first 3 hours and was markedly reduced at 24 hours. The interface of viable and necrotic cells also contained the most extensive inflammatory infiltration. CONCLUSIONS: Evidence is presented that induction of ICAM-1 mRNA has highly specific localization to ischemic but viable myocardium. Induction of ICAM-1 mRNA transcription in early reperfusion may render the viable "border zone" susceptible to neutrophil-induced injury.

Animals↗
PubMed1994

Recent advances in lipoprotein and atherosclerosis research at Baylor College of Medicine. Apolipoprotein B, lipoprotein[a], and transplantation arteriopathy.

A multidisciplinary team approach with focused objectives characterizes research at Baylor College of Medicine into the causes, prevention, and treatment of atherosclerotic disease. Current clinical activities range from programs to modify lifestyle for the primary prevention of coronary artery disease to a large, angiographically monitored lipid-lowering trial. In basic research, much attention has been focused on the plasma lipoproteins and their roles in atherogenesis. The current review highlights recent advances in ongoing basic research involving 1) apolipoprotein (apo) B, whose form apo B-100 serves as a ligand for the low-density lipoprotein receptor; 2) lipoprotein[a], elevated plasma levels of which are predictive of atherosclerotic disease; and 3) transplantation arteriopathy, which impedes long-term survival of cardiac transplant recipients.

Amino Acid Sequence↗
PubMed1993

Inflammatory and immune responses are impaired in mice deficient in intercellular adhesion molecule 1.

Gene targeting was used to produce mice deficient in intercellular adhesion molecule 1 (ICAM-1) or CD54, an immunoglobulin-like cell adhesion molecule that binds beta 2 integrins. Homozygous deficient animals develop normally, are fertile, and have a moderate granulocytosis. The nature of the mutation, RNA analysis, and immunostaining are consistent with complete loss of surface expression of ICAM-1. Deficient mice exhibit prominent abnormalities of inflammatory responses including impaired neutrophil emigration in response to chemical peritonitis and decreased contact hypersensitivity to 2,4-dinitrofluorobenzene. Mutant cells provided negligible stimulation in the mixed lymphocyte reaction, although they proliferated normally as responder cells. These mutant animals will be extremely valuable for examining the role of ICAM-1 and its counterreceptors in inflammatory disease processes and atherosclerosis.

Animals↗
PubMed1993

Gene targeting yields a CD18-mutant mouse for study of inflammation.

CD18 is the common beta subunit for the heterodimeric leukocyte integrins that mediate many inflammatory cell adhesion responses including binding to intercellular adhesion molecules 1 and 2. CD18 deficiency in humans causes a severe granulocyte disorder with susceptibility to bacterial infections and high morbidity and mortality. Gene targeting was used to prepare an insertion mutation in the murine CD18 gene. The insertion mutation resulted in a hypomorphic rather than a null allele due to low expression from a cryptic promoter in the plasmid construct. Homozygous mutant mice are viable and fertile, demonstrate a mild granulocytosis, and have 2 or 16% of normal CD18 expression on granulocytes in the resting or activated state, respectively. Mutant mice show an impaired inflammatory response to a chemical peritonitis and delayed rejection of cardiac transplants. These CD18-mutant mice provide a model of the moderate form of the human disease and should be extremely valuable for in vivo analysis of the role of leukocyte integrin-dependent adhesion in inflammatory disease models.

Animals↗
PubMed1993

Increases in lung tissue expression of intercellular adhesion molecule-1 are associated with hyperoxic lung injury and inflammation in mice.

Lung injury caused by breathing enriched oxygen continues to be a major problem in clinical medicine. Experimentally, hyperoxic lung injury is characterized by pulmonary edema and associated neutrophil accumulation. Although extensively investigated, the mechanisms for neutrophil accumulation and the role of this accumulation in hyperoxic lung injury remain controversial. Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that when increased on endothelium by inflammatory cytokines leads to increased adhesion of neutrophils to the inflamed endothelium and transendothelial migration. The purpose of this study was to examine the role of inflammation in hyperoxia-induced lung injury by investigating ICAM-1 expression in the lungs of mice exposed to > 95% oxygen continuously. Lung tissue from mice exposed to > 95% oxygen was analyzed for ICAM-1 mRNA by slot blot analysis and for ICAM-1 protein expression. We also examined lungs from mice exposed to hyperoxia for up to 96 h by light microscopy to correlate pulmonary inflammation with ICAM-1 expression. We found that mRNA for ICAM-1 increased 56% over baseline after 48 h of exposure to hyperoxia, that ICAM-1 protein increased by more than 5-fold over baseline after 96 h of exposure to hyperoxia, and that lung inflammation and injury were not evident until 96 h of exposure. Our data demonstrate that exposure to hyperoxia causes an increase in ICAM-1 gene transcription and/or mRNA stability in mouse lungs, and that this increase is followed by an increase in ICAM-1 protein.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Molecular evidence for a border zone vulnerable to inflammatory reperfusion injury.

Acute inflammation has been suggested as a potential mechanism for some of the injury associated with reperfusion of the ischemic myocardium. This hypothesis implies that viable myocardial cells adjacent to the lethally injured cells are vulnerable to injury induced by the neutrophil influx observed to attend reperfusion. In our previous work, we demonstrated that the presence of ICAM-1 on the surface of cardiac myocytes is required for neutrophils to directly damage them; blocking monoclonal antibodies to either ICAM-1 on cardiac myocytes or Mac-1 on activated neutrophils completely precluded neutrophil-induced myocyte injury. We also demonstrated that postischemic cardiac lymph (cardiac extracellular fluid) contained leukotactic factors (primarily C5a) and cytokines present in concentrations sufficient to maximally induce Mac-1 on the surface of neutrophils and ICAM-1 on the surface of isolated dog cardiac myocytes. The present study sought to further these observations by examining the site of potential ICAM-1 induction as a function of time of reperfusion, degree of ischemia, and viability of myocardial cells. Our evidence suggests that ICAM-1 mRNA is induced very early after reperfusion only in the previously ischemic myocardium and is not seen in the nonischemic myocardium during the early hours of reperfusion. Moreover, ICAM-1 mRNA induction is seen most intensely in the ischemic area directly bordering the necrotic area (which, after 1-hr reperfusion, does not contain any ICAM-1 mRNA) and immediately abutting the site of maximal influx of neutrophils. Thus, the induction of ICAM-1 and the influx of neutrophils (presumably activated by the chemotactic factors that guided their migration) exists on the border between viable and necrotic cells. This provides the first direct molecular evidence for a jeopardized border zone on the edge of myocardial infarction during reperfusion. As previously demonstrated, this reaction is wholly dependent upon tissue injury of the ischemic myocardium and therefore represents an example of a mechanism of injury extension induced as a reaction to a primary injury. The degree of specificity of this reaction demonstrated by the subendocardial sparing directly adjacent to ischemic cells suggests finely modulated mechanisms by which this process is controlled.

Animals↗
PubMed1992

Molecular cloning and analysis of in vivo expression of murine P-selectin.

P-selectin (CD62) is a rapidly inducible cell surface adhesion molecule that is expressed on platelets and endothelial cells and mediates their interaction with leukocytes. In vitro studies have suggested that this receptor may play an important role in hemostasis and in inflammatory response to tissue injury. We report the molecular cloning and sequencing of murine cDNA for P-selectin. The lectin, epidermal growth factor (EGF)-like, transmembrane, and cytoplasmic domains are highly conserved between mouse and human, with an overall amino acid identity of 79%. To further investigate the biology of this adhesion molecule in vivo, we analyzed mRNA levels for P-selectin in mice after injection with endotoxin. Northern blot data indicate that the cellular response in vivo includes a rapid increase in the level of mRNA, presumably for new synthesis of P-selectin. The increase in mRNA is maximal at 4 hours, and turnover is relatively rapid, with levels of RNA having decreased substantially by 6 hours following stimulation with endotoxin. After administration of endotoxin, the highest levels of mRNA expression were detected in liver, lung, kidney, and heart.

3T3 Cells↗
PubMed1992

Hyperlipidemia after heart transplantation: report of a 6-year experience, with treatment recommendations.

Mean plasma lipid values in 100 patients who survived greater than 3 months after heart transplantation increased significantly at 3 months over pretransplantation values: total cholesterol from 168 +/- 7 to 234 +/- 7 mg/dl, low density lipoprotein (LDL) cholesterol from 111 +/- 6 to 148 +/- 6 mg/dl, high density lipoprotein (HDL) cholesterol from 34 +/- 1 to 47 +/- 1 mg/dl and triglycerides from 107 +/- 6 to 195 +/- 10 mg/dl. There were no significant increases after this time. The LDL cholesterol values reamined greater than or equal to 130 mg/dl in 64% of patients and triglyceride values remained greater than or equal to 200 mg/dl in 41% of patients 6 months after postoperative dietary instructions. Beginning in 1985, select patients whose total cholesterol values remained greater than 300 mg/dl despite 6 months of dietary intervention were treated with lovastatin given alone in a high dose (40 to 80 mg/day) or in combination with another hypolipidemic agent. Four of the five patients so treated developed rhabdomyolysis; two of the four had acute renal failure. Beginning in 1988, a second protocol--lovastatin at 20 mg/day as monotherapy--was used in patients who despite dietary intervention had total cholesterol greater than 240 mg/dl (mean follow-up 13 months). In the 15 patients so treated, mean total cholesterol decreased from 299 +/- 10 mg/dl before treatment with lovastatin to 235 +/- 9 mg/dl during treatment (21% reduction, p less than 0.001) and mean LDL cholesterol was reduced from a baseline value of 190 +/- 10 to 132 +/- 12 mg/dl during treatment (31% reduction, p less than 0.001). In this study, lovastatin at a dose of less than or equal to 20 mg/day as monotherapy was a well tolerated, effective treatment for hyperlipidemia after heart transplantation. It did not result in rhabdomyolysis and required no alteration in immunosuppressive therapy. However, the dose should not exceed 20 mg/day and combination therapy with either gemfibrozil or nicotinic acid should be avoided, even if the target LDL cholesterol value is not reached.

Analysis of Variance↗
PubMed1992

Characterization of the murine Icam-1 gene.

Intercellular adhesion molecule-1 (ICAM-1, CD54) is a cell adhesion molecule that interacts with the leukocyte beta 2 integrins, LFA-1 and Mac-1. Murine inflammatory models are being utilized increasingly to define the role that ICAM-1 induction plays in the initiation of inflammation. We have isolated murine genomic clones that contain the Icam-1 gene including over 2 kb of 5' flanking sequence. The gene for murine Icam-1 spans over 13 kb and is composed of seven exons and six introns. Each of the extracellular immunoglobulin-like domains of ICAM-1 is encoded by a single exon that ends with the first base of the next codon. Examination of ICAM-1 expression in vivo shows that mRNA levels of ICAM-1 are low in all organs except for the lung but increase markedly in multiple organs at 3 h after administration of endotoxin. The 5' flanking region of the murine gene contains a putative TATA box and potential SP-1, AP-1, and AP-3 sites in positions nearly identical to those in the human gene.

Animals↗