Lesions of atherosclerosis occur in the innermost layer of the artery wall and consist primarily of proliferated smooth muscle cells surrounded by large amounts of connective tissue, numerous lipid-laden macrophages, and varying numbers of lymphocytes. Growth-regulatory molecules may be involved in intimal accumulation and proliferation of smooth muscle cells responsible for the occlusive lesions of atherosclerosis. Platelet-derived growth factor (PDGF) B-chain protein was found within macrophages in all stages of lesion development in both human and nonhuman primate atherosclerosis. Thus macrophages may play a critical role in the disease by providing PDGF, a potent chemotactic and growth-stimulatory molecule, to the intimal smooth muscle cells.

Atherosclerosis is primarily a lesion that progresses due to a series of reactions that are induced by repair of injured intima. The intercellular networking that occurs among smooth muscle cells, macrophages, T lymphocytes and endothelial cells leads to a fibroproliferative response, in which the extracellular matrix (ECM) plays an important role. The ECM, composed of a mixture of vastly different macromolecules including collagen, elastin, glycoproteins and proteoglycans, confers tensile strength and viscoelasticity to the arterial wall. Each component of the ECM possesses unique structural properties that determine its own roles during the development of atherosclerotic plaques. Not only does the ECM provide the structural integrity of the plaques, but it also participates in several key events such as cell migration and proliferation, lipoprotein retention and thrombosis. The various matrix metalloproteinases (MMPs), major enzymes in ECM degradation, and their inhibitors (tissue inhibitors of MMPs) are demonstrated in plaque. An excess of MMPs over inhibitors contributes significantly to ECM destruction rendering the plaque more prone to rupture. Accumulating information on the molecular regulation of ECM synthesis and degradation will help investigators attain a more thorough understanding of the mechanisms of plaque formation and plaque instability and rupture.

Background —The precise molecular mechanism of Adriamycin-induced cardiomyopathy (ADR-CM) is still unknown. We address the demonstration of apoptotic myocardial cell death and the apoptosis-inducing molecules in ADR-CM induced in rats. Methods and Results —Until 8 weeks after the first administration of ADR, there was no increase in the number of labeled cells by terminal deoxynucleotidyl transferase assay (TUNEL method). Apoptotic indices increased significantly at weeks 9 and 10 in hearts of the ADR-treated group but not in those of the control group (0.42±0.12% versus 0.10±0.02% and 0.86±0.11% versus 0.09±0.04% at weeks 9 and 10, respectively). DNA ladder formation was also observed in the myocardial tissues during the late stages of the ADR-CM of rats. There was no significant difference in expression of p53 gene between the ADR group and the control group at either the message or the protein level. An overexpression of Fas antigen was shown in myocardial cells of ADR-treated hearts at weeks 9 and 10 by both Western blotting and immunofluorescent staining. Furthermore, we confirmed that neutralization of anti–Fas ligand antibody inhibited ADR-induced apoptosis. Conclusions —Apoptotic cell death was observed in the hearts of ADR-CM rats, and the number of apoptotic myocardial cells increased with the deterioration of morphological findings and cardiac function, indicating that apoptosis may be an important mechanism of loss of myocardial cells and cardiac dysfunction in ADR-CM. Apoptosis in ADR-CM rats is not p53-dependent but rather is executed through a Fas-mediated pathway.

This study represents a systematic analysis of the distribution of collagen types in human atherosclerotic lesions. Formalin-fixed, paraffin-embedded aortic tissues of 40 lesions from 16 different individuals ranging in age from 1 month to 84 years were examined immunohistochemically using antibodies to type I, III, IV, V, and VI collagens. Preembedding immunoelectron microscopy was used to simultaneously localize type V and VI collagens within the lesions. Localization of type HI collagen was very similar to that of type L and type VI collagen appeared together with these two types of collagen in the thickened intlmas of all stages of the lesion. Type V collagen was not detected in either fatty streaks or the mild Intimal thickening of the aortas of children. With advancing age and lesion progression, the immunoreactivity with anti-type V collagen antibody became more intense. Type IV collagen was detected in the basement membrane region of intimal cells. In advanced lesions thick deposits of type IV collagen were found around the elongated smooth muscle cells. Using immunoelectron microscopy, type V collagen was found to be localized to cross-banded collagen fibers, and type VI collagen was found to be localized to beaded filaments present throughout the interstitium of the thickened intima. These findings suggest that collagens preserve the pathophysiological and functional integrity of the vascular wall by providing mechanical support as well as assuring the proper interaction of cells during the formation of atherosclerotic lesions. (Arteriosclerosis and Thrombosis 1992;12:494-502) KEYWORDS • atherosclerosis • collagen • immunohistochemistryA therosclerosis is a disease of large and medium-/ \ sized arteries and is characterized by focal X A . thickening of the inner portion of the artery wall in association with fatty deposits.1 -2 The common underlying events responsible for lesion formation are intimal smooth muscle cell proliferation, formation of new extracellular matrix by these cells, and the possible accumulation of lipid. Collagens are regarded as important in this disease not only because they represent the major extracellular component in the atherosclerotic plaque and thereby contribute to the occlusive nature of the disease but also because they may play an important role in hemostasis and thrombosis through stimulation of blood platelets. 3 In addition, recent studies have indicated that collagens can influence the proliferation and state of differentiation of smooth muscle cells in vitro.4 -6 Thus, it seems likely that collagens could play a vital role in the pathogenesis of this disease.Collagen is now recognized as a family of proteins of at least 13 genetically distinct subtypes, each of which has a unique tissue specificity. -9 Of these 13 collagen types, six (I, III, IV, V, VI, and VIII) are present in blood vessels. 10 All of these collagen types except type VIII collagen are known to be synthesized by smooth From the Department of Pathology, School of Medicine, Kanazawa University, K...

Positron emission tomography (PET) with [18F]2-fluoro-2-deoxy-D-glucose (FDG) may show negative results for bronchioloalveolar lung carcinoma. We investigated the correlation of Glut-1 glucose transporter expression with [18F]FDG uptake in non-small cell lung cancer. Thirty-two patients with 34 non-small cell lung cancers (7 bronchioloalveolar carcinomas, 23 non-bronchioloalveolar adenocarcinomas, 3 squamous cell carcinomas, and 1 adenosquamous cell carcinoma) were studied. Final diagnoses were established by histology (via thoracotomy) in all patients. [18F]FDG PET was performed 40 min after i.v. injection of 185 MBq [18F]FDG. For semi-quantitative analysis of [18F]FDG uptake, standardized uptake values (SUVs) were calculated. Glut-1 expression was studied in terms of the immunohistochemistry of paraffin sections using anti-Glut-1 antibody to determine the intensity (0-3) of Glut-1 immunoreactivity and percentage of the Glut-1-positive area. Of seven bronchioloalveolar carcinomas, six (85.7%) were negative for the expression of Glut-1, while only one (4.3%) of 23 non-bronchioloalveolar adenocarcinomas was negative (P < 0.0001). The percentages of Glut-1-positive area, as well as the SUVs, were significantly lower in bronchioloalveolar carcinomas (n = 7) (2.86% +/- 7.56% and 1.25 +/- 0.75, respectively) than in non-bronchioloalveolar adenocarcinomas (n = 23) (54.83% +/- 25.64%, P < 0.0001, and 3.94 +/- 1.93, P = 0.001, respectively). The degree of cell differentiation correlated with the percentage of Glut-1-positive area and SUVs in adenocarcinoma of the lung. Correlations between SUVs and the intensity of Glut-1 immunoreactivity were also significant (intensities 0 and 1, n = 11, SUV 1.47 +/- 0.63; intensities 2 and 3, n=23, SUV 4.78 +/- 2.13; P < 0.0001). The percentage of Glut-1-positive area correlated significantly with SUVs (n = 34, r = 0.658, P < 0.01). Overexpression of Glut-1 correlated with high [18F]FDG uptake. These findings suggest that Glut-1 expression is related to [18F]FDG uptake in non-small cell lung cancer. Glut-1 expression, as well as [18F]FDG uptake, correlated with the degree of cell differentiation in adenocarcinomas, and both Glut-1 expression and [18F]FDG uptake were significantly lower in bronchioloalveolar carcinomas than in non-bronchioloalveolar carcinomas.

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Oxidative injury was demonstrated soon after the administration of methylprednisolone in a rabbit model prior to the development of osteonecrosis. This finding may suggest new strategies to prevent steroid-induced osteonecrosis, such as the optimally timed (early) administration of antioxidant agents.