Fibrosis is the production of excessive amounts of connective tissue, i.e., scar formation, in the course of reactive and reparative processes. Fibrosis develops as a consequence of various underlying diseases and presents a major diagnostically and therapeutically unsolved problem. In this review, we postulate that fibrosis is always a sequela of inflammatory processes and that the many different causes of fibrosis all channel into the same final stereotypical pathways. During the inflammatory phase, both innate and adaptive immune mechanisms are operative. This concept is exemplified by fibrotic diseases that develop as a consequence of tissue damage, primary inflammatory diseases, fibrotic alterations induced by foreign body implants, "spontaneous" fibrosis, and tumor-associated fibrotic changes.
Background-Work from our laboratory has proven that increased titers of anti-heat shock protein 60 (HSP60) antibodies are associated with atherosclerosis and that HSP60-reactive T-cells are present in atherosclerotic lesions. Recent studies from others demonstrated that HSP60 directly activates endothelial cells and macrophages. Methods and Results-To explore the possibility that HSP60 exists in the circulation, where it could exert its functions, we performed a population-based study with 826 subjects aged 40 to 79 years. The following items were measured in all participants: serum soluble HSP60 (sHSP60); anti-Escherichia coli lipopolysaccharide; anti-HSP65, anti-Chlamydia, and anti-Helicobacter pylori antibodies; and a variety of acute phase reactants (C-reactive protein, ␣ 1 -antitrypsin, and ceruloplasmin) and markers of systemic inflammation. Carotid atherosclerosis was assessed twice (1990 and 1995), and 15 other risk factors were evaluated. Our data show that levels of sHSP60 were significantly elevated in subjects with prevalent/incident carotid atherosclerosis and that these levels were correlated with common carotid artery intima/media thickness. Multiple logistic regression analysis documented these associations as independent of age, sex, and other risk factors. Interestingly, sHSP60 was also correlated with anti-lipopolysaccharide, anti-Chlamydia and anti-HSP60 antibodies, various markers of inflammation, and the presence of chronic infections. The risk of atherosclerosis associated with high sHSP60 levels was amplified when subjects had clinical and/or laboratory evidence of chronic infections. Conclusions-Our data provide the first evidence of a strong correlation between sHSP60 and atherosclerosis, suggesting that sHSP60 may play important roles in activating vascular cells and the immune system during the development of atherosclerosis. (Circulation. 2000;102:14-20.)
The mechanism that may cause degenerative fibrotic skin lesions was studied in situ using skin biopsies from patients with systemic sclerosis (
Stress or heat shock proteins (hsp) are a family of approximately two dozen proteins with a high degree of amino acid sequence homology between different species, ranging from prokaryotes to humans, and are representative of a generalized response to environmental and metabolic stressors. Our previous studies showed increased expression of human hsp6O on endothelial cells of arterial intima with atherosclerotic lesions, and elevated levels of serum antibodies (Ab) against hsp65/60 in subjects with carotid atherosclerosis. To investigate the possible involvement of anti-hsp65/60 Ab in endothelial injury, specific hsp-Ab were isolated from human high titer sera by affinity chromatography and probed on heat-shocked human umbilical vein endothelial cells. Purified human anti-hsp65/60 Ab reacted specifically with mycobacterial hsp65, human hsp60, and a 60-kD protein band of heat-shocked endothelial cells. (5, 6). As a matter of fact, immunization of rabbits with recombinant mycobacterial hsp65 induced the development of atherosclerotic lesions at characteristic predilection sites known to be subject to increased hemodynamic stress, such as the aortic and the branching of large vessels (7). A previous epidemiological study (8) from our laboratory had demonstrated that serum antibodies to mycobacterial hsp65, which is a homologue of human hsp6O, were significantly increased in clinically healthy subjects with sonographically demonstrable carotid atherosclerosis compared to those without lesions. This increased antibody level was independent of other established risk factors, such as hyperlipidemia, smoking, hypertension, diabetes mellitus, and obesity, thus providing evidence for a strong correlation of hsp65 antibodies with carotid atherosclerosis. These serum antibodies cross-reacted with recombinant human hsp6O homologue, and also with homogenates of atherosclerotic lesions both showing a 60-kD protein band on Western blots (9). Double-immunofluorescence labeling of atherosclerotic lesions with human anti-hsp65 sera and cell marker-specific antibodies demonstrated expression of hsp60 by endothelial cells, as well as by macrophages and smooth muscle cells therein. These findings indicated the existence of serum antibodies reacting not only with mycobacterial hsp65 but also with mammalian hsp60, expressed as an autologous cellular component (6,9).Based on these observations we next addressed the question whether human anti-hsp65/60 antibody (Ab) from high titer sera could react with surface proteins, e.g., hsp60 on stressed endothelial cells, and whether these antibodies could mediate 1. Abbreviations used in this paper: ADCC, antibody-dependent cellular cytotoxicity; hsp, heat shock protein.Schett, Xu, Amberger, Van der Zee, Recheis, Willeit, and Wick 2569 J. Clin. Invest.
Objectives-Although cadmium (Cd) is an important and common environmental pollutant and has been linked to cardiovascular diseases, little is known about its effects in initial stages of atherosclerosis. Methods and Results-In the 195 young healthy women of the Atherosclerosis Risk Factors in Female Youngsters(ARFY) study, cadmium (Cd) level was independently associated with early atherosclerotic vessel wall thickening (intima-media thickness exceeding the 90th percentile of the distribution; multivariable OR 1.6[1.1.-2.3], Pϭ0.016). In line, Cd-fed ApoE knockout mice yielded a significantly increased aortic plaque surface compared to controls (9.5 versus 26.0 mm 2 , PϽ0.004). In vitro results indicate that physiological doses of Cd increase vascular endothelial permeability up to 6-fold by (1) inhibition of endothelial cell proliferation, and (2) induction of a caspase-independent but Bcl-xL-inhibitable form of cell death more than 72 hours after Cd addition. Both phenomena are preceded by Cd-induced DNA strand breaks and a cellular DNA damage response. Zinc showed a potent protective effect against deleterious effects of Cd both in the in vitro and human studies. Conclusion-Our research suggests Cd has promoting effects on early human and murine atherosclerosis, which were partly offset by high Zn concentrations. Key Words: cadmium, zinc Ⅲ endothelial Ⅲ dysfunction Ⅲ injury Ⅲ permeability Ⅲ necrosis Ⅲ ApoE Ⅲ atherosclerosis Ⅲ vascular Ⅲ pathophysiology Ⅲ risk factor Ⅲ intima media thickness Ⅲ apoptosis Ⅲ cell death S ince the use of Cd in manifold industrial applications, sources for and the amount of Cd uptake by humans has increased dramatically. Cd is, for example, released into the air through the burning of fossil fuels (coal, oil) and the incineration of municipal waste (Environmental Protection Agency, 2000). The most relevant sources for Cd uptake by humans are, however, cigarette smoking (one cigarette contains Ϸ1 to 2 g; daily uptake of Cd Ϸ1 to 3 g per pack smoked) and food for nonsmokers (daily intake Ϸ30 g; daily uptake Ϸ1 to 3 g), as well as exhaust gases (Agency for Toxic Substances and Disease Registry, 1999). After inhalation or ingestion of Cd, it is transferred into the bloodstream (whole blood and serum Cd concentrations range between Ϸ0.2 and Ϸ20 nmol/L 1,2 ), where Cd is transported either as a free ion or protein-bound, eg, attached to albumin or metallothioneins. Cd is taken up by cells of Cd target organs (liver, kidneys, and testis) via solute carriers, calcium and manganese channels, and iron transporters. [3][4][5] In 2001, Abu-Hayyeh et al 6 demonstrated that the aortic vessel wall is another under-recognized target organ for Cd accumulation (aortic wall concentrations of Cd are up to 20 mol/ L). Epidemiologically, high Cd level was found to be associated with hypertension, stroke, and cardiac arrest, 7-9 but confirmatory data are sparse and the mechanistic basis for these interactions remains unclear. Houtman et al observed a higher than expected frequency of atherosclerosis in a...
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