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Biomedical subjects

J Everitt

Publications and source records attributed to J Everitt.

At least 37 records · Page 2Linked to original sources
PubMed1992

Predisposition to renal cell carcinoma due to alteration of a cancer susceptibility gene.

A single germ line gene mutation at a tumor susceptibility locus in a rodent model of hereditary human renal cancer caused a 70-fold increase in susceptibility to chemical carcinogenesis. A carcinogen that targeted both renal epithelial and mesenchymal cells caused an increase in tumors of epithelial origin in susceptible animals; the number of carcinogen-induced mesenchymal tumors was unaffected by the presence of the mutation at the susceptibility locus. Thus, this mutation defines a genetic locus for susceptibility to carcinogen-induced tumors and modulation of carcinogen susceptibility by this locus exhibits cell-type specificity.

Animals↗
PubMed1992

Characterization of platelet-derived growth factor and platelet-derived growth factor receptor expression in asbestos-induced rat mesothelioma.

Although altered expression of platelet-derived growth factor (PDGF) is a hallmark of human mesothelioma, expression of PDGF receptors has not been characterized in this cell type. In addition, the expression of this growth factor and its cognate receptor in rodent mesothelioma has not been investigated. In this study, examination of transformed mesothelial cells derived from asbestos-induced rat mesotheliomas revealed that these cells expressed high affinity PDGF receptors (Kd = 0.5 nM) and receptor number was 1.6 x 10(5)/cell. Western analysis using antibodies specific for either the alpha-type or beta-type PDGF receptor and Northern analysis using probes specific for alpha- and beta-type receptor RNA transcripts indicated that these cells expressed beta-type PDGF receptors but that alpha-type receptors could not be detected. However, when the mesothelioma-derived cells were examined for the expression of PDGF, no expression of this growth factor could be detected. The transformed cells expressed no detectable A- or B-chain PDGF RNA transcripts; and using a competitive enzyme immunoassay specific for isoforms containing the B chain of PDGF and a sandwich enzyme-linked immunosorbent assay specific for A-chain-containing isoforms, neither AA, nor AB, nor BB isoforms of this growth factor could be detected in medium conditioned by these cells. The absence of alterations in PDGF expression in rat mesothelioma, in contrast to the data for the human disease, suggests that the production of this growth factor by transformed mesothelial cells may be species specific.

Animals↗
PubMed1992

Possible cellular and molecular mechanisms for asbestos carcinogenicity.

Asbestos fibers may exert their carcinogenic effects on mesothelial cells and bronchial epithelial cells by direct and indirect mechanisms. Direct effects can occur following the physical interaction of fibers with target cells or by the generation of free radicals from the fiber surface; indirect effects, following the interaction of fibers with inflammatory cells can result in the production of cellular mediators such as cytokines and various reactive oxygen species. As a result, target cells may be induced to proliferate and/or sustain genetic alterations, which lead to tumor development.

Animals↗
PubMed1992

Tumor necrosis factor mediates experimental pulmonary edema by ICAM-1 and CD18-dependent mechanisms.

(TNF alpha)-induced sequestration of neutrophils (PMN) in lungs and of the resultant PMN-dependent pulmonary edema. Guinea pig lungs perfused with Ringers-albumin were challenged with TNF alpha (1,000 U/ml) for 90 min, followed by addition of fresh perfusate containing 2 x 10(7) human PMN. TNF alpha challenge caused sequestration of PMN in the pulmonary vascular bed as indicated by a threefold increase in lung tissue myeloperoxidase activity (MPO). The activation of the sequestered PMN with phorbol 12-myristate 13-acetate (PMA; 5 x 10(-9) M) produced threefold increases in pulmonary artery (Ppa) and pulmonary capillary hydrostatic (Pcap) pressures, and twofold increases in lung wet-to-dry weight (W/D) ratio and capillary filtration coefficient (Kf,c) over baseline. TNF alpha prestimulation was required for these responses since activation of PMN with PMA in control lungs produced smaller increases in Ppa and Pcap (P less than 0.01) and did not change the W/D and Kf,c. TNF alpha prestimulation also induced the expression of intercellular adhesion molecule (ICAM-1) on pulmonary vascular endothelial cells. Monoclonal antibodies (mAbs) to the neutrophil CD18 integrin (beta-chain of CD11/CD18 complex) (mAb IB4) and to its endothelial cell ligand ICAM-1 (mAb RR1/1) were used to examine the role of PMN adhesion in the TNF alpha-induced responses. Pretreatment of PMN with mAb IB4 prevented PMN uptake and increases in Ppa, Pcap, Kf,c, and W/D ratio. Addition of mAb RR1/1 to the perfusate reduced PMN uptake by 58%, and prevented the increases in Ppa, Pcap, Kf,c, and W/D ratio, as with mAb IB4. The findings indicate that TNF alpha prestimulation of lungs mediates PMN uptake and that this requires the expression of ICAM-1 and its interaction with CD18 integrin on PMN. The activation of PMN sequestered by ICAM-1-dependent mechanism contributes to the development of pulmonary vascular injury and edema.

Animals↗
PubMed1992

Cytogenetic and molecular correlates between rodent and human renal cell carcinoma.

In man, RCC makes up the largest proportion of primary kidney cancers, comprising approximately 85% of renal tumors and accounting for approximately 2% of the cancer deaths each year (Richie and Skinner 1981). As shown in Table 2, there are many similarities between spontaneous rat RCC and human RCC. Therefore, rat RCC and the Eker rat model in particular appear to be well suited to investigations into the mechanisms by which this disease occurs. In addition, animal models such as the Eker rat may also be valuable as human surrogates for developing and testing new approaches for treatment of human renal cancer.

Animals↗
PubMed1991

Design and synthesis of a specific endothelin 1 antagonist: effects on pulmonary vasoconstriction.

The 21-amino acid vasoconstrictor peptide endothelin (Et) contains two disulfide bonds. We investigated the importance of the outer disulfide bond in Et-1 by replacing it with an amide linkage. Bioactivity was assessed in an isolated guinea pig lung preparation (perfused at constant flow with Ringer's solution/0.5% albumin) in which pulmonary artery pressure was monitored. Et-1 produced concentration-dependent pulmonary vasoconstriction at concentrations of 1 x 10(-10) M and higher. [Dpr1, Asp15]Et-1 (where Dpr is diaminopropionic acid), in which the outer disulfide was replaced by an amide bond and the inner disulfide was left intact, showed no agonist activity at 1 x 10(-6) M but 1 x 10(-7) M [Dpr1, Asp15]Et-1 inhibited Et-1-induced pulmonary vasoconstriction: effects of 1 x 10(-10) M 2 x 10(-10) M, and 1 x 10(-9) M Et-1 were inhibited by 98%, 75%, and 65%, respectively. Furthermore, this analog did not alter pulmonary vasoconstriction induced by thrombin, norepinephrine, or, most significantly, Et-3. A monocyclic Et-1 analog with the same sequence but in which the amide bond was not formed showed weak pulmonary vasoconstrictor activity (300-500 times less potent than Et-1) but had no antagonist activity. In addition, both the monocyclic control peptide and [Dpr1, Asp15]Et-1 competed effectively with 125I-labeled Et-1 for binding to cultured rat pulmonary artery smooth muscle cells. Thus, an Et-1 structural analog produced by replacement of the outer disulfide bond with an amide linkage displayed potent and specific Et-1 antagonism.

Amino Acid Sequence↗
PubMed1991

Hereditary renal cell carcinoma in the rat associated with nonrandom loss of chromosomes 5 and 6.

A spontaneous form of renal cell carcinoma occurs in rats that arises as the result of the inheritance of a mutation in a single autosomal gene. Cytogenetic analysis was performed on seven cell lines and four primary tumor cell preparations derived from this hereditary form of renal cell carcinoma. Banded karyotypes prepared from these seven lines exhibited loss and/or partial deletion of both chromosomes 5 and 6. Translocations involving chromosome 4, resulting in a net loss of genetic material located near the centromere (4q11), were observed in three of the cell lines. Monosomy, translocation, and breakage of chromosome 5 involving band 5q31 and monosomy and partial deletion of chromosome 6 involving band 6q22-q24 were independently observed in primary tumor cells from three of four tumors examined. Monosomy of chromosome 4 was observed in cells from a single tumor. The smallest region of deletion of chromosome 6 common to all the cell lines and tumor cells was 6q24, suggesting the presence of a tumor suppressor gene at this locus. These results indicate that loss of genes located on chromosomes 4, 5, and 6, possibly tumor suppressor gene(s), may be important for tumor development and/or progression in rat renal cell carcinoma and is consistent with the hypothesis that a gene locus on one of these chromosomes may be the site of the original predisposing mutation.

Animals↗
PubMed1991

Trisomy of rat chromosome 1 associated with mesothelial cell transformation.

Identification of specific chromosomal aberrations in transformed mesothelial cells is an important step in elucidating the mechanism of transformation of these cells which are targets for occupational and environmental carcinogens, such as asbestos fibers. Cytogenetic analysis of normal rat mesothelial cell lines revealed that at late passage (p20-p34), trisomy of chromosome 1 was present in greater than 80% of the cells in four spontaneously immortalized lines examined, whereas at early passage (p8-p10), only 15-44% of the cells had trisomy 1. Trisomy of chromosome 1 had increased in the population as a function of passage, suggesting that cells with trisomy 1 had a selective growth advantage under in vitro culture conditions and that this alteration was associated with transformation. A commercially available rat mesothelial cell line (4/4 RM4, ATCC), was also found to have a duplication of a portion of the long arm of chromosome 1. To determine if chromosome 1 alterations have relevance to the transformed phenotype in vivo, a neoplastic cell line was established from a spontaneous rat mesothelioma. At passage 15, trisomy of chromosome 1 was observed in 26% of the metaphases in this line. However, when these cells were injected into nude mice, 99% of the cells from the resulting tumor contained an additional copy of chromosome 1. Therefore, trisomy 1 also conferred a selective growth advantage in vivo and/or was associated with the malignant subpopulation in the tumor derived cell line. These studies suggest that chromosome 1 contains a gene(s) involved in transformation of rat mesothelial cells.

Animals↗
PubMed1991

Altered expression of transforming growth factor-alpha in hereditary rat renal cell carcinoma.

A hereditary form of renal cell carcinoma exists in rats that results from a single gene mutation and is histologically similar to that described in humans. Cell lines derived from these rat tumors were shown to express abundant transforming growth factor-alpha (TGF-alpha) and epidermal growth factor (EGF)-receptor RNA transcripts, but no EGF mRNA. In contrast, normal kidney expressed EGF and EGF-receptor transcripts, but TGF-alpha transcripts were barely detectable. Other kidney epithelial cell lines examined (NRK 52E, MDCK, and LLCPK) were negative for expression of both TGF-alpha and EGF transcripts, but expressed EGF receptors. In addition, the renal cell carcinoma-derived lines secreted TGF-alpha into the media. Immunohistochemistry of normal kidney with a TGF-alpha specific antibody revealed a characteristic pattern of staining of collecting ducts and, to a lesser degree, proximal tubules. In the neoplastic kidney tissue, both the cystic and solid portions of the tumors displayed intense immunoreactivity, indicating that altered expression of this growth factor by the transformed cells occurred in situ. These results suggest that altered TGF-alpha expression is an important aspect of the neoplastic phenotype in rodent as well as human renal cell carcinoma, and support the use of this hereditary rodent tumor model for studying the pathogenesis of this disease.

Animals↗
PubMed1990

Expression of growth factor and growth factor receptor RNA in rat pleural mesothelial cells in culture.

Mineral fiber-induced pleural mesothelioma in the rat is a suitable model for asbestos-induced mesothelioma in humans. A proposed mechanism for the genesis of mesotheliomas is the initiation of an autocrine pathway leading to unregulated growth of the mesothelium. To understand if changes in the expression of mRNA of critical growth factors and receptors occur in target mesothelial cells, it is first necessary to characterize the pattern of expression of these genes in normal mesothelial cells. Rat mesothelial cells were isolated from the parietal pleura and strains of these cells were propagated in vitro. The cells were diploid, had epithelial gross morphology and ultrastructure, and coexpressed keratins and vimentin. Northern blot analysis demonstrated that the cells expressed transforming growth factor beta 1 and fibroblast growth factor. Transcripts for transforming growth factor alpha, platelet-derived growth factor A-chain, and platelet-derived growth factor B-chain were not detected. Receptors for platelet-derived growth factor, epidermal growth factor, and insulin were detected. Although normal mesothelial cells express receptors for these growth factors, no production of their corresponding ligands by these cells could be detected, suggesting that autocrine stimulation of growth via the production of such factors may be specific to transformed mesothelial cells.

Animals↗
PubMed1989

IL-2 induces pulmonary edema and vasoconstriction independent of circulating lymphocytes.

We investigated the effect of IL-2 in the isolated guinea pig lung perfused with phosphate-buffered Ringer's solution (containing 0.5 g/100 ml albumin and 5.5 mM dextrose) to determine the mechanism of IL-2-induced pulmonary edema. IL-2 (0 to 10,000 U/ml) was added to the perfusate following a 10 min baseline steady-state period. Pulmonary arterial pressure (Ppa), pulmonary capillary pressure (Ppc), and change in lung weight (as a measure of developing pulmonary edema) were recorded at 0, 10, 30, 40, and 60 min. The capillary filtration coefficient (Kf.c), an index of vascular permeability to water, was measured at 30 and 60 min. Infusion of IL-2 increased Ppc (from 3.9 +/- 0.1 cm H2O at baseline to 8.8 +/- 1.1 cm H2O at 60 min for IL-2 at 2000 U/ml, p less than 0.01; and from 3.8 +/- 0.1 cm H2O at baseline to 8.9 +/- 0.6 cm H2O at 60 min for IL-2 at 10,000 U/ml, p less than 0.01. The lung weight also increased (32% at IL-2 concentration of 2000 U/ml, and 26% at IL-2 concentration of 10,000 U/ml) The capillary filtration coefficient did not change with IL-2 infusion. The IL-2 response was prevented using the pulmonary vasodilator, papaverine. The infusion of IL-2 was associated with the generation of thromboxane A2(TxA2) in the effluent perfusate. Inhibition of TxA2 synthetase using Dazoxiben prevented the pulmonary vasoconstriction and edema response to IL-2. In addition, IL-2 had no effect on the transendothelial clearance of 125I-albumin. The results indicate that IL-2 causes pulmonary edema secondary to an increase in Ppc. The response is mediated by IL-2 stimulation of TxA2 generation from the lung.

Animals↗
PubMed1984

Cardiopulmonary effects of unilateral airway pressure changes in intact infant lambs.

Direct effects of airway pressure changes on the pulmonary vascular bed of the intact infant lamb were studied under chloralose anesthesia using a preparation developed to permit independent ventilation of right and left lungs and independent measurement of right and left lung blood flow. A specially designed endobronchial tube eliminated the need for thoracotomy the day of study. Unilateral changes in positive end-expiratory pressure (PEEP) during volume-regulated ventilation increased ipsilateral but not contralateral airway pressure, confirming adequate separation of right and left lungs and suggesting rigidity of the mediastinum. Such interventions ( UPEEP ) at levels of 5, 10, and 15 cmH2O reduced ipsilateral but not contralateral pulmonary blood flow (by 10, 25, and 46%, respectively) but did not alter end-tidal PCO2 of either lung. UPEEP had less effect on cardiac output, stroke volume, right atrial, left atrial, esophageal, and pulmonary arterial pressures than did PEEP applied to both lungs. Because this preparation separates the predominantly direct effects of UPEEP on the ipsilateral lung from its indirect effects on the contralateral lung, it is well suited to studies of direct pulmonary vascular effects of airway pressure changes in an intact closed-chest preparation with reactive pulmonary vasculature.

Airway Resistance↗
PubMed1978

Mianserin--an analysis of its peripheral autonomic actions.

The autonomic profile of mianserin has been compared with that of yohimbine, phentolamine, phenoxybenzamine and desmethylimipramine. The effects of mianserin on tyramine and noradrenaline pressor responses in the pithed rat were consistent with alpha-adrenoceptor antagonist and uptake blocking properties. In isolated tissue experiments, the selectivity of mianserin for pre- and postsynaptic alpha-adrenoceptors was similar to that of phentolamine. In pitched rats mianserin antagonised the pressor response produced by clonidine and reversed the inhibitory actions of clonidine on cardiac nerve stimulation. In contrast mianserin only caused slight reversal of the inhibitory effects of clonidine on hypogastric nerve stimulation. Uptake blockade itself inhibits hypogastric nerve stimulation and this could counteract any antagonism of the effects of clonidine at the presynaptic alpha-adrenoceptor. The results demonstrate the uptake blocking properties of mianserin and its antagonism at both pre- and postsynaptic alpha-adrenoceptors.

Adrenergic alpha-Antagonists↗
PubMed1978

Comparison of plasma hormone changes using a "conventional" and a "paper" pill formulation of a low-dose oral contraceptive.

Two formulations of a low-dose oral contraceptive (Microgynon: 150 microgram of levonorgestrel [NG] +30 micrograms of ethynylestradiol [EE2]) were studied. The first was the "conventional" pill; the second was a "paper" pill prepared by evaporation of aliquots of a solution of the component steroids onto squares of edible cellulose separated by perforations, similar to a sheet of postage stamps. The effects of the two formulations on plasma levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), 17beta-estradiol (E2), and progesterone were compared. Samples of blood were obtained from five women during a treatment period on the "conventional" pill and from five on the "paper" pill. When possible, blood samples were also obtained from a "control" cycle of each of these female subjects. Plasma LH, FSH, E2, and progesterone levels were determined by specific radioimmunoassay methods during control and treatment periods and NG and EE2 levels during treatment periods. Eight-hour plasma profiles for NG and EE2 at the beginning and in the later stage of the treatment periods were obtained and these samples were also analyzed for LH, FSH, E2, and progesterone. Results showed that with one exceptcrogynon were equally effective in suppressing ovulation. As in a previous study, FSH levels appeared to be one of the most sensitive indices of suppression.

Adult↗