Biomedical subjects

J W Olson

Publications and source records attributed to J W Olson.

At least 55 records · Page 3Linked to original sources

PubMed1993

Temporal alterations in specific basement membrane components in lungs from monocrotaline-treated rats.

The present study utilized the monocrotaline (MCT) model of pulmonary hypertension in rats to examine temporal alterations in steady-state levels of basement membrane (BM) component mRNA and deposition of protein using Northern analysis and immunohistochemistry, respectively. MCT (60 mg/kg, subcutaneous) produced sustained increases in lung dry tissue mass by 7 days, right ventricular mass by 14 days, and pulmonary arterial pressure by 21 days after administration. mRNA levels specific for laminin (LM) were elevated as early as 1 day after MCT treatment, while mRNA for all BM components examined except type IV collagen were increased in lungs from MCT-treated rats by day 4. Differences in LM, perlecan (PN), and type IV collagen-specific mRNAs from lung tissue between MCT-treated and control rats disappeared by day 14. In contrast, fibronectin (FN) mRNA remained elevated in lung tissue from MCT-treated rats from day 4 onward. Increases in immunolocalizable FN and LM in the vasculature, and PN and type IV collagen in gas exchange areas, were observed 4 days after MCT treatment compared with controls. These changes generally became more pronounced by 21 days after MCT administration, at which time the parenchyma of MCT-treated rats also demonstrated increases in immunolocalizable FN, LM, and BM-chondroitin sulfate proteoglycan (BM-CSPG). The pulmonary vasculature additionally showed increases in type IV collagen, PN, and BM-CSPG in MCT-treated rats compared with controls by 21 days. These observations suggest that the accumulation of specific BM components in the pulmonary vasculature and parenchyma may contribute to the pathogenesis and maintenance of MCT-induced hypertensive pulmonary vascular disease.

Analysis of Variance↗

PubMed1992

Surface lysine and tyrosine residues are required for interaction of the major herpes simplex virus type 1 DNA-binding protein with single-stranded DNA.

Modification of the herpes simplex virus type 1 major DNA-binding protein (ICP8) with reagents and conditions specific for arginine, lysine, and tyrosine residues indicates that surface lysine and tyrosine residues are required for the interaction of this protein with single-stranded DNA. Modification of either of these two amino acids resulted in a loss and/or modification of binding activity as judged by nitrocellulose filter assays and gel shift. Modification specific for arginine residues did not affect binding within the limits of the assays used. Finally, quenching of the intrinsic tryptophan fluorescence of ICP8 in the presence of single-stranded DNA either suggests involvement of this amino acid in the binding reaction or reflects a conformational change in the protein upon binding.

Acetic Anhydrides↗

PubMed1992

Polyamine transport and ornithine decarboxylase activity in hypoxic pulmonary artery smooth muscle cells.

Hypoxia causes remodeling of the pulmonary circulation that is dependent on increases in lungs polyamine contents. Mechanisms by which polyamines are regulated in hypoxic lung cells are unknown, but ornithine decarboxylase (ODC) activity, the initial enzyme in de novo biosynthesis, is depressed and polyamine transport is augmented in lungs from hypoxic rats (R.-T. Shiao et al. 1990. Am. J. Physiol. 259:L351-L358). To determine if hypoxia directly influences polyamine regulatory mechanisms in pulmonary vascular cells, we examined [14C]spermidine (SPD) transport and ODC activity in bovine main pulmonary artery smooth muscle cells (PASMCs) cultured under standard (culture medium Po2: greater than 100 mm Hg), "normoxic" (culture medium Po2: 50 to 70 mm Hg), or "hypoxic" (culture medium Po2: 18 to 30 mm Hg) conditions. Uptake of [14C]SPD in cells cultured under standard conditions was temperature- and concentration-dependent, exhibited saturation kinetics, and was abolished by metabolic inhibition. Modeling of transport according to Michaelis-Menten kinetics revealed that [14C]SPD uptake in cells cultured under standard conditions was characterized by Km and Vmax values of 0.78 microM and 4.5 pmol/min/10(6) cells, respectively. In comparison to cells cultured under standard conditions, Km was unaffected by culture under normoxic or hypoxic conditions while Vmax was increased to 18 pmol/min/10(6) cells in normoxic cells and to 33 pmol/min/10(6) cells in preparations cultured under hypoxic conditions. Inhibition of ODC with alpha-difluoromethylornithine (DFMO) also induced SPD transport, as evidenced by an increase in the Vmax to 65 pmol/min/10(6) cells. Both hypoxia- and DFMO-induced increases in [14C]SPD transport were suppressed by cycloheximide and actinomycin D, thus highlighting the importance of protein and RNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

The major herpes simplex virus type-1 DNA-binding protein is a zinc metalloprotein.

The primary amino acid sequence of the major herpes simplex virus type 1 (HSV-1)-infected cell polypeptide 8 (ICP8) deduced from the DNA sequence of the unique long open reading frame 29 (UL29 ORF) contains a potential metal-binding domain of the form Cys-X2-5-Cys-X2-15-A-X2-4-A where A may be either histidine or cysteine and X is any amino acid. The putative metal-binding sequence in ICP8 encompasses residues 499-512 as follows: C-N-L-C-T-F-D-T-R-H-A-C-V-H-. Atomic absorption analysis of several preparations of ICP8 indicates the presence of 1 mol of zinc/mol of protein. The zinc is resistant to removal by dialysis against concentrations of EDTA which deplete zinc from alcohol dehydrogenase. The bound zinc can be removed by reaction with the reversible sulfhydryl reagent p-hydroxymercurimethylsulfonate and the zinc-depleted protein transiently retains DNA binding activity. Digestion of both native and zinc-depleted ICP8 with V8 protease indicates that the bound zinc is required for the structural integrity of the protein.

Amino Acid Sequence↗

PubMed1991

The development of competence in resting B cells. The induction of cyclic AMP and ornithine decarboxylase activity after direct contact between B and T helper cells.

In the present communication, an experimental approach is utilized that facilitates the study of biochemical processes induced in B cells after their interaction with Th cells. In this approach, Th cell clones are stimulated for 18 h upon anti-CD3-coated plates, fixed with paraformaldehyde, and added at a 2 to 3:1 ratio to small, resting B cells (isolated from Percoll gradients). Th cells not stimulated on anti-CD3-coated plates, but fixed with paraformaldehyde, serve as controls for these experiments. The activated, fixed Th cells induce a transient, sixfold increase in B cell levels of cAMP, as well as an increase in B cell expression of ornithine decarboxylase (ODC) activity. This enzyme initiates the synthesis of polyamines and has been shown to be increased as cells enter the growth phase. In addition, previous studies have shown that the cellular levels of ODC activity are controlled by a multi-tiered regulatory cascade. To examine this aspect, polyclonally stimulated B cells were studied. Such cells demonstrated a gradual increase in ODC mRNA levels that peaked between 6 and 15 h and can be partially explained by a three- to fourfold increase in mRNA stability but not by changes in the enzyme affinity for substrate. The increase in ODC mRNA occurs in the absence of protein synthesis, suggesting that the ODC gene is a member of the immediate/early gene family. Finally, the early increase in ODC mRNA was enhanced in cells in which cAMP levels were artificially elevated, suggesting the possibility that the cAMP-dependent signaling pathway participates during the regulation of this gene expression. The significance of these experimental results concerning the process of B cell activation is discussed.

Animals↗

PubMed1991

Lifetime toxicity/carcinogenicity studies of FD & C red no. 40 (allura red) in mice.

FD & C Red No. 40 (allura red) was fed to Charles River HaM/ICR (CD-1) (study A) and CD-1 outbred (study B) mice as a dietary admixture in two separate lifetime toxicity/carcinogenicity studies. Each study included an in utero exposure phase during which the colouring was fed at dietary concentrations of 0.0, 0.37, 1.39 or 5.19% throughout the mating, gestation and lactation periods. After random selection, the lifetime exposure phase was initiated using the same dietary concentrations with 50 mice/sex/group in study A and 100 mice/sex/group in study B. Exposure was for 104 wk in study A and 109 wk in study B. No compound-related adverse effects were observed. The no-observable-adverse-effect level in these studies was 5.19%; approximately 7300 and 8300 mg/kg body weight/day for male and female mice, respectively.

Administration, Oral↗

PubMed1991

Ventilatory dysfunction precedes pulmonary vascular changes in monocrotaline-treated rats.

Rats with established monocrotaline (MCT)-induced pulmonary hypertension also exhibit a profound increase in lung resistance (RL) and a decrease in lung compliance. Because airway/lung dysfunction could precede and influence the evolution of MCT-induced pulmonary vascular disease, it is important to establish the temporal relationship between development of pulmonary hypertension and altered ventilatory function in MCT-treated rats. To resolve this issue, we segregated 47 young Sprague-Dawley rats into four groups: control (n = 13), MCT1 (n = 9), MCT2 (n = 11), and MCT3 (n = 14). Each MCT rat received a single subcutaneous injection of MCT (60 mg/kg) 1 MCT1), 2 (MCT2), or 3 (MCT3) wk before the functional study. At 1 wk after MCT, significant increases in RL and alveolar wall thickness were observed, as was a significant decrease in carbon monoxide diffusing capacity (DLCO). Medial thickness of pulmonary arteries (50-100 microns OD) and right ventricular hypertrophy were not observed until 2 and 3 wk post-MCT, respectively. Coincident with the right ventricular hypertrophy at 3 wk post-MCT were decreased DLCO and increased alveolar wall thickness and lung dry weight. Pressure-volume curves of air-filled and saline-filled lungs showed marked rightward shifts during the 1st and 2nd wk after MCT administration and then decreased at the 3rd wk. These data suggest that MCT-induced alterations in airway/lung function preceded those of pulmonary vasculature and, therefore, implicate airway/lung dysfunctions as potentially contributing to the later development of pulmonary vascular abnormalities.

Airway Resistance↗

PubMed1991

Polyamines, vascular smooth muscle, and deoxycorticosterone acetate-salt hypertension.

This study was performed to determine if an alteration in vascular polyamine contents is associated with the development of deoxycorticosterone acetate-salt hypertension. The effects of chronic administration of alpha-difluoromethylornithine, a specific irreversible inhibitor of ornithine decarboxylase and thus polyamine biosynthesis, on vascular polyamine contents, structure, and function as well as the development of hypertension was studied. Control and deoxycorticosterone acetate-salt rats received either tap water or a drinking solution containing alpha-difluoromethylornithine for 6 weeks, during which period systolic blood pressures were recorded. Vascular reactivity studies were performed on rings of aorta and tail artery. Medial thickness, vessel weight, and vascular polyamine contents were also assessed in these arteries. alpha-difluoromethylornithine treatment had no significant effect on either systolic blood pressure or vascular structure, function, and polyamine contents of control animals. The elevation in blood pressure and the increase in medial thickness, ring weight, and vascular polyamine contents as well as altered vascular reactivity observed in deoxycorticosterone acetate-salt rats was significantly attenuated by alpha-difluoromethylornithine treatment. These results are the first to demonstrate that vascular polyamine contents are elevated in the deoxycorticosterone acetate-salt rat and that chronic alpha-difluoromethylornithine treatment prevents the rise in vascular polyamines as well as the elevation in blood pressure and attendant changes in the vasculature. Thus, the increase in vascular polyamines may comprise a critical link between the initiating stimuli and the alterations in vascular structure and function implicated in the pathogenesis of deoxycorticosterone acetate-salt hypertension.

Acetylcholine↗

PubMed1990

Mechanisms of lung polyamine accumulation in chronic hypoxic pulmonary hypertension.

Chronic hypoxia causes polyamine-dependent hypertensive pulmonary vascular remodeling (J. E. Atkinson. J. W. Olson, R. J. Altierre, and M. N. Gillespie, J. Appl. Physiol. 62: 1562-1568, 1987), but mechanisms by which lung polyamine contents are elevated have not been established. This study measured polyamine contents, biosynthetic activities, and transport in lungs of rats exposed to hypobaric hypoxia (simulated altitude: 4,570 m) for 4-14 days. Hypoxia increased lung contents of spermidine and spermine within 40 h and of putrescine within 4 days. These changes preceded hypoxia-induced increases in pulmonary arterial pressure and development of right ventricular hypertrophy. Additional experiments determined whether increased lung polyamine contents could be ascribed to elevated activity of ornithine decarboxylase (ODC), the rate-limiting enzyme in conversion of ornithine to putrescine. Lung ODC activity did not differ from controls at 40 h posthypoxia and was reduced below control levels from 4-14 days of exposure. Putrescine transport kinetics were assessed in isolated, salt solution-perfused lungs. Apparent Km for putrescine uptake was increased from 10.4 microM in control lungs to 16.9 microM in lungs from rats maintained for 7 days in an hypoxic environment. Maximal velocity (Vmax) of lung putrescine transport was increased from 1.67 nmol.g-1.min-1 in controls to 2.65 in hypoxic lungs. Putrescine efflux also was altered by hypoxic exposure; T1/2 for loss of diamine from a slowly effluxing pool was increased from 60.6 min in controls to 91.5 min in hypoxic lungs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

A Veterans Administration Cooperative Study of biphasic calcium phosphate ceramic in periodontal osseous defects.

One hundred thirty-seven V.A. patients were randomized to one of three treatment groups to evaluate the efficacy of biphasic calcium phosphate (BCP) ceramic in the treatment of periodontal osseous defects. This material was tested against both autogenous bone implant and open flap curettage procedures. Baseline probing attachment level, Navy plaque index, and gingival index were recorded for all patients. These parameters were monitored for 3 years. At the end of this period, 101 patients had completed the study. Although the plaque and gingival indices steadily increased with time, there were no statistically significant differences among the treatment groups. Patients in the ceramic group had a gain in attachment level of 1.0 mm; those in the curettage group, 0.9 mm; and 0.4 mm for those in the bone implant group. Although the BCP patients had a greater gain, the difference was not statistically significant. In this veteran population, not only did BCP patients fail to outperform those in the control groups, all three treatment groups were similarly ineffective.

Adolescent↗

PubMed1989

Polyamine synthesis blockade in monocrotaline-induced pneumotoxicity.

Based on the documented regulatory role of polyamines in cell growth and differentiation, we have proposed that these organic cations are involved with the development of monocrotaline (MCT)-induced hypertensive pulmonary vascular disease. Two lines of evidence support this hypothesis: (1) MCT causes progressive increases in lung polyamine contents which are temporarily related to the development of cardiopulmonary abnormalities, and (2) blockade of polyamine synthesis with the site-selective enzyme-activated inhibitor, alpha-difluoromethylornithine (DFMO), attenuates development of medial arterial thickening, increased pulmonary arterial pressure, and right ventricular hypertrophy. To evaluate the mechanism of DFMO protection, the present study assessed when, during the course of MCT-induced pneumotoxicity, DFMO exerts its salutary effects, and determined if the protection afforded by DFMO could be reversed through supplementation with exogenous polyamines. To address the first issue, rats were treated with 30 mg/kg MCT and, 10 days after administration when lung polyamine contents were augmented and when pulmonary edema was evident, DFMO treatment was initiated as a 2% solution in the drinking water. In animals receiving MCT only, lung polyamine contents were elevated and right ventricular hypertrophy was evident at both 20 and 35 days after treatment. DFMO treatment initiated at day 10 attenuated the increases in putrescine and spermidine but not spermine and reduced the degree of right ventricular hypertrophy at both the 20- and 35-day time points. To determine if the blockade by DFMO could be reversed by supplementation with exogenous polyamines, animals were treated simultaneously with MCT and DFMO as described above and the immediate precursor to the polyamines, ornithine, was added to the drinking water as a 2% solution. Relative to animals receiving MCT and DFMO, ornithine supplementation increased lung polyamine contents to levels normally associated with MCT treatment only. Ornithine also reversed the protection against right ventricular hypertrophy normally afforded by DFMO. These observations indicate that the salutary effects of DFMO in MCT-induced pulmonary hypertension cannot be ascribed solely to interference in the early events after MCT treatment and that restoration of lung polyamine contents to high levels by supplementation with exogenous ornithine reverses DFMO protection against sustained pulmonary hypertension. It is concluded, therefore, that polyamines play a central role in delayed responses of lung cells underlying the development of MCT-induced sustained pulmonary hypertension.

Animals↗

PubMed1989

Polyamine synthesis in rat lungs injured with alpha-naphthylthiourea.

The diamine, putrescine, and polyamines, spermidine and spermine, are low molecular weight organic cations with documented regulatory roles in cell growth and differentiation. Multiple lines of direct and indirect evidence suggest that these organic cations also may function in stimulus-response coupling processes regulating cellular injury and repair. For example, recent studies in monocrotaline-treated rats, hyperoxic rats, and in cultured pulmonary endothelial cells suggest that polyamines regulate pulmonary endothelial integrity and may thus participate in development and/or regression of acute edematous lung injury. To determine if the polyamines are involved in a well-characterized animal model of acute lung injury, the present experiments assessed the relation between changes in polyamine synthesis and development of edema in lungs from rats treated with alpha-naphthylthiourea (ANTU). ANTU caused dose- and time-dependent increases in the lung activity of the initial and rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC) and in the lung contents of the polyamines putrescine, spermidine, and spermine. ANTU also caused dose- and time-dependent increases in the lung wet-to-dry weight ratio indicative of pulmonary edema formation. Changes in lung polyamine biosyntheic activity after ANTU did not relate temporally to changes in the lung wet-to-dry weight ratio: ODC activity was depressed during the 3-h period immediately following ANTU administration, a period when the wet-to-dry weight ratio was increasing, and markedly elevated at 18 h after ANTU administration when the wet-to-dry weight ratio had returned to control levels. Pretreatment of the animals with alpha-difluoromethylornithine, a highly specific inhibitor of ODC, failed to attenuate ANTU-induced increases in lung wet-to-dry weight ratio. These observations indicate polyamine synthesis is enhanced in rat lungs with ANTU-induced pulmonary edema but, unlike certain other models of lung injury and pulmonary edema, accumulation of polyamines probably is not essential for development of edematous lung injury. It is conceivable that in this animal model polyamines play a role in lung repair processes or some longer-term consequence of lung injury.

Animals↗

PubMed1989

Monokine-induced lung injury in rats: similarities to monocrotaline-induced pneumotoxicity.

Previous studies have shown that abnormal alveolar macrophages and biological activity resembling the macrophage-derived mediator interleukin-1 (IL-1) can be detected in bronchoalveolar lavage fluid from rats with monocrotaline-induced lung injury and pulmonary hypertension. To determine if monokines might play a pathogenic role in this model, the present study evaluated the effects of a murine monokine preparation enriched in IL-1 bioactivity on selected events characterizing the early pneumotoxic response to monocrotaline, including pulmonary edema and protein extravasation, pulmonary vascular hyperreactivity, and enhanced lung tissue activity of the rate-limiting enzyme in polyamine biosynthesis, ornithine decarboxylase (ODC). Intravenous injection of the monokine preparation containing 200 units/kg IL-1 (quantified by lymphocyte activating factor assay) into intact rats produced pulmonary edema within 3 hr manifested by increases in the lung wet-to-dry weight ratio and in the extent of pulmonary albumin extravasation. The edema had resolved within 24 hr of monokine administration as indicated by a return to control levels of the wet-to-dry weight ratio and albumin extravasation index. The monokine preparation also increased the transfer of albumin across monolayers of cultured porcine pulmonary vascular endothelial cells. While salt solution-perfused rat lungs isolated from animals treated 3 hr previously with the monokine preparation were hyporesponsive to angiotensin II, preparations derived from animals treated 24 hr previously were markedly hyperresponsive to the vasoconstrictor actions of the peptide. Pressor responses to potassium chloride and prostaglandin F2a were unaffected by exposure to the monokine preparation. Lung ODC activity in monokine-exposed animals did not differ from control at 3, 6, or 24 hr after treatment. In contrast, a 24-hr exposure of cultured pulmonary vascular endothelial cells to the monokine preparation increased ODC activity approximately 100-fold. These observations indicate that a monokine preparation containing IL-1 bioactivity causes transient pulmonary edema and pulmonary vascular hyperreactivity and increases ODC activity in pulmonary vascular endothelial cells. Because the monokine preparation mimics certain aspects of monocrotaline-induced pneumotoxicity in the rat, it is reasonable to postulate that monokines could play a pathogenic role in this and similar animal models of lung injury and pulmonary hypertension.

Animals↗

PubMed1989

Acetylated polyamines in lungs from rats with monocrotaline-induced pneumotoxicity.

Multiple lines of evidence implicate the polyamines, putrescine, spermidine, and spermine in the lung injury and hypertensive pulmonary vascular disease produced in rats by the pyrrolizidine alkaloid monocrotaline. While increases in lung polyamine content evoked by monocrotaline can be attributed in part to induction of the two rate-limiting enzymes in de novo polyamine synthesis, ornithine decarboxylase and S-adenosylmethionine decarboxylase, little attention has been paid to the role that catabolic interconversion processes might play in lung polyamine accumulation. Accordingly, the present study evaluated dose (10-60 mg/kg)- and time (0-21 days)-dependent effects of monocrotaline on lung contents of acetylated polyamines and on the activity of spermidine/spermine acetyltransferase (SAT), the enzyme affecting spermidine acetylation. A single subcutaneous injection of monocrotaline produced dose- and time-dependent increases in the lung content of N1-acetylspermidine. Neither N1-acetylspermine nor N1-acetylputrescine could be detected in lungs from control rats or from rats treated with monocrotaline. SAT activity also was increased in monocrotaline-treated rat lungs in a dose- and time-dependent manner that was closely related to increases in the lung burden of N1-acetylspermidine. As expected, monocrotaline also caused dose- and time-dependent elevations in the lung contents of the primary polyamines, putrescine, spermidine, and spermine. Right ventricular hypertrophy, an index of sustained pulmonary hypertension, did not develop in animals treated with 10 or 20 mg/kg monocrotaline despite elevations in the lung contents of putrescine and N1-acetylspermidine and increases in the activity of SAT. In contrast, 30 and 60 mg/kg monocrotaline provoked right ventricular hypertrophy accompanied by elevations in the primary polyamines, N1-acetyl spermidine and SAT activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylation↗

PubMed1989

Lifetime toxicity/carcinogenicity study of FD & C Red No. 40 (allura red) in Sprague-Dawley rats.

FD & C Red No. 40 was fed to Charles River CD (Sprague-Dawley) rats as a dietary admixture in a lifetime toxicity/carcinogenicity study. The study included a phase during which the colouring was administered to parental rats (30 of each sex per group) at concentrations of 0.0, 0.37, 1.39 and 5.19%, throughout the mating, gestation and lactation periods. The concurrent control group received the basal diet. After random selection of the first-generation rats, the lifetime phase was initiated using the same dietary concentrations with 50 rats of each sex per group. The maximum durations of exposure to the colouring were 118 and 121 for males and females, respectively. No compound-related adverse effects were observed, except for a reduction in body weight in high-dose females at the end of the study. The no-adverse-effect levels in this study were 5.19% (2829 mg/kg/day) for male rats, and 1.39% (901 mg/kg/day) for female rats.

Animals↗

PubMed1989

Epidermal growth factor augments reactivity to angiotensin II in the rat pulmonary circulation.

To determine if epidermal growth factor (EGF), a vascular smooth muscle mitogen exhibiting systemic vasoactivity, causes constriction or dilation of the pulmonary vascular bed, this study evaluated the actions of EGF in isolated, buffer-perfused rat lungs and in isolated rat pulmonary arteries. In perfused rat lungs with baseline vasomotor tone, EGF administered at bolus doses of 10(-9) to 3 x 10(-7) M failed to exert either constrictor or dilator actions or to promote edema formation as evidenced by a constant lung wet-to-dry-weight ratio. Elevation of baseline tone with either prostaglandin (PG)F2 alpha or angiotensin II also failed to unmask an effect of EGF on pulmonary vascular resistance. In contrast to these negative observations, pretreatment with 5 x 10(-8) M EGF consistently augmented pressor responses evoked by angiotensin II. Constrictor responses to potassium chloride and to PGF2 alpha were unaffected by EGF pretreatment. In isolated rat extrapulmonary arteries, EGF provoked contraction in 40% of the preparations studied. Responsive vessels exhibited maximal EGF-induced contractions that were approximately 25% of that associated with angiotensin II and were characterized by an ED50 of 7 x 10(-8) M. Relaxant activity of EGF could not be demonstrated in isolated arterial preparations with normal resting tone or with tone elevated by addition of norepinephrine to the tissue bath. Endothelial denudation also failed to unmask contractile or relaxant effects of EGF. Similar to its actions in isolated, perfused rat lungs, EGF potentiated contractions of isolated pulmonary arteries induced by angiotensin II.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1989

Polyamines and epidermal growth factor in monocrotaline-induced pulmonary hypertension.

Multiple lines of evidence suggest that the polyamines, a family of low-molecular-weight organic cations with documented regulatory note in cell growth and differentiation, are involved with hyperplastic and hypertrophic responses of lung cells underlying hypertensive pulmonary vascular disease. Little is known, however, of the factor(s) initiating polyamine synthesis in pulmonary hypertension. This study tested the key aspects of the hypothesis that augmented polyamine synthesis, and attendent vascular structural alterations in monocrotaline (MCT)-treated rats can be ascribed to elaboration of an epidermal growth factor (EGF)-like mitogen. In lungs of rats treated 4 days previously with 60 mg/kg, EGF-like immunoreactivity was detected diffusely throughout perivascular regions. Intravenous administration of human recombinant EGF (125 pg/h) to rats for 1 wk was associated with medial thickening in pulmonary arteries between 100 and 200 microns in diameter, significant increases in lung polyamine contents, and a moderate elevation in mean pulmonary arterial pressure. These observations indicate that EGF can be detected in the lungs of MCT-treated rats and that exogenous EGF mimics some of the action of MCT on the rat lung. It is thus reasonable to speculate that an EGF-like mitogen may participate in the response to MCT in part through a polyamine-dependent mechanism.

Animals↗

PubMed1988

Ornithine decarboxylase activity and immunohistochemical location in postischemic brain.

Ornithine decarboxylase, rate-limiting in polyamine formation, has been found to be necessary for the development of vasogenic edema after cryogenic cerebral injury and is postulated to be of importance in late ischemic brain edema formation. Ornithine decarboxylase activity and accompanying edema was studied after transient cerebral ischemia in Mongolian gerbils. Bilateral carotid artery occlusion was utilized to produce dense forebrain ischemia. After 4 h of reperfusion a significant elevation in ornithine decarboxylase activity was present (72.5 +/- 24.7 vs 8.5 +/- 2 pmoles/mg protein/h, p less than 0.05). Immunohistochemical localization of ornithine decarboxylase indicated its presence in cortical neurons of ischemic gerbils. This was typically located in the perinuclear cytoplasm and extended into proximal dendrites. Nonischemic animals did not contain ornithine decarboxylase immunoreactivity. These studies show the presence and location of ornithine decarboxylase in cerebral tissue subjected to transient ischemia. The increase in this marker of polyamine activity paralleled previous studies in this model of cerebral edema formation and reperfusion deficit in blood flow and evoked potential, suggesting that ornithine decarboxylase is a marker for and may be associated with those late metabolic events leading to progressive functional deterioration after incomplete cerebral ischemia.

Animals↗