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Biomedical subjects

R H Goldstein

Publications and source records attributed to R H Goldstein.

71 records · Page 4Linked to original sources
PubMed1984

Activation of protein formation and cell division by bradykinin and des-Arg9-bradykinin.

We employed des-Arg9-bradykinin to investigate the relation between bradykinin-induced prostaglandin (PG) synthesis and bradykinin-induced protein accumulation. In this feedback control system, bradykinin-induced PG synthesis limits bradykinin-induced protein production. At low concentration (5 X 10(-8) M), des-Arg9-bradykinin was significantly less active than bradykinin in stimulating the formation of prostaglandins by human fetal lung fibroblasts in culture. At high concentration (5 X 10(-6) M), bradykinin induced a 24% increase in protein formation, while des-Arg9-bradykinin induced a 61% increase in collagen formation and an 80% increase in total protein accumulation. In the presence of indomethacin, bradykinin-induced protein formation was increased further, whereas des-Arg9-bradykinin-induced protein formation was unchanged. The bradykinin derivative increased the production of types I and III procollagens without affecting the distribution of procollagen types. The incorporation of [3H]thymidine into DNA in lung fibroblast cultures was increased 3-fold by des-Arg9-bradykinin alone or by bradykinin in combination with indomethacin. Des-Arg9-[Leu8]bradykinin inhibited the des-Arg9-bradykinin-induced protein formation and cell division. These data indicate that both bradykinin and des-Arg9-bradykinin stimulate protein formation and cell division; des-Arg9-bradykinin alone stimulates protein formation and cell division without activating PG synthesis and PG feedback control.

Arachidonic Acid↗
PubMed1982

The effect and interaction of bradykinin and prostaglandins on protein and collagen production by lung fibroblasts.

Bradykinin stimulates protein production as well as prostaglandin production by lung fibroblasts in culture. When prostaglandin (PG) synthesis by the fibroblasts is inhibited with indomethacin, then bradykinin also stimulates collagen production. In the presence of indomethacin, the increase in protein production by bradykinin is much higher than in its absence. The addition of exogenous PGE2 to the fibroblasts which have been treated with indomethacin inhibited the stimulating effect of bradykinin on total protein production, especially collagen production. The concentration of PGE2 added was in the range of that produced by the fibroblasts. The degree of inhibition by PGE2 was dependent on the concentration of PGE2 added to the cultures. These results point out an interaction between bradykinin and PGE2 in the regulation of protein production by fibroblasts with PGE2 acting as a feedback mechanism to dampen the effect of bradykinin.

Bradykinin↗
PubMed1982

A gelatin-specific protease from hamster lung-derived cell cultures.

Gelatin-specific protease activity from hamster lung fibroblasts and their culture media is described. The fibroblasts were derived from hamster lung explant cultures. The gelatin-specific protease activity is latent and seen only after dialysis of either cells or media. The enzyme activity shares many properties of previously reported gelatinases. The activity is inhibited by EDTA, cysteine, and dithioerythritol, whereas it is not inhibited by p-chloromecuribenzoate, N-ethyl maleimide, or phenylmethylsulfonyl fluoride. Of all substrates tested, activity was observed only against gelatin and not against other substrates tested. It was inactive toward collagen, elastin, and methemoglobin. This enzyme may have a role in the digestion of collagen that has been previously cleaved by mammalian collagenase.

Animals↗
PubMed1982

Response of the aging hamster lung to elastase injury.

The effect of age on the induction of emphysema in hamsters was investigated by administering porcine pancreatic elastase endotracheally to old (18 months of age) and young (4 months of age) hamsters; age-matched untreated animals served as controls. Lung volumes, quasi-static deflation volume pressure relations, and mean linear intercept, an index of alveolar size, were measured. Elastase-treated young hamsters demonstrated an increased volume of air in the lungs at a transpulmonary pressure of 25 cm H2O and an increased mean linear intercept. The lungs of old elastase-treated animals showed less pronounced changes than those of young hamsters in lung volume at transpulmonary pressure of 25 cm H2O and in mean linear intercept. Untreated old hamsters had a larger lung volume at a transpulmonary pressure of 25 cm H2O and an 85% increase in total lung collagen. Age-related alterations in connective tissues may account for the increased resistance of old lungs to injury by pancreatic elastase.

Aging↗
PubMed1982

Modification of oxygen toxicity after lung injury by bleomycin in hamsters.

In order to explore the interactions between oxygen toxicity and a model of interstitial pulmonary fibrosis, we studied the effects of exposure to 100% O2 at 1 atmosphere and exposure to 60% O2 for 21 days on survival, lung statics, and lung weight in hamsters previously treated intratracheally with bleomycin sulfate for 8 days (BLEO-8) and for 21 days (BLEO-21). All 10 saline-treated control animals died between 5 and 7.5 days in 100% O2; 7 of 15 BLEO-8 hamsters died before Day 5 (Fisher's exact test, p = 0.01) and 7 BLEO-21 hamsters died after Day 7.5 (Fisher's exact test, p = 0.03). Five of 11 BLEO-8 hamsters died in 60% O2, but there were no deaths among 8 BLEO-21 hamsters so exposed (Fisher's exact test, p = 0.04). There were slight decreases in the volume of air in the lungs at 25 cm H2O transpulmonary pressure (TLC25), vital capacity (VC), and quasi-static lung compliance (Cst(L)) in the saline-treated hamsters breathing 60% O2, compared with air-breathing control animals. The BLEO-8 animals exposed to 60% O2 showed greater decreases in TLC25, VC, and Cst(L) than the air-breathing control animals, and the mean dry lung weight of the O2-breathing group was significantly greater than that of the control animals. The BLEO-21 hamsters exposed to 60% O2 showed only a 15 to 18% greater decrease in TLC25, VC, and Cst(L) than the air-breathing control animals; the mean dry lung weight of the O2-breathing group was similar to the air-breathing control group. We concluded that the breathing of either 100 or 60% O2 adds to the severity of the lung injury previously induced by bleomycin; the degree of worsening is greater at 8 days than at 21 days after bleomycin treatment. These findings suggest that concentrations of inhaled oxygen used in treating human interstitial lung diseases should be kept at the lowest levels compatible with adequate tissue oxygenation.

Animals↗
PubMed1982

Influence of asbestos fibers on collagen and prostaglandin production in fibroblast and macrophage co-cultures.

The interaction of fibroblasts, macrophages, and crocidolite asbestos fibers was studied in cell culture. We determined the effects of co-cultivation and asbestos fibers on collagen, total protein, and PG production. The co-cultivation of guinea pig alveolar macrophages and fetal lung fibroblasts resulted in a 155% increase in protein and a 31% increase in collagen production above fibroblast controls. The collagen was derived exclusively from the fibroblasts. Although total protein production was derived predominantly from the fibroblasts, the macrophages in co-culture also contributed to the protein levels. The addition of asbestos fibers to fibroblast cultures resulted in a decrease in collagen and total protein production. The addition of asbestos fibers to fibroblast and macrophage co-cultures prevented the enhancement of collagen production and limited the increase in protein production above fibroblast controls. PGE2, PGI2, and TXA2 were measured in macrophage and fibroblast cultures. Very low, almost undetectable PG production was observed under basal conditions by either cell type alone or in co-culture. Bradykinin induced release of these PGs in fibroblast but not macrophage cultures. This release was enhanced in co-cultures. Asbestos fibers, when added to the co-cultures caused a significant increase in the release of PGs, particularly PGE2. PGE2 is known to inhibit collagen and total protein production by fibroblasts. The increased release of PGs in asbestos-treated co-cultures may have contributed to the described asbestos suppression of collagen production

Animals↗
PubMed1980

Lung statics and connective tissues after penicillamine in bleomycin-treated hamsters.

Penicillamine was administered intraperitoneally to male golden hamsters for 30 days following a single intratracheal dose of bleomycin. Penicillamine treatment increased soluble collagen and decreased glycosaminoglycans in both normal and fibrotic lungs; total collagen and elastin were not significantly changed in normals but were lower in fibrotic animals. The proportions of the different glycosaminoglycans were not affected by penicillamine treatment. When related to body weight, the total lung capacity, vital capacity, and compliance both at low and high lung volumes were increased in animals that received only penicillamine when compared with animals that did not, but interpretation of these results is difficult because penicillamine-treated animals had low body weights. Lung statics were the same in animals that received penicillamine after bleomycin as in those that received bleomycin only, though penicillamine partially reversed the connective tissue expression of the bleomycin lung injury. We conclude that factors other than connective tissue levels are important in determining the mechanical behavior of fibrotic lungs.

Animals↗
PubMed1979

Failure of mechanical properties to parallel changes in lung connective tissue composition in bleomycin-induced pulmonary fibrosis in hamsters.

Lung volumes and volume pressure (V-P) relationships were measured in anesthetized hamsters 8, 30, 60, and 90 days after induction of interstitial pulmonary fibrosis by intratracheal administration of bleomycin. Subsequently, total collagen, elastin, protein, deoxyribonucleic acid (DNA), and dry weight were determined in the lungs of each animal. The mean volume of air in the lungs at a transpulmonary pressure of 25 cm H2O and mean quasi-static compliance were decreased at 8 and 30 days and had returned toward normal by 60 and 90 days. Dry lung weight and total protein content were increased at 8 days, peaked at 30 days, and were still greater than normal at 90 days; DNA peaked at 8 days, remained unchanged through day 60, and returned to normal by day 90. Collagen and elastin content, although not significantly different from control at day 8, was increased at day 30 with peak values attained at day 90. Ratios of collagen or elastin to dry weight, total protein, and DNA were decreased at 8 days, normal at 30 days, and increased at 90 days. The ratios of collagen or elastin to total protein, dry lung weight, or DNA cannot be used as indicators of the amounts of these proteins in the whole lung. We conclude that in interstitial pulmonary fibrosis induced with bleomycin the pattern of changing biochemical composition of the lungs cannot be inferred from the lung volumes or V-P relations.

Administration, Topical↗
PubMed1978

The fate of newly synthesized lung collagen after endotracheal administration of C-proline to hamsters.

The endotracheal administration of 14C-proline to young adult golden hamsters was effective in radiolabeling collagen and resulted in a greater specific activity for hydroxyproline than did intraperitoneal administration of the amino acid. The isolation of purified isoluble collagen was accomplished with the aid of pancreatic elastase. Enzyme treatment of lung homogenates resulted in the solubilization of 35 per cent of total lung collagen. The residue obtained after elastase treatment was pure collagen. A significant portion of the radiolabeled collagen was solubilized by the elastase treatment, which suggests that elastase may be helpful in distinguishing between newly synthesized and total lung collagen. Studies performed at various times after administration of 14C-proline indicate that a greater portion of the collagen radioactivity is solubilized during the early days after treatment with the amino acid. The methodology and procedures outlined in this communication allow for additional insights into the metabolism of connective tissue, specifically collagen, in normal and diseased lungs.

Animals↗
PubMedDate not supplied

Amelioration of bleomycin-induced pulmonary injury by cyclosporin A.

This study evaluated the effect of cyclosporin-A (CyA), a potent immunosuppressive drug, on Bleomycin (Bleo)-induced pulmonary inflammation in hamsters. Pulmonary injury was induced by a single intratracheal (i.t.) instillation of Bleo. Four groups of 10 male Syrian hamsters each received one of four treatments: (1) i.t. Bleo and daily intraperitoneal (i.p.) injections of CyA starting 1 day before i.t. instillation of Bleo (Bleo-CyA); (2) i.t. Bleo and i.p. injections of saline (Bleo-Sal); (3) i.t. saline and i.p. CyA (Sal-CyA); (4) i.t. saline and i.p. saline (Sal-Sal). Animals were sacrificed 14 days after i.t. treatment. Lung injury was evaluated histologically, biochemically, and by analysis of bronchoalveolar lavage (BAL) fluid. Treatment of hamsters with CyA significantly ameliorated the Bleo-induced lung injury, as determined by a semiquantitative morphological index that assesses the severity and extent of the injury on a scale of 0-3. Lung hydroxyproline measurements were lower in Bleo-CyA compared to Bleo-Sal, comparable to Sal-Sal and Sal-CyA controls. The percentage of neutrophils, eosinophils, and lymphocytes in BAL fluid was higher in Bleo-Sal and Bleo-CyA animals when compared with control Sal-CyA or Sal-Sal animals. A further increase in percentage of eosinophils was observed in Bleo-CyA compared with Bleo-Sal animals (13.3 +/- 6.6% [mean +/- SE] and 3.7 +/- 2.1%, respectively, p = .0007). BAL fluid protein content was higher in Bleo-Sal compared to Sal-Sal animals, but BAL fluid protein content from Bleo-CyA was not significantly different from that of Bleo-Sal animals. These results indicate that CyA ameliorates the Bleo-induced inflammation but does not prevent leakage of plasma protein or cells into the airspaces. The increased eosinophil numbers in Bleo-CyA-treated hamsters suggests enhanced production of interleukin-4 and -5.

Animals↗
PubMedDate not supplied

Regulation of type I collagen mRNA translation by TGF-beta.

We found that TGF-beta caused a sustained increase in type I collagen production up to 48 hr after addition to human lung fibroblast cultures. Northern analysis demonstrated that although TGF-beta increased alpha 1(I) mRNA levels 4-fold at 24 hr and 3-4-fold at 48 hr after addition to cultures, there were minimal or no effects on alpha 2(I) mRNA levels at these time points. In vitro translation of RNA derived from TGF-beta-stimulated cells yielded a 2-3-fold increase in the amount of alpha 2(I) peptide when compared with the in vitro translation of RNA from unstimulated cells. Taken together, these studies showed that TGF-beta increased the translatability of the alpha 2(I) transcript. To examine whether increased translatability of the alpha 2(I) transcript resulted from structural changes in the 5' and 3' untranslated regions, primer extension and S1 nuclease protection assays were employed. These studies demonstrated no gross structural changes in the untranslated regions of the alpha 2(I) transcript induced by TGF-beta-stimulation. Overall, our results suggest the presence of a TGF-beta-regulatable factor which controls translation of type I collagen mRNAs.

Cell Line↗