Differential suppression of pressure-overload cardiac and aortic hypertrophy in rats by angiotensin-converting enzyme inhibitors.
(25/1144)
Role of tissue angiotensin-converting enzyme (ACE) in the development of pressure-overload cardiovascular hypertrophy was examined in rats by comparing the inhibitory effect of trandolapril (high efficiency on tissue ACE) with that of enalapril (low efficiency) at equally antihypertensive doses. Rats with abdominal aorta banded or sham-operated were orally treated with trandolapril (0.5 mg/kg per day), enalapril (20 mg/kg per day) or vehicle for 8 weeks after the surgical maneuvers. In vehicle-treated rats, the banding raised the intra-aortic systolic pressure by 58%, diastolic pressure by 31%, maximum velocity of pressure rise by 65%, left ventricular (LV) weight by 41%, LV hydroxyproline concentration by 56%, aortic mass by 46%, LV ACE activity by 45%, and aortic ACE activity by 265%. Although both drugs equally reduced the aortic systolic pressure to approx. 70% and diastolic pressure to approx. 80% that of banded rats receiving vehicle, trandolapril partially prevented the LV hypertrophy, whereas enalapril yielded nonsignificant suppression. Trandolapril completely prevented the LV increments in hydroxyproline and ACE activity, whereas enalapril partially inhibited the LV hydroxyproline increase with little inhibition of LV ACE activity. In contrast, both inhibitors almost completely prevented the aortic hypertrophy, with the ACE activity of the aorta being potently inhibited. These results suggest that tissue ACE is the principal factor for pressure-induced aortic hypertrophy and an important yet non-essential factor for LV hypertrophy. (+info)
Application of laser scanning confocal microscopy in the analysis of particle-induced pulmonary fibrosis.
(26/1144)
Laser scanning confocal microscopy (LSCM) allows us to simultaneously quantitate the degree of lung fibrosis and distinguish various pathological lesions of intact lung tissue. Lucifer Yellow has been shown an ideal fluorescent stain to examine the connective tissue matrix components of embedded lung tissue with LSCM. We evaluated the use of LSCM in quantitating lung fibrosis and compared this procedure with the more traditional method of assessing fibrosis by measuring hydroxyproline, a biochemical assay of collagen. CD/VAF rats were intratracheally dosed with silica (highly fibrogenic), Fe2O3 (non-fibrogenic), and saline (vehicle control) at a high dose of 10-mg/100 g body weight. At 60 days post-instillation, the left lung was dissolved in 6 M HCl and assayed for hydroxyproline. Silica induced increases of 58% and 94% in hydroxyproline content over the Fe2O3 and control groups, respectively. The right lung lobes were fixed, sectioned into blocks, dehydrated, stained with Lucifer Yellow (0.1 mg/ml), and embedded in Spurr plastic. Using LSCM and ImageSpace software, the tissue areas of ten random scans from ten blocks of tissue for each of the three groups were measured, and three-dimensional reconstructions of random areas of lung were generated. The silica group showed increases of 57% and 60% in the lung areas stained by Lucifer Yellow over the Fe2O3 and control groups, respectively. Regression analysis of hydroxyproline vs. lung tissue area demonstrated a significant positive correlation (p < 0.05) with a correlation coefficient of 0.91. Histological analysis of right lung tissue revealed a marked degree of granulomatous interstitial pneumonitis for the silica group, which was absent in the Fe2O3 and control groups. No significant differences (p < 0.05) in hydroxyproline content and measured tissue area were observed between the Fe2O3 and control groups. LSCM, and its associated advanced image analysis and three-dimensional capabilities, is an alternative method to both quickly quantitate and examine fibrotic lung disease without physical disruption of the tissue specimen. (+info)
Effect of superoxide dismutase on bleomycin-induced dermal sclerosis: implications for the treatment of systemic sclerosis.
(27/1144)
Bleomycin has a chemical toxicity capable of inducing superoxide radicals, which are suggested to play an important part in bleomycin-induced pulmonary fibrosis. We have recently established a mouse model for scleroderma induced by repeated local injections of bleomycin. In this study, we examined the inhibitory effect of superoxide dismutase on the development of dermal sclerosis induced by bleomycin using this mouse model. PC-superoxide dismutase, which is a lecithinized superoxide dismutase with high tissue accumulation and long half-life in blood, was administered (3000 U per kg; dissolved in 5% mannitol) 3 h before the injection of bleomycin in C3H mice for 3 wk. Systemic PC-superoxide dismutase markedly inhibited the development of dermal sclerosis, which was also accompanied by a decrease in the number of infiltrating mast cells and eosinophils. Furthermore, the hydroxyproline content in the skin was significantly reduced, as compared with mice treated with bleomycin only or bleomycin and 5% mannitol. In a separate experiment, after the development of dermal sclerosis following treatment with bleomycin for 3 wk, PC-superoxide dismutase was administered for 2 wk. Histologic examination again revealed a reduction of dermal sclerosis, followed by a significant associate in the number of both mast cells and eosinophils. The hydroxyproline content in the skin was not significantly decreased, however, even after injections of high amounts of PC-superoxide dismutase (30,000 U per kg). These results support the involvement of oxygen free radicals in bleomycin-induced dermal sclerosis, and also indicate that administration of superoxide dismutase may be effective in the therapeutic approach in systemic sclerosis. (+info)
Involvement of type VI collagen in interleukin-4-induced mineralization by human osteoblast-like cells in vitro.
(28/1144)
We recently showed that interleukin-4 (IL-4) enhanced collagen and osteocalcin accumulation and caused mineralization in human periosteal osteoblast-like (SaM-1) cells. At that time, the expression of alpha1(VI) collagen mRNA was induced. In the present study, the possible role of IL-4-induced type VI collagen in the in vitro mineralization in osteoblasts was investigated. Addition of IL-4 in the early stage (for the first 10 days) was essential for the mineralization. The mRNA levels of alpha1(VI) and alpha2(VI) collagen and protein level of type VI collagen were transiently increased by IL-4 treatment up to day 5, whereas the alpha1(I) procollagen mRNA level was greater at day 10 than at day 5. Addition of anti-type VI collagen antibody remarkably reduced the extracellular accumulations of calcium and hydroxyproline induced by IL-4. Furthermore, the transfection of antisense oligonucleotides of alpha1(VI) to SaM-1 cells in the presence of IL-4 partially inhibited IL-4-induced type I collagen accumulation. These results demonstrated that type VI collagen played important roles for IL-4-induced mineralization and hydroxyproline accumulation mostly type I collagen accumulation, in human periosteal osteoblast-like cells. (+info)
Cross-linked telopeptides of type I and III collagens in malignant ovarian tumours in vivo.
(29/1144)
Malignant tumours often induce a fibroproliferative response in the adjacent stroma, characterized by increased expression of type I and type III procollagens. In normal tissues, fibrillar collagens normally undergo extensive intermolecular cross-linking that provides tensile strength to the tissue. Here we set out to characterize collagen cross-linking in human ovarian carcinoma tissue in vivo. Biochemical and immunochemical methods were used for cross-linked telopeptides of type I and III collagens in samples of benign and malignant serous tumours. The locations and staining patterns of these proteins were visualized immunohistochemically. The contents of both total collagen and the cross-linked type I and type III collagens in the malignant samples were only about 20% of those in the benign tumours. The cross-linked telopeptide antigens derived from the collagens were smaller and more heterogeneous in size in the malignant than in the benign tumours, indicating a defective cross-linking process scarcely leading to the formation of mature cross-links in the collagen fibres in malignancy. Immunostaining revealed disorganized type I and type III collagen bundles in carcinomas. These findings suggest that the collagen cross-linking process is aberrant in malignant tumours, possibly resulting in increased susceptibility of tumour collagens for the proteolysis often associated with tumour invasion. (+info)
Response to the sexual pheromone and wounding in the green alga volvox: induction of an extracellular glycoprotein consisting almost exclusively of hydroxyproline.
(30/1144)
The extracellular matrix (ECM) of Volvox is modified during development or in response to external stimuli, like the sex-inducing pheromone. It has recently been demonstrated that a number of genes triggered by the sex-inducing pheromone are also inducible by wounding. By differential screening of a cDNA library, a novel gene was identified that is transcribed in response to the pheromone. Its gene product was characterized as an ECM glycoprotein with a striking feature: it exhibits a hydroxyproline content of 68% and therefore is an extreme member of the family of hydroxyproline-rich glycoproteins (HRGPs). HRGPs are known as constituents of higher plant ECMs and seem to function as structural barriers in defense responses. The Volvox HRGP is also found to be inducible by wounding. This indicates that the wound response scenarios of higher plants and multicellular green algae may be evolutionary related. (+info)
Exacerbation of bleomycin-induced lung injury in mice by amifostine.
(31/1144)
Bleomycin (BLM) induces lung injury and fibrosis in the murine lung and enhances tumor necrosis factor (TNF)-alpha and collagen mRNA expression in the murine lung. Amifostine is a cytoprotective agent that protects normal tissues from the cytotoxic effects of chemo- and radiation therapy. We investigated the effect of amifostine in BLM-induced lung injury in mice. Mice received intraperitoneal amifostine (200 mg/kg) 30 min before and/or 1, 3, and 7 days after an intratracheal injection of saline or BLM (4 U/kg). The animals were killed 14 days after BLM exposure, and their lungs were studied for TNF-alpha and collagen mRNA expression, hydroxyproline content, and histopathology. Light microscopy demonstrated that amifostine exacerbated the BLM-induced lung injury in mice. Increased TNF-alpha mRNA expression as a result of BLM exposure was not modulated by amifostine treatment. In contrast, amifostine treatment enhanced the BLM-induced expression of alpha(1)(I) procollagen mRNA in the lung. Similarly, mice treated with amifostine before BLM exposure accumulated significantly higher amounts of hydroxyproline (111 +/- 5 microg/lung) than BLM-treated animals (90 +/- 6 microg/lung). These data suggest that amifostine treatment exacerbates BLM-induced lung injury in mice. (+info)
Induction of human fibroblast proliferation by epidermal growth factor (EGF): enhancement by an EGF-binding arginine esterase and by ascorbate.
(32/1144)
The effect of mouse epidermal growth factor (mEGF) and an mEGF-binding arginine esterase on the growth of cultured human fibroblasts has been studied. Physiological concentrations (10(-9)-10(-10) M) of the growth factor were found to stimulate DNA replication and cell proliferation in quiescent cultures, and the arginine esterase, which is normally associated with mEGF in vivo, was shown to enhance this growth effect synergistically. The cellular response to mEGF was dependent upon a low, growth-limiting concentration of serum in the extracellular medium. Ascorbic acid, which alone exhibited no growth-promoting effect, could partially replace this requirement, and was found to elicit a rapid and marked increase in proline hydroxylation. Quiescent cultures in serum-free medium containing ascorbic acid were stimulated by the combination of mEGF and the esterase in a manner comparable to that achieved with serum shift-up. The possible requirement of a collagen-containing extracellular matrix for the growth response to mEGF is discussed. (+info)