PubMed Health⌕ Search

Biomedical subjects

J Herget

Publications and source records attributed to J Herget.

At least 19 recordsLinked to original sources
PubMed2000

Role of nitric oxide in the pathogenesis of chronic pulmonary hypertension.

Chronic pulmonary hypertension is a serious complication of a number of chronic lung and heart diseases. In addition to vasoconstriction, its pathogenesis includes injury to the peripheral pulmonary arteries leading to their structural remodeling. Increased pulmonary vascular synthesis of an endogenous vasodilator, nitric oxide (NO), opposes excessive increases of intravascular pressure during acute pulmonary vasoconstriction and chronic pulmonary hypertension, although evidence for reduced NO activity in pulmonary hypertension has also been presented. NO can modulate the degree of vascular injury and subsequent fibroproduction, which both underlie the development of chronic pulmonary hypertension. On one hand, NO can interrupt vascular wall injury by oxygen radicals produced in increased amounts in pulmonary hypertension. NO can also inhibit pulmonary vascular smooth muscle and fibroblast proliferative response to the injury. On the other hand, NO may combine with oxygen radicals to yield peroxynitrite and other related, highly reactive compounds. The oxidants formed in this manner may exert cytotoxic and collagenolytic effects and, therefore, promote the process of reparative vascular remodeling. The balance between the protective and adverse effects of NO is determined by the relative amounts of NO and reactive oxygen species. We speculate that this balance may be shifted toward more severe injury especially during exacerbations of chronic diseases associated with pulmonary hypertension. Targeting these adverse effects of NO-derived radicals on vascular structure represents a potential novel therapeutic approach to pulmonary hypertension in chronic lung diseases.

Adult↗
PubMed2000

A possible role of the oxidant tissue injury in the development of hypoxic pulmonary hypertension.

Chronic sojourn in hypoxic environment results in the structural remodeling of peripheral pulmonary arteries and pulmonary hypertension. We hypothesize that the pathogenesis of changes in pulmonary vascular structure is related to the increase of radical production induced by lung tissue hypoxia. Hypoxia primes alveolar macrophages to produce more hydrogen peroxide. Furthermore, the increased release of oxygen radicals by other hypoxic lung cells cannot be excluded. Several recent reports demonstrate the oxidant damage of lungs exposed to chronic hypoxia. The production of nitric oxide is high in animals with hypoxic pulmonary hypertension and the serum concentration of nitrotyrosine (radical product of nitric oxide and superoxide interaction) is also increased in chronically hypoxic rats. Antioxidants were shown to be effective in the prevention of hypoxia induced pulmonary hypertension. We suppose that the mechanism by which the radicals stimulate of the vascular remodeling is due to their effect on the metabolism of vascular wall matrix proteins. Non-enzymatic protein alterations and/or activation of collagenolytic matrix metalloproteinases may also participate. The presence of low-molecular weight cleavage products of matrix proteins stimulates the mesenchymal proliferation in the wall of distal pulmonary arteries. Thickened and less compliant peripheral pulmonary vasculature is then more resistant to the blood flow and the hypoxic pulmonary hypertension is developed.

Animals↗
PubMed2000

Perinatal history of hypoxia leads to lower vascular pressures and hyporeactivity to angiotensin II in isolated lungs of adult rats.

The most dramatic changes in pulmonary circulation occur at the time of birth. We hypothesized that some of the effects of perinatal hypoxia on pulmonary vessels are permanent. We studied the consequences of perinatal exposure to hypoxia (12 % O2 one week before and one week after birth) in isolated lungs of adult male rats (approximately 12 weeks old) perfused with homologous blood. Perfusion pressure-flow relationship was tilted towards lower pressures in the perinatally hypoxic as compared to the control, perinatally normoxic rats. A non-linear, distensible vessel model analysis revealed that this was due to increased vascular distensibility in perinatally hypoxic rats (4.1 +/- 0.6 %/mm Hg vs. 2.3 +/- 0.4 %/mm Hg in controls, P = 0.03). Vascular occlusion techniques showed that lungs of the perinatally hypoxic rats had lower pressures at both the pre-capillary and post-capillary level. To assess its role, basal vascular tone was eliminated by a high dose of sodium nitroprusside (20 microM). This reduced perfusion pressures only in the lungs of rats born in hypoxia, indicating that perinatal hypoxia leads to a permanent increase in the basal tone of the pulmonary vessels. Pulmonary vasoconstrictor reactivity to angiotensin II (0.1-0.5 microg) was reduced in rats with the history of perinatal-hypoxia. These data show that perinatal hypoxia has permanent effects on the pulmonary circulation that may be beneficial and perhaps serve to offset the previously described adverse consequences.

Angiotensin II↗
PubMed1999

Binding of lead to collagen type I and V and alpha2(I) CNBr (3,5) fragment by a modified Hummel-Dreyer method.

Binding of lead (as lead acetate) to collagen type I alpha, and alpha2 chains, collagen type V and a large cyanogen bromide fragment of type I collagen [alpha2(I)CB(3,5)] was investigated by the large-zone Hummel-Dreyer method. It was demonstrated that two categories of binding sites exist in the collagen molecule, the number of which correlates rather well with the available aspartic and glutamic acid residues. Similar results were obtained for all collagen chains (fragments) used. The number of sites thus obtained was compared with the cross-striation pattern (reflecting areas where lead is bound) of the SLS form of collagen type I (alpha1 chain); it is suggested that the number of bands seen in the SLS form reflects primarily the number of available aspartic acid residues in the molecule. The association constants obtained are comparable with the low affinity interactions seen e.g., between Cu and bovine serum albumin.

Collagen↗
PubMed1999

Hypoxia induces free radical damage to rat erythrocytes and spleen: analysis of the fluorescent end-products of lipid peroxidation.

Several studies have shown that hypoxia induces alterations in the lipid membranes of many cell types. The mechanism of these changes might consist in membrane lipid peroxidation. Lipid peroxidation in erythrocytes and spleen is easily detected by measurement of the concentration of fluorescent end-products. Exposure of rats to hypoxia for various time periods induced formation of lipophilic fluorescent products both in erythrocytes and spleen. A new kind of fluorophore was found in chloroform extracts from erythrocytes with excitation maximum at 270 nm and emission maximum at 310 nm. Additionally, two minor fluorophores were observed, emitting at 360 nm and in the region of 415-440 nm. Only one type of fluorophore was detected in spleen, emitting at 445 nm after excitation at 315 nm. The concentration of fluorophores was dependent on the time of hypoxic exposure both in erythrocytes and spleen. In erythrocytes there was a decrease of the predominant fluorophore after 3 hours (54%, P < 0.05) and 21 days (54%, P < 0.05) of hypoxia in relation to normoxic controls, accompanied by changes in spectral patterns of tridimensional fluorescence spectra. There was also a significant increase in the concentration of fluorophore in spleen (to 164%, P < 0.05, after 3 h, and to 240%, P < 0.05, after 21 days). The fluorophores, both in erythrocytes and spleen, were resolved into several distinct fractions with HPLC. The presented results support the hypothesis of hypoxia-induced lipid peroxidation and create a basis for further characterization of the fluorescent products.

Animals↗
PubMed1999

Influence of macrophages and macrophage-modified collagen I on the adhesion and proliferation of vascular smooth muscle cells in culture.

The adhesion, proliferation and morphology of rat vascular smooth muscle cells (VSMC) in cocultures with macrophages or in cultures on type I collagen modified by activated macrophages were evaluated. In the first set of experiments, rat alveolar macrophages were added to 24-hour-old VSMC cultures. Between days 2 and 5 after VSMC seeding, the population densities and doubling times of cells were similar in both VSMC-macrophage and pure VSMC cultures. However, from day 5, the cocultures proliferated about two times more rapidly and on day 7, they reached higher cell population density by 40%. The pure macrophage cultures did not proliferate. In the second set of experiments, rat alveolar macrophages were activated by non-toxic TiO2 dust to produce reactive oxygen species and incubated for 120 min with collagen I. The collagen was then adsorbed on plastic culture dishes and seeded with VSMC. The collagen exposed for 10 min only, the unmodified collagen and pure culture dishes were used as control growth supports. On all four tested substrates, the number of initially adhered cells was similar, but on the collagen modified for 120 min, the cells were less spread. Moreover, on day 2 to 3 after seeding, some cells on this collagen became vacuolated and detached spontaneously from the growth support. The remaining VSMC, however, rapidly proliferated, so that on day 9, the cell population density on 120-min-modified collagen was similar as on both control collagens and significantly higher compared to that on uncoated dishes. Our results suggest that 1. The delayed growth-stimulating effect of macrophages on VSMC-macrophage mixed population is probably due to autocrine production of mitogens by both cell types rather than due to an acute effect of short-living oxygen radicals released from macrophages immediately after adding to VSMC cultures. 2. The effect of collagen I exposed to activated macrophages for 120 min is slightly cytotoxic, which could, however, stimulate a release of mitogens from damaged as well as surviving VSMC.

Animals↗
PubMed1999

[Mechanisms of remodeling of pulmonary blood vessels in chronic hypoxia].

Chronic lung hypoxia results in the hypoxic pulmonary hypertension, which is caused by the remodeling of peripheral pulmonary blood vessels. Vascular smooth muscle cells proliferate into the prealveolar arteries, the turnover and deposition of connective tissue proteins is increased. We observed an enhanced collagenolytic activity in the extracts from isolated peripheral lung arteries of hypoxic rats. SDS electrophoresis of collagenous proteins extracted from these vessels showed presence of the low molecular weight cleavages of collagen type I. We hypothesize that the activation of collagenolytic metalloproteinases is related to the release of reactive oxygen species, NO and products of their interaction (peroxynitrite). Collagen cleavages may stimulate mesenchymal proliferation in the vascular wall.

Animals↗
PubMed1998

Micropreparation of tissue collagenase fragments of type I collagen in the form of surfactant-peptide complexes and their identification by capillary electrophoresis and partial sequencing.

Combination of standard approaches like pepsin digestion and slab gel electrophoresis with capillary separations allows a relatively easy identification of in vivo occurring collagen fragments. Capillary electrophoresis can be done either in 25 mM phosphate buffer (pH 2.5) or in a 25 mM phosphate buffer (pH 4.5) made 0.1% with respect to sodium dodecyl sulfate (SDS). While in the first case peptides move to the cathode in a molecular mass dependent manner, in the second case they move towards anode (also in a molecular mass dependent manner). The profiles obtained by the two approaches resemble mirror images with low molecular mass peptides moving first in the acid background electrolyte while they move last in the presence of SDS. It is proposed that in the capillary electrophoretic separation at pH 2.5 the separation mechanism involves the interaction of the individual peptides with the capillary wall while in the second case (pH 4.5) the leading mechanism of separation involves the interaction of the analytes with the micellar phase. For micellar phase separation the system must be run at reversed polarity. Capillary electrophoretic separation in the pH 2.5 buffer is considerably affected by the presence of SDS in the previous steps of peptide preparation. If the peptides are obtained from SDS slab gel electrophoresis, their movement in the capillary electrophoresis step is about three times faster that the movement of corresponding peptides which have not been complexed with SDS.

Animals↗
PubMed1998

Exposure to chronic hypoxia induces qualitative changes of collagen in the walls of peripheral pulmonary arteries.

Qualitative changes of vascular wall matrix collagens in chronic hypoxic pulmonary hypertension were studied by gel electrophoresis. Male adult rats (n = 12) were exposed to hypoxia (FiO2 = 0.1, 3 wks). Control rats (n = 13) were kept in air. Samples of peripheral pulmonary arteries (PPA, diam. 100-400 microm), main branches of pulmonary artery, and aorta were dissected. Arterial samples were treated with 4M guanidine-HCl to remove noncollagenous moieties and the collagenous stroma was dissolved by limited pepsin digestion at low pH. Low molecular mass peptides (M. W. approx. 76 and 66 kD) were detected in the gel electrophoretic profile of collagen peptides of PPA of the chronically hypoxic animals and in aorta of both hypoxic and normoxic groups. These peptides were absent in the PPA of normoxic rats. Since the 76 kD peptide bound anticollagen type I antibodies, it appears to be of collagenous nature and it may be the result of collagenolytic activity in PPA isolated from hypoxic lungs. This was confirmed by zymography. We conclude that exposure of rats to chronic hypoxia results in the presence of low molecular mass peptides in the wall matrix of PPA which resemble those found in aorta of normoxic animals. Collagenolytic activity in the walls of peripheral pulmonary arteries may participate in the mechanism of lung vascular remodelling in chronic hypoxia.

Animals↗
PubMed1998

Accumulation of lead in tissues after its administration in drinking water to laboratory rats.

Lead administered to laboratory rats in drinking water (0.1-0.8%) as lead acetate solution tends to accumulate in collagen-rich tissues such as tendons and the skin. The amount of lead deposited (and also zinc present in the tissue without its supplementation) correlates with the blood supply to the tissue investigated. The highest deposits of lead were observed in placenta and chorionic membranes, though here only about 60% are collagen-bound. No differences in the drinking habits of the animals were observed and also at lower concentrations of lead in the drinking water no dose dependence was revealed. However, at 0.8% of lead in drinking water considerable accumulation of lead was observed in all tissues investigated.

Animals↗
PubMed1997

Oxidized collagen stimulates proliferation of vascular smooth muscle cells.

We hypothesize that the vascular smooth muscle proliferation after lung injury results from oxidative damage to the matrix proteins in the walls of pulmonary blood vessels. The smooth muscle cells (SMC) isolated from rat aorta were cultured on the surface coated with oxidized and nonoxidized (control) collagen of type I. Oxidation of collagen was induced by UV irradiation and characterized by fluorescence tridimensional spectral arrays and by gel electrophoresis. From day 1 to 6 of the experiment, SMC proliferated more rapidly on the oxidized collagen than on the control surface. At high SMC population densities (day 9 of experiment) the difference disappeared. After 10 min of trypsinization the cells growing on oxidized collagen rounded and detached completely from the growth surface. The control cells on nonoxidized collagen detached only after 30 min of trypsinization. We conclude that oxidation of collagen of vascular wall matrix may participate in stimulation of SMC proliferation after oxidant tissue injury.

Animals↗
PubMed1997

Pulmonary haemodynamics in acute experimental lung vascular injury.

Acute lung injury was induced by intravenous injection of 20 microl of a mixture of equivalent volumes of capronic acid, caprilic acid and olive oil in intact anaesthetized rats and in isolated perfused rat lung preparations. Lung injury in intact rats resulted in an increase in lung weight related to body weight and in a decrease in the lung dry/wet weight ratio. Lung compliance, measured in a body plethysmograph, was decreased. PaO2 decreased and PaCO2 increased in 10 and 20 min, respectively, after the beginning of the experiment. Mean blood pressure in pulmonary artery increased immediately after the injection. Isolated rat lungs were perfused at constant flow with physiological saline solution containing bovine albumin and meclofenamate. The injection of a mixture of capronic acid, caprilic acid and olive oil increased the baseline perfusion pressure and led to a release of endothelial cells into the perfusate. The perfusion flow-pressure relationship was shifted upwards. Both the extrapolated pressure axis, intercept and slope of the plot were significantly elevated. The described experimental lung injury is a suitable model for studies on the effects of vascular wall damage and transvascular fluid leak in pulmonary vasculature.

Animals↗
PubMed1996

Production of hydrogen peroxide by alveolar macrophages from rats exposed to subacute and chronic hypoxia.

We have studied in vitro alveolar macrophages (AMs) obtained by tracheobronchial lavage from rats exposed to subacute (3 hours and 3 days) and chronic (3 weeks) hypoxia (FiO2 = 0.1) and from rats recovering from chronic hypoxia. Hydrogen peroxide production by AMs was measured by luminol-dependent chemiluminescence after AMs adhered to the walls of the measuring cuvette, after stimulation with phorbol-myristate-acetate (PMA), and when N-formyl-methionyl-leucyl-phenylanine (FMLP) was added subsequently to the cells which had been previously stimulated by adherence or PMA. H2O2 production after cell adherence and adherence combined with FMLP stimulation did not differ between the groups. The increase of H2O2 production after adding PMA, and FMLP in addition to PMA was significantly higher in AMs from rats exposed to hypoxia for 3 days than in the controls. Other experimental groups did not differ from their controls. It is concluded that 3 days' hypoxia primes AMs for enhanced production of H2O2 upon stimulation. The mechanism is probably at the level of synthesis of proteins involved in H2O2 production, or the shift to a more reactive phenotype of alveolar macrophages subpopulations.

Animals↗
PubMed1996

The inhibition of angiotensin converting enzyme attenuates the effects of chronic hypoxia on pulmonary blood vessels in the rat.

The effect of chronic administration of angiotensin converting enzyme inhibitor on the development of hypoxic pulmonary hypertension was studied in rats. Male Wistar rats were-exposed for 3 weeks to isobaric hypoxia (10% O2) and treated with 10 mg/kg b.w. of Ramipril daily. The haemodynamic properties of the pulmonary vasculature were then measured in isolated blood-perfused lung preparation. Ramipril administration during the sojourn in hypoxia resulted in lower baseline perfusion pressure and lower slope of perfusion pressure-flow relationship compared to non-treated hypoxic rats. Partitioning of the distribution of pulmonary vascular resistance across the vascular bed by the occlusion technique showed that it was mainly due to a decrease of arterial and venous vascular resistances to blood flow. It is suggested that Ramipril attenuates the process of morphological reconstruction of pulmonary vasculature by chronic hypoxia rather than the level of vascular smooth muscle tone.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Long-term effects of prenatal indomethacin administration on the pulmonary circulation in rats.

Mechanical properties of the adult pulmonary vasculature are affected by perinatal experience of hypoxic pulmonary hypertension. In the present study, we followed the long-term effects of perinatal pulmonary hypertension induced by means other than hypoxia in rats. Daily injections of indomethacin (1 mg.kg-1 body weight (BW)) were given to the parturient rats. Their newborn pups had significantly increased number of muscularized peripheral pulmonary vessels. Pulmonary hypertension, however, did not persist to adulthood (mean pulmonary arterial pressure (Ppa) was 17.2 +/- 1.3 torr in the experimental group and 16.4 +/- 0.8 torr in controls). Pulmonary hypertension induced in adult rats by exposure to chronic hypoxia or by acute hypoxic challenges was similar in indomethacin-treated and control rats. Normoxic perfusion pressure/flow (P/Q) plots in isolated lungs were less steep in indomethacin-treated than in control rats. Acute hypoxia increased the slope of P/Q plots in indomethacin treated rats but not in controls. The described changes in the pulmonary vasculature induced by indomethacin are similar to those found previously in adult rats born in hypoxia. We conclude that perinatal pulmonary hypertension permanently modifies the pulmonary vasculature.

Animals↗
PubMed1995

Perinatal lung injury extends in adults the site of hypoxic pulmonary vasoconstriction upstream.

Adult rats born in hypoxia but raised in air are more reactive to acute hypoxic challenges. The relation between perfusion pressure and perfusion flow (P/Q plot) was analyzed in the preparation of ventilated perfused lungs isolated from 3 groups of adult rats. Control animals of the first group were born and lived in air, the second group was born in hypoxic chamber and then the rats were raised in air. Rats of the third group were born in air and exposed to hypoxia in adulthood. The P/Q plot in rats born in hypoxia had lower slope than that in controls. Acute hypoxia in control group resulted in parallel shift of P/Q line to higher pressures. In rats born in hypoxia, however, both intercept with pressure axis and slope were increased. This may be explained by the participation of both collapsible and non-collapsible parts of pulmonary vascular bed in hypoxic pulmonary vasoconstriction. Analysis of distribution of pulmonary vascular resistances by the double occlusion technique confirmed this possibility. In rats born in hypoxia both arterial and middle vascular segment resistances increased during acute hypoxic challenge. In control rats, however, the increase in resistance was restricted to the middle segment only.

Animals↗