J Peake

University of California, Davis, Davis, California, United States

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Publications (24)138.76 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Infants exposed to second hand smoke (SHS) experience more problems with wheezing. This study was designed to determine if perinatal SHS exposure increases intrinsic and/or in vivo airway responsiveness to methacholine and whether potential structural/cellular alterations in the airway might explain the change in responsiveness. Pregnant rhesus monkeys were exposed to filtered air (FA) or SHS (1 mg/m3 total suspended particulates) for 6 h/day, 5 days/week starting at 50 days gestational age. The mother/infant pairs continued the SHS exposures postnatally. At 3 months of age each infant: 1) had in vivo lung function measurements in response to inhaled methacholine, or 2) the right accessory lobe filled with agarose, precision-cut to 600 μm slices, and bathed in increasing concentrations of methacholine. The lumenal area of the central airway was determined using videomicrometry followed by fixation and histology with morphometry. In vivo tests showed that perinatal SHS increases baseline respiratory rate and decreases responsiveness to methacholine. Perinatal SHS did not alter intrinsic airway responsiveness in the bronchi. However in respiratory bronchioles, SHS exposure increased airway responsiveness at lower methacholine concentrations but decreased it at higher concentrations. Perinatal SHS did not change eosinophil profiles, epithelial volume, smooth muscle volume, or mucin volume. However it did increase the number of alveolar attachments in bronchi and respiratory bronchioles. In general, as mucin increased, airway responsiveness decreased. We conclude that perinatal SHS exposure alters in vivo and intrinsic airway responsiveness, and alveolar attachments.
    Toxicology and Applied Pharmacology 01/2009; · 3.98 Impact Factor
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    ABSTRACT: Epidemiologic studies associate environmental tobacco smoke (ETS) exposure with childhood asthma. To investigate whether specific pathophysiological alterations that contribute to asthma development in human beings can be induced in infant monkeys after perinatal ETS exposure. Rhesus macaque fetuses/infants were exposed to ETS at 1 mg/m(3) of total suspended particulate matter from 50 days gestational age to 2.5 months postnatal age. Inflammatory and neural responses to ETS exposure were measured in the infant monkeys. Perinatal ETS exposure could induce systemic and local responses, which include significant elevation of plasma levels of C5a and brain-derived neurotrophic factor, as well as significant increases in pulmonary expression of proinflammatory cytokine TNF-alpha and T(H)2 cytokine IL-5, chemokine monocyte chemoattractant protein 1, and the density of substance P-positive nerves along the bronchial epithelium. Perinatal ETS exposure also significantly increased the numbers of mast cells, eosinophils, monocytes, and lymphocytes in the lungs of infant monkeys. In addition, ex vivo measurements showed significantly increased levels of IL-4 and brain-derived neurotrophic factor in the culture supernatant of PBMCs. Interestingly, as an important component of cigarette smoke, LPS was detected in the plasma of infant monkeys subjected to perinatal exposure to ETS. In contrast, an inhibitory effect of perinatal ETS exposure was also observed, which is associated with decreased phagocytic activity of alveolar macrophages and a significantly decreased level of nerve growth factor in the bronchoalveolar lavage fluid. Perinatal ETS exposure can induce a T(H)2-biased inflammatory response and alter airway innervation in infant monkeys.
    The Journal of allergy and clinical immunology 07/2008; 122(3):640-7.e1. · 12.05 Impact Factor
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    ABSTRACT: Inhaled corticosteroids (ICS) are recommended to treat infants with asthma, some with intermittent asthma. We previously showed that exposing infant monkeys to allergen/ozone resulted in asthma-like characteristics of their airways. We evaluated the effects of ICS on histology and intrinsic responsiveness of allergen/ozone-exposed and normal infant primate airways. Infant monkeys were exposed by inhalation to (1) filtered air and saline, (2) house dust mite allergen (HDMA)+ozone and saline, (3) filtered air and ICS (budesonide) or (4) HDMA+ozone and ICS. Allergen/ozone exposures started at 1 month and ICS at 3 months of age. At 6 months of age, methacholine-induced changes in luminal area of airways in proximal and distal lung slices were determined using videomicrometry, followed by histology of the same slices. Proximal airway responsiveness was increased by allergen/ozone and by ICS. Eosinophil profiles were increased by allergen/ozone in both proximal and distal airways, an effect that was decreased by ICS in distal airways. In both allergen/ozone- and air-exposed monkeys, ICS increased the number of alveolar attachments in distal airways, decreased mucin in proximal airways and decreased epithelial volume in both airways. ICS increased smooth muscle in air-exposed animals while decreasing it in allergen/ozone-exposed animals in both airways. In proximal airways, there was a small but significant positive correlation between smooth muscle and airway responsiveness, as well as between alveolar attachments and responsiveness. ICS change morphology and function in normal airways as well as allergen/ozone-exposed airways, suggesting that they should be reserved for infants with active symptoms.
    Toxicology and Applied Pharmacology 02/2008; 226(2):153-60. · 3.98 Impact Factor
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    ABSTRACT: Both allergen and ozone exposure increase asthma symptoms and airway responsiveness in children. Little is known about how these inhalants may differentially modify airway responsiveness in large proximal as compared to small distal airways. We evaluated whether bronchi and respiratory bronchioles from infant monkeys exposed episodically to allergen and/or ozone differentially develop intrinsic hyperresponsiveness to methacholine and whether eosinophils and/or pulmonary neuroendocrine cells play a role. Infant monkeys were exposed episodically for 5 months to: (1) filtered air, (2) aerosolized house dust mite allergen, (3) ozone 0.5 ppm, or (4) house dust mite allergen + ozone. Studying the function/structure relationship of the same lung slices, we evaluated methacholine airway responsiveness and histology of bronchi and respiratory bronchioles. In bronchi, intrinsic responsiveness was increased by allergen exposure, an effect reduced by bombesin antagonist. In respiratory bronchioles, intrinsic airway responsiveness was increased by allergen + ozone exposure. Eosinophils were increased by allergen and allergen + ozone exposure in bronchi and by allergen exposure in respiratory bronchioles. In both airways, exposure to allergen + ozone resulted in fewer tissue eosinophils than did allergen exposure alone. In bronchi, but not in respiratory bronchioles, the number of eosinophils and neuroendocrine cells correlated with airway responsiveness. We conclude that episodically exposing infant monkeys to house dust mite allergen with or without ozone increased intrinsic airway responsiveness to methacholine in bronchi differently than in respiratory bronchioles. In bronchi, eosinophils and neuroendocrine cells may play a role in the development of airway hyperresponsiveness.
    Toxicology and Applied Pharmacology 09/2006; 214(3):237-43. · 3.98 Impact Factor
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    ABSTRACT: This study was performed to determine the effects of environmental tobacco smoke (ETS) on nitric oxide (NO) and immunoglobulin (Ig) production in a murine model of allergic bronchopulmonary aspergillosis (ABPA). Adult BALB/c mice were exposed to aged and diluted sidestream cigarette smoke from day 0 through day 43 to simulate "second-hand smoke". During exposure, mice were sensitized to soluble Aspergillus fumigatus (Af) antigen intranasally between day 14 and 24. All Af sensitized mice in ambient air (Af + AIR) made elevated levels of IgE, IgG1, IgM, IgG2a and IgA. Af sensitized mice housed in ETS (Af + ETS) made similar levels of immunoglobulins except for IgE that was significantly reduced in the serum and bronchoalveolar lavage (BAL). However, immunohistochemical evaluation of the lung revealed a marked accumulation of IgE positive cells in the lung parenchyma of these Af + ETS mice. LPS stimulation of BAL cells revealed elevated levels of NO in the Af + AIR group, which was further enhanced in the Af + ETS group. In vitro restimulation of the BAL cells on day 45 showed a THO response with elevated levels of IL3, 4, 5, 10 and IFN-gamma. However, by day 28 the response shifted such that TH2 cytokines increased while IFN-gamma decreased. The Af + ETS group showed markedly reduced levels in all cytokines tested, including the inflammatory cytokine IL6, when compared to the Af + AIR group. These results demonstrate that ETS affects ABPA by further enhancing the NO production and reduces the TH2 and the inflammatory cytokines while altering the pattern of IgE responses.
    Clinical and Developmental Immunology 07/2005; 12(2):113-24. · 3.06 Impact Factor
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    ABSTRACT: Particulate matter (PM) has been associated with a variety of negative health outcomes in children involving the respiratory system and early development. However, the precise mechanisms to explain how exposure to airborne particles may cause adverse effects in children are unknown. To study their influence on early postnatal development, a simple, laminar diffusion flame was used to generate an aerosol of soot and iron particles in the size range of 10 to 50 nm. Exposure of 10-day-old rat pups to soot and iron particles was for 6 h/day for 3 days. The lungs were examined following a single injection of bromodeoxyuridine (BrdU) 2 h prior to necropsy. Neonatal rats exposed to these particles demonstrated no effect on the rate of cell proliferation within terminal bronchioles or the general lung parenchyma. In contrast, within those regions arising immediately beyond the terminal bronchioles (defined as the proximal alveolar region), the rate of cell proliferation was significantly reduced compared with filtered air controls. These findings strongly suggest exposure to airborne particles during early neonatal life has significant direct effects on lung growth by altering cell division within critical sites of the respiratory tract during periods of rapid postnatal development. Such effects may result in altered growth in the respiratory system that may be associated with lifelong consequences.
    Inhalation Toxicology 02/2004; 16 Suppl 1:73-81. · 1.89 Impact Factor
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    ABSTRACT: Involuntary inhalation of tobacco smoke has been shown to aggravate the allergic response. Antibodies to fungal antigens such as Aspergillus fumigatus (Af) cause an allergic lung disease in humans. This study was carried out to determine the effect of environmental tobacco smoke (ETS) on a murine model of allergic bronchopulmonary aspergillosis (ABPA). BALB/c mice were exposed to aged and diluted sidestream cigarette smoke to simulate 'second-hand smoke'. The concentration was consistent with that achieved in enclosed public areas or households where multiple people smoke. During exposure, mice were sensitized to Af antigen intranasally. Mice that were sensitized to Af antigen and exposed to ETS developed significantly greater airway hyperreactivity than did mice similarly sensitized to Af but housed in ambient air. The effective concentration of aerosolized acetylcholine needed to double pulmonary flow resistance was significantly lower in Af + ETS mice compared to the Af + AIR mice. Immunological data that supports this exacerbation of airway hyperresponsiveness being mediated by an enhanced type 1 hypersensitivity response include: eosinophilia in peripheral blood and lung sections. All Af sensitized mice produced elevated levels of IL4, IL5 and IL10 but no IFN-gamma indicating a polarized Th2 response. Thus, ETS can cause exacerbation of asthma in ABPA as demonstrated by functional airway hyperresponsiveness and elevated levels of blood eosinophilia.
    Clinical and Developmental Immunology 04/2003; 10(1):35-42. · 3.06 Impact Factor
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    ABSTRACT: Exposure to environmental tobacco smoke (ETS) has been shown to increase allergic sensitization and reactivity and there has been some suggestion that the influence of ETS on the allergic response is dissimilar in males and females. It is to be determined whether gender differences exist in the IgE response to ovalbumin (OVA) sensitization following ETS exposure from the neonatal period through adulthood. To address this thesis, we examined gender differences in OVA sensitization of BALB/c mice housed from birth through adulthood under smoking and nonsmoking conditions. At 6 weeks of age (day 0) all mice were injected i.p. with OVA in aluminum hydroxide adjuvant followed by three 20 min exposures to 1% aerosolized OVA between day 14 and 80. There were significantly (p < 0.05) more total and OVA specific IgE and IgG1 in the serum of females compared to males. Moreover, these sex responses, along with eosinophilia, were further enhanced in mice exposed to ETS. There were also significantly more IgE positive cells in the lungs of female, but not male, mice exposed to ETS compared with ambient air (p < 0.05). There was also an elevation of Th2 cytokines (IL4, IL5, IL10, and IL13) after re-stimulation of lung homogenates following ETS exposure. These data demonstrate that female animals are significantly more susceptible than males to the influence of ETS on the allergic response.
    Developmental Immunology 04/2002; 9(1):47-54.
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    ABSTRACT: To determine whether human X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome (IPEX; MIM 304930) is the genetic equivalent of the scurfy (sf) mouse, we sequenced the human ortholog (FOXP3) of the gene mutated in scurfy mice (Foxp3), in IPEX patients. We found four non-polymorphic mutations. Each mutation affects the forkhead/winged-helix domain of the scurfin protein, indicating that the mutations may disrupt critical DNA interactions.
    Nature Genetics 02/2001; 27(1):18-20. · 35.21 Impact Factor
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    ABSTRACT: The role of a lysosome fraction from rabbit type II cells in surfactant dipalmitoylphosphatidylcholine (DPPC) catabolism was investigated in vivo using radiolabeled DPPC and dihexadecylphosphatidylcholine (1, 2-dihexadecyl-sn-glycero-3-phosphocholine; DEPC), a phospholipase A(1)- and A(2)-resistant analog of DPPC. Freshly isolated type II cells were gently disrupted by shearing, and lysosomes were isolated with Percoll density gradients (density range 1.0591-1.1457 g/ml). The lysosome fractions were relatively free of contaminating organelles as determined by electron microscopy and organelle marker enzymes. After intratracheal injection of rabbits with [(3)H]DPPC and [(14)C]DEPC associated with a trace amount of natural rabbit surfactant, the degradation-resistant DEPC accumulated 16-fold compared with DPPC in lysosome fractions at 15 h. Lysosomes can be isolated from freshly isolated type II cells, and lysosomes from type II cells are the primary catabolic organelle for alveolar surfactant DPPC following reuptake by type II cells in vivo.
    AJP Lung Cellular and Molecular Physiology 02/2000; 278(1):L68-74. · 3.52 Impact Factor
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    ABSTRACT: Whole-mount airway preparations isolated from the lungs of mice treated by intraperitoneal injection of naphthalene and allowed to recover for 5 days were examined for the distribution and abundance of solitary pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) along the main axial pathway of the right middle lobe. Sham mice treated with corn oil vehicle were examined in a similar manner. An antibody to calcitonin gene-related peptide, a neuroendocrine cell marker, was used to identify the location, size, and number of PNECs and NEBs in the airways. After naphthalene treatment and epithelial repair, NEBs were significantly increased along the walls of the airways as well as on branch point ridges. The surface area covered by NEBs composed of 20 or fewer PNECs was significantly enlarged after naphthalene treatment compared with control NEBs of an equivalent cell number. The PNEC number per square millimeter was also increased more than threefold above control values after naphthalene treatment. These findings provide further support for a key role of neuroendocrine cells in the reparative process of airway epithelial cell renewal after injury.
    American Journal Of Pathology 02/2000; 156(1):279-86. · 4.60 Impact Factor
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    ABSTRACT: Severe immunodeficiency characterized by lymphopenia was found in two siblings, one of whom was examined in detail. The calcium flux, pattern of tyrosine phosphorylation of proteins, and interleukin 2 (IL-2) production and proliferation in response to mitogens suggested that the peripheral blood T cells activated normally. The peripheral blood T cells were shown to have an activated phenotype with increased expression of CD45RO+ and CD95/Fas. Increased spontaneous apoptosis occurred in unstimulated lymphocyte cultures. The elevated apoptosis was not due to alterations in expression or to mutations in Bcl-2, Bcl-X(L), or Flip, nor could the spontaneous apoptosis be prevented by blocking Fas, suggesting that it was independent of Fas signaling. This is the first inherited combined immunodeficiency associated with impaired lymphocyte survival. Fibroblasts derived from the patient showed appreciable radiosensitivity in clonal assays, but apoptosis was not elevated. Our results show that the fibroblasts represent a new radiosensitive phenotype not associated with cell cycle checkpoint defects, V(D)J recombination defects, or elevated chromosome breakage. We suggest that the affected gene plays a role in an undetermined damage response mechanism that results in elevated spontaneous apoptosis in lymphoid cells and radiosensitivity in fibroblasts.
    Cancer Research 08/1999; 59(14):3454-60. · 8.65 Impact Factor
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    ABSTRACT: Exposing rats to aged and diluted sidestream cigarette smoke (ADSS) throughout in utero and postnatal life results in airway hyperresponsiveness and an increase in pulmonary neuroendocrine cells (PNECs) and neuroepithelial bodies (NEBs) in 7- to 10-week-old rats. Since human epidemiologic studies suggest that perinatal exposure to environmental tobacco smoke (ETS) may be detrimental to the lung function of older children, this study was designed to determine if perinatal exposure alone results in airway hyperresponsiveness and increased PNECs/NEBs later in life in rats. Pregnant Sprague-Dawley rats were exposed to filtered air (FA, n = 7) or ADSS (1 mg/m3 total suspended particulates, n = 7) for 4 to 6 h/day starting on Day 3 of gestation. Their pups continued to receive the same exposure regimen postnatally until 21 days of age. Thereafter all pups were exposed to FA until about 8 weeks of age. The airway responsiveness of one female pup from each litter was then assessed using an isolated perfused lung system whereby increasing doses of methacholine (-9.25 to -7.50 log mol) were administered into the pulmonary artery and lung resistance (Rl), dynamic compliance (Cdyn), and pulmonary pressure (Ppa) were measured. The number of PNECs/NEBs and mast cells per millimeter basal lamina were determined using immunocytochemical and histological staining and morphometric analysis. Statistics were performed using an unpaired Student's t test and repeated measures analysis of variance. Perinatal ADSS exposure enhanced methacholine-induced changes in Rl (p = 0.02), Cdyn (p = 0.004), and Ppa (p = 0.007). At the highest dose of methacholine, Rl in the ADSS-exposed lungs was threefold that in FA-exposed lungs. Although total PNEC number increased approximately twofold in the ADSS-exposed animals, this change was not found to be statistically significant. Mast cell number also was not different between groups. These data suggest that exposure to ADSS during the perinatal period followed by 5 weeks exposure to FA induces airway hyperresponsiveness in the absence of a significant change in PNECs, NEBs, or mast cells.
    Toxicology and Applied Pharmacology 04/1999; 155(3):253-60. · 3.98 Impact Factor
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    ABSTRACT: Osteopetrosis has been described in mice generated by homozygous gene disruption of c-src gene encoding for the p60c-Src protein tyrosine kinase (Src-/- mice). The similarities of bone histologic findings in this murine model to those observed in some patients first seen with autosomal recessive osteopetrosis, "malignant" osteopetrosis, led us to investigate the potential role of p60c-Src in the pathogenesis of malignant osteopetrosis in 13 children. In 4 patients a c-src mutation was ruled out by an intragenic microsatellite segregation study. In the other 9 we analyzed p60c-Src expression and function, as well as c-src sequence. The expression was normal in all of the patients tested. In addition, the tyrosine phosphorylation and kinase activity of p60c-Src were also normal in all of the patients. Moreover, in these patients, sequences of the coding region of c-src were identical to the published sequence of the human c-src complementary DNA. These results exclude a role for c-src in the pathogenesis of human malignant osteopetrosis in the 13 patients analyzed.
    Journal of Pediatrics 11/1998; 133(4):537-43. · 4.04 Impact Factor
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    ABSTRACT: We have previously shown that CD4 ligands inhibit interleukin-2 (IL-2) production and T cell proliferation in human peripheral CD4+ T lymphocytes, in an MHC-independent way. Two major pathways implicated in T cell activation are inhibited by binding of CD4 ligands to the CD4 molecule, i.e. Ca2+ signaling by phospholipase Cgamma1 (PLCgamma1), and ERK-2 activation, suggesting a p21ras inhibition. We have correlated these inhibitions with the disruption of multifunctional complexes containing PLCgamma1, p120GAP and Sam68, induced by T cell activation. We report here that T cell activation through the TCR/CD3 induces an association of the phosphoinositide 3 kinase (PI3 kinase) with PLCgamma1, both in peripheral CD4+ T lymphocytes and the HUT-78 CD4+ T cell line. PI3 kinase is present in the multifunctional complexes that we have described previously. Preincubation of human peripheral CD4+ T cells and HUT-78 CD4+ T cells with gp160 or a peptide analogue of the HLA class II DR molecule precludes the association of PLCgamma1 with PI3 kinase. We also demonstrate, using two specific inhibitors of PI3 kinase activity (LY294002 and wortmannin), that this activity plays a key role in the association of PLCgamma1 with PI3 kinase. Moreover, we demonstrate the implication of the PI3 kinase activity in the negative signal mediated by HIV gp160 binding to CD4 molecules. We propose that the products of the PI3 kinase are important mediators of the negative signaling induced by the binding of CD4 ligands to the CD4 molecule implicated in the regulation of the formation of multifunctional complexes.
    European Journal of Immunology 11/1998; 28(10):3183-91. · 4.97 Impact Factor
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    ABSTRACT: Prenatal glucocorticoid plus T4 treatment of fetal sheep results in improvements in oxygenation, gas exchange, lung mechanics, and lung volumes after preterm delivery. We have evaluated the morphometric changes in the lungs of lambs exposed to betamethasone and T4 48 h before preterm delivery at 121 and 135 d gestation and related those changes to the physiologic improvements in lung function. The lungs used for the morphometric studies were from lambs with postnatal physiologic responses similar to those of the entire group of lambs reported previously (16). At both 121 and 135 d gestation, lung gas volumes and fixed tissue volumes increased, the percent of collapsed (nonaerated) parenchyma decreased, and the percent of perilobular connective tissue decreased with both gestational age and prenatal hormone exposure. Alveolar size, as estimated by mean linear intercept length, did not change with gestation or hormone exposure, but there was a decrease in alveolar wall thickness with advancing gestation and at each gestation with hormone exposure. The major anatomic effect of prenatal hormone exposure was a decrease in alveolar wall thickness and an increase in aerated parenchyma, effects that were consistent with the physiologic improvements in postnatal lung function.
    American Journal of Respiratory and Critical Care Medicine 09/1997; 156(2 Pt 1):624-30. · 11.04 Impact Factor
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    ABSTRACT: Administration of a single i.p. dose of 115 microg/kg of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) to homozygous and heterozygous c-src deficient mice (i.e. c-src -/- and -/+ mice) and their wild-type littermates (c-src +/+ mice) induced differential toxic responses. In c-src +/+ mice, there were clear-cut signs of the toxicity of TCDD, such as the loss of weight in the body, thymus and adipose tissue, whereas in c-src -/+ mice these effects were modest and were not statistically significant. Yet, hepatomegaly, a characteristic effect of TCDD, took place in all three strains of mice. Histological examination of liver samples from control mice and from mice treated with TCDD for 10 days showed that there are qualitative differences in the expression of the effects of TCDD between control and treated mice as well as between c-src -/+ and +/+ mice. In the case of c-src +/+ mice, the predominant lesions were lipid accumulation, glycogen depletion, edema formation and necrosis, as shown by the presence of large areas of ballooning degeneration, and cellular influx of fluid. These changes were demonstrated only marginally in c-src -/+ mice. The predominant effect in -/+ mice was edema formation. At a high dose of TCDD (345 microg/kg), all of the +/+ mice died within 34 days, whereas none of the c-src -/+ mice died. Together these results clearly indicate that some of the toxic effects of TCDD are not fully expressed in c-src deficient mice.
    Biochemical Pharmacology 06/1997; 53(10):1397-404. · 4.58 Impact Factor
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    ABSTRACT: Male strain A/J mice were exposed for 6 h a day, 5 days a week to environmental tobacco smoke (ETS) generated from Kentucky 1R4F reference cigarettes. Chamber concentrations were 87 mg/m3 of total suspended particulate matter (TSP), 246 p.p.m. of CO and 16 mg/m3 of nicotine. After 5 months, 33% of the ETS exposed and 11% of the control animals had one or several lung tumors; the difference was statistically not significant. A second group of animals exposed for 5 months to ETS was allowed to recover for another 4 months in filtered air. When they were killed, 85% of the ETS animals had lung tumors (average number per lung: 1.4 +/- 0.2), whereas in the control group 38% had lung tumors (average number of lung tumors in all animals 0.5 +/- 0.2). The differences in tumor incidence and multiplicity were statistically significant. More than 80% of all tumors were adenomas, the rest adenocarcinomas. When animals were pretreated with a carcinogen, lung tumor multiplicity was lower in the ETS exposed animals after 5 months compared with controls injected with a carcinogen and kept in air. However, after an additional 4 month recovery period in air, lung tumor multiplicities were the same in ETS plus carcinogen exposed mice as in carcinogen-treated air-exposed controls. Histopathologic and morphometric analysis of the lung tissue failed to reveal any differences between ETS exposed and control animals. However, immediately after ETS exposure, immunohistochemistry revealed increased staining for CYP1A1 in airway epithelia and lung parenchyma; following recovery in air, the staining disappeared again. Analysis of cell kinetics showed an initial burst of increased DNA synthesis in the epithelial cells of the airways and a smaller early positive response in the parenchyma. Feeding of butylated hydroxytoluene during ETS exposure did not modulate lung tumor development. It was concluded that ETS is a pulmonary carcinogen in strain A/J mice.
    Carcinogenesis 04/1997; 18(3):575-86. · 5.64 Impact Factor
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    ABSTRACT: Pulmonary neuroendocrine cells (PNECs) are airway epithelial cells that are capable of secreting a variety of neuropeptides. PNECs are scattered throughout the bronchial tree either as individual cells or clusters of cells termed neuroepithelial bodies (NEBs). PNECs and their secretory peptides have been considered to play a role in fetal lung development. Although the normal physiological function of PNECs and neuropeptides in normal adult lungs and in repair from lung injury is not known, PNEC hyperplasia has been associated with chronic lung diseases, such as bronchopulmonary dysplasia, and with chronic exposures, such as hypoxia, tobacco smoke, nitrosamines, and ozone. To evaluate changes in PNEC number and distribution after acute airway injury, FVB/n mice were treated with either naphthalene or vehicle. Naphthalene is an aromatic hydrocarbon that, at the dose used in this study, selectively destroys nonciliated bronchial epithelial cells (Clara cells) through cytochrome P-450-mediated metabolic activation into cytotoxic epoxides. PNECs were identified by immunohistochemical analysis of calcitonin gene-related peptide-like immunoreactivity (CGRP-IR). Proliferating cells were marked with [(3)H]thymidine incorporation. Acute naphthalene toxicity results in PNEC hyperplasia that is detectable after 5 days of recovery. PNEC hyperplasia is characterized by increased numbers of NEBs without significant changes in the number of isolated PNECs and by increased [(3)H]thymidine labeling of CGRP-IR cells. These data show that cell proliferation contributes to PNEC hyperplasia after acute airway injury and suggest that PNECs may be capable of more rapidly increasing their number in response to injury than previously recognized.
    The American journal of physiology 04/1997; 272(3 Pt 1):L486-93. · 3.28 Impact Factor
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    ABSTRACT: The action of deltamethrin, a potent type II synthetic pyrethroid insecticide, on the thymus of the Balb/c mouse was studied in vivo and in vitro. We found that deltamethrin produced atrophy in the thymus in a dose- and time-dependent fashion. The lowest effective dose was found to be 6 mg/kg, 24 hr after a single intraperitoneal treatment. Treated animals did not recover during the time-course of the experiment (365 days after treatment); however, deltamethrin did not affect the body weight of the treated animals during the course of the study. To determine if deltamethrin-induced [Ca2+]i signaling could lead to thymic atrophy via programmed cell death, mice were treated with 25 mg deltamethrin/kg for 24 hr or the isolated thymocyte suspension was treated with 50 microM deltamethrin. A significant stimulation of inositol 1,4,5-triphosphate (IP3) and inositol 1,4-diphosphate (IP2) production was found after 24 hr of deltamethrin-1R (active isomer) treatment. An inactive stereoisomer of deltamethrin (i.e. 1S) did not cause a significant rise in the production of 1P3 and 1P2. In addition, deltamethrin-1R induced a transient increase of [Ca2+]i mobilization in the thymocyte suspension after 10 min of in vitro treatment, and substantially reduced the rate of calcium-calmodulin (Ca/CaM)-dependent protein dephosphorylation in in vivo treated animals (25 mg deltamethrin/kg for 24 hr). The in vivo effects of deltamethrin treatment demonstrated induction of DNA fragmentation and cell death in thymocytes. Moreover, using a histochemical approach, it was evident that deltamethrin at 25 mg/kg was able to produce cell death in the thymus of treated animals 72 hr after treatment. In the present work, we found that cell death was apoptotic in nature as noted first by the inhibition of deltamethrin-induced cell death by aurintricarboxylic acid, an inhibitor of apoptosis, and second, by internucleosomal DNA fragmentation, a hallmark of apoptosis, produced by deltamethrin in treated animals as well in thymocyte suspensions. In addition, the involvement of the Ca/CaM-dependent protein phosphorylation-dephosphorylation cascade in the induction of apoptosis by deltamethrin was supported by the protective role of the calmodulin inhibitor trifluoperazine against the apoptotic effect of deltamethrin on thymocyte suspension. Our results suggest that deltamethrin induced thymus atrophy and altered the Ca/CaM-dependent protein kinase-phosphatase cascade, which might induce programmed cell death.
    Biochemical Pharmacology 03/1996; 51(4):447-54. · 4.58 Impact Factor

Publication Stats

1k Citations
138.76 Total Impact Points

Institutions

  • 1994–2009
    • University of California, Davis
      • • Center for Health and the Environment (CHE)
      • • Department of Pediatrics
      • • Department of Pathology, Microbiology and Immunology (VM)
      • • Department of Anatomy, Physiology and Cell Biology (VM)
      • • Center for Comparative Medicine
      • • School of Medicine
      • • Department of Cell Biology and Human Anatomy
      Davis, California, United States
  • 1999
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France