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  • 1
    Online Resource
    Online Resource
    Maternal allergen exposure reprograms the developmental lung transcriptome in atopic and normoresponsive rat pups
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 303, No. 10 ( 2012-11-15), p. L899-L911
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 303, No. 10 ( 2012-11-15), p. L899-L911
    Abstract: The “fetal origins hypothesis” argued that physiological changes consequent to in utero exposures ultimately contribute to disease susceptibility in later life. The dramatic increase in asthma prevalence is attributed to early exposures acting on preexisting asthma-susceptible genotypes. We showed previously that distinct transcriptome signatures distinguish the developmental respiratory phenotype of atopic (Brown Norway, BN) and normoresponsive (Lewis) rats. We aimed to determine whether maternal allergen exposure would influence asthma pathogenesis by reprogramming primary patterns of developmental lung gene expression. Postnatal offspring of dams sensitized to ovalbumin before mating and challenged during pregnancy were assessed for lung function, inflammatory biomarkers, and respiratory gene expression. Although maternal ovalbumin exposure resulted in characteristic features of an allergic response (bronchoalveolar lavage neutrophils, IgE, methacholine-induced lung resistance) in offspring of both strains, substantial strain-specific differences were observed in respiratory gene expression. Of 799 probes representing the top 5% of transcriptomic variation, only 112 (14%) were affected in both strains. Strain-specific gene signatures also exhibited marked differences in enrichment for gene ontologies, with immune regulation and cell proliferation being prominent in the BN strain, cell cycle and microtubule assembly gene sets in the Lewis strain. Multiple ovalbumin-specific probes in both strains were also differentially expressed in lymphoblastoid cell lines from human asthmatic vs. nonasthmatic sibling pairs. Our data point to the existence of distinct, genetically programmed responses to maternal exposures in developing lung. These different response patterns, if recapitulated in human fetal development, can contribute to long-term pulmonary health including interindividual susceptibility to asthma.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00179.2012
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
    detail.hit.zdb_id: 1477300-4
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  • 2
    Online Resource
    Online Resource
    Genomics and proteomics of lung disease: conference summary
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 293, No. 1 ( 2007-07), p. L45-L51
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 293, No. 1 ( 2007-07), p. L45-L51
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00139.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477300-4
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  • 3
    Online Resource
    Online Resource
    Patterns of wave break during ventricular fibrillation in isolated swine right ventricle
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 281, No. 1 ( 2001-07-01), p. H253-H265
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 281, No. 1 ( 2001-07-01), p. H253-H265
    Abstract: Several different patterns of wave break have been described by mapping of the tissue surface during fibrillation. However, it is not clear whether these surface patterns are caused by multiple distinct mechanisms or by a single mechanism. To determine the mechanism by which wave breaks are generated during ventricular fibrillation, we conducted optical mapping studies and single cell transmembrane potential recording in six isolated swine right ventricles (RV). Among 763 episodes of wave break (0.75 times · s −1 · cm −2 ), optical maps showed three patterns: 80% due to a wave front encountering the refractory wave back of another wave, 11.5% due to wave fronts passing perpendicular to each other, and 8.5% due to a new (target) wave arising just beyond the refractory tail of a previous wave. Computer simulations of scroll waves in three-dimensional tissue showed that these surface patterns could be attributed to two fundamental mechanisms: head-tail interactions and filament break. We conclude that during sustained ventricular fibrillation in swine RV, surface patterns of wave break are produced by two fundamental mechanisms: head-tail interaction between waves and filament break.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.2001.281.1.H253
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477308-9
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  • 4
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    Online Resource
    Anisotropic conduction block and reentry in neonatal rat ventricular myocyte monolayers
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 300, No. 1 ( 2011-01), p. H271-H278
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 300, No. 1 ( 2011-01), p. H271-H278
    Abstract: Anisotropy can lead to unidirectional conduction block that initiates reentry. We analyzed the mechanisms in patterned anisotropic neonatal rat ventricular myocyte monolayers. Voltage and intracellular Ca (Ca i ) were optically mapped under the following conditions: extrastimulus (S1S2) testing and/or tetrodotoxin (TTX) to suppress Na current availability; heptanol to reduce gap junction conductance; and incremental rapid pacing. In anisotropic monolayers paced at 2 Hz, conduction velocity (CV) was faster longitudinally than transversely, with an anisotropy ratio [AR = CV L /CV T , where CV L and CV T are CV in the longitudinal and transverse directions, respectively], averaging 2.1 ± 0.8. Interventions decreasing Na current availability, such as S1S2 pacing and TTX, slowed CV L and CV T proportionately, without changing the AR. Conduction block preferentially occurred longitudinal to fiber direction, commonly initiating reentry. Interventions that decreased gap junction conductance, such as heptanol, decreased CV T more than CV L , increasing the AR and causing preferential transverse conduction block and reentry. Rapid pacing resembled the latter, increasing the AR and promoting transverse conduction block and reentry, which was prevented by the Ca i chelator 1,2-bis oaminophenoxy ethane- N, N, N′, N′-tetraacetic acid (BAPTA). In contrast to isotropic and uniformly anisotropic monolayers, in which reentrant rotors drifted and self-terminated, bidirectional anisotropy (i.e., an abrupt change in fiber direction exceeding 45°) caused reentry to anchor near the zone of fiber direction change in 77% of monolayers. In anisotropic monolayers, unidirectional conduction block initiating reentry can occur longitudinal or transverse to fiber direction, depending on whether the experimental intervention reduces Na current availability or decreases gap junction conductance, agreeing with theoretical predictions.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00758.2009
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477308-9
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  • 5
    Online Resource
    Online Resource
    RUNX transcription factors: association with pediatric asthma and modulated by maternal smoking
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 301, No. 5 ( 2011-11), p. L693-L701
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 301, No. 5 ( 2011-11), p. L693-L701
    Abstract: Intrauterine smoke exposure (IUS) is a strong risk factor for development of airways responsiveness and asthma in childhood. Runt-related transcription factors (RUNX1–3) have critical roles in immune system development and function. We hypothesized that genetic variations in RUNX1 would be associated with airway responsiveness in asthmatic children and that this association would be modified by IUS. Family-based association testing analysis in the Childhood Asthma Management Program genome-wide genotype data showed that 17 of 100 RUNX1 single-nucleotide polymorphisms (SNPs) were significantly ( P 〈 0.03–0.04) associated with methacholine responsiveness. The association between methacholine responsiveness and one of the SNPs was significantly modified by a history of IUS exposure. Quantitative PCR analysis of immature human lung tissue with and without IUS suggested that IUS increased RUNX1 expression at the pseudoglandular stage of lung development. We examined these associations by subjecting murine neonatal lung tissue with and without IUS to quantitative PCR ( N = 4–14 per group). Our murine model showed that IUS decreased RUNX expression at postnatal days (P)3 and P5 ( P 〈 0.05). We conclude that 1) SNPs in RUNX1 are associated with airway responsiveness in asthmatic children and these associations are modified by IUS exposure, 2) IUS tended to increase the expression of RUNX1 in early human development, and 3) a murine IUS model showed that the effects of developmental cigarette smoke exposure persisted for at least 2 wk after birth. We speculate that IUS exposure-altered expression of RUNX transcription factors increases the risk of asthma in children with IUS exposure.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00348.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
    detail.hit.zdb_id: 1477300-4
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  • 6
    Online Resource
    Online Resource
    Short-term cardiac memory and mother rotor fibrillation
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 292, No. 1 ( 2007-01), p. H180-H189
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 292, No. 1 ( 2007-01), p. H180-H189
    Abstract: Short-term cardiac memory refers to the effects of pacing history on action potential duration (APD). Although the ionic mechanisms for short-term memory occurring over many heartbeats (also called APD accommodation) are poorly understood, they may have important effects on reentry and fibrillation. To explore this issue, we incorporated a generic memory current into the Phase I Luo and Rudy action potential model, which lacks short-term memory. The properties of this current were matched to simulate quantitatively human ventricular monophasic action potential accommodation. We show that, theoretically, short-term memory can resolve the paradox of how mother rotor fibrillation is initiated in heterogeneous tissue by physiological pacing. In simulated heterogeneous two-dimensional tissue and three-dimensional ventricles containing an inward rectifier K + current gradient, short-term memory could spontaneously convert multiple wavelet fibrillation to mother rotor fibrillation or to a mixture of both fibrillation types. This was due to progressive acceleration and stabilization of rotors as accumulation of memory shortened APD and flattened APD restitution slope nonuniformly throughout the tissue.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00944.2005
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
    detail.hit.zdb_id: 1477308-9
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  • 7
    Online Resource
    Online Resource
    Intracellular Ca dynamics in ventricular fibrillation
    American Physiological Society ; 2004
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 286, No. 5 ( 2004-05), p. H1836-H1844
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 286, No. 5 ( 2004-05), p. H1836-H1844
    Abstract: In the heart, membrane voltage ( V m ) and intracellular Ca (Ca i ) are bidirectionally coupled, so that ionic membrane currents regulate Ca i cycling and Ca i affects ionic currents regulating action potential duration (APD). Although Ca i reliably and consistently tracks V m at normal heart rates, it is possible that at very rapid rates, sarcoplasmic reticulum Ca i cycling may exhibit intrinsic dynamics. Non-voltage-gated Ca i release might cause local alternations in APD and refractoriness that influence wavebreak during ventricular fibrillation (VF). In this study, we tested this hypothesis by examining the extent to which Ca i is associated with V m during VF. Ca i transients were mapped optically in isolated arterially perfused swine right ventricles using the fluorescent dye rhod 2 AM while intracellular membrane potential was simultaneously recorded either locally with a microelectrode (5 preparations) or globally with the voltage-sensitive dye RH-237 (5 preparations). Mutual information (MI) is a quantitative statistical measure of the extent to which knowledge of one variable ( V m ) predicts the value of a second variable (Ca i ). MI was high during pacing and ventricular tachycardia (VT; 1.13 ± 0.21 and 1.69 ± 0.18, respectively) but fell dramatically during VF (0.28 ± 0.06, P 〈 0.001). Ca i at sites 4–6 mm apart also showed decreased MI during VF (0.63 ± 0.13) compared with pacing (1.59 ± 0.34, P 〈 0.001) or VT (2.05 ± 0.67, P 〈 0.001). Spatially, Ca i waves usually bore no relationship to membrane depolarization waves during nonreentrant fractionated waves typical of VF, whereas they tracked each other closely during pacing and VT. The dominant frequencies of V m and Ca i signals analyzed by fast Fourier transform were similar during VT but differed significantly during VF. Ca i is closely associated with V m closely during pacing and VT but not during VF. These findings suggest that during VF, non-voltage-gated Ca i release events occur and may influence wavebreak by altering V m and APD locally.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00123.2003
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2004
    detail.hit.zdb_id: 1477308-9
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  • 8
    Online Resource
    Online Resource
    Variable-length poly-C tract polymorphisms of the β 2 -adrenergic receptor 3′-UTR alter expression and agonist regulation
    American Physiological Society ; 2008
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 294, No. 2 ( 2008-02), p. L190-L195
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 294, No. 2 ( 2008-02), p. L190-L195
    Abstract: β 2 -Adrenergic receptors (β 2 -AR) expressed on airway epithelial and smooth muscle cells regulate mucociliary clearance and relaxation and are the targets for β-agonists in the treatment of obstructive lung disease. However, the clinical responses display extensive interindividual variability, which is not adequately explained by genetic variability in the 5′-flanking or coding region of the intronless β 2 -AR gene. The nonsynonymous coding polymorphism most often associated with a bronchodilator phenotype (Arg16) is found within three haplotypes that differ by the number of Cs (11, 12, or 13) within a 3′-untranslated region (UTR) poly-C tract. To examine potential effects of this variability on receptor expression, BEAS-2B cells were transfected with constructs containing the β 2 -AR (Arg16) coding sequence followed by its 3′-UTR with the various polymorphic poly-C tracts. β 2 Arg16-11C had 25% lower mRNA expression and 33% lower β 2 -AR protein expression compared with the other two haplotypes. Consistent with this lower steady-state expression, β 2 Arg16-11C mRNA displayed more rapid and extensive degradation after actinomycin D treatment compared with β 2 Arg16-12C and -13C. However, β 2 Arg16-12C underwent 50% less downregulation of receptor expression during β-agonist exposure compared with the other two haplotypes. Thus these haplotypes direct a potential low-response phenotype due to decreased steady-state receptor expression combined with wild-type agonist-promoted downregulation (β 2 Arg16-11C) and a high-response phenotype due to increased baseline expression combined with decreased agonist-promoted downregulation (β 2 Arg16-12C). This heterogeneity may contribute to the variability of clinical responses to β-agonist, and genotyping to identify these 3′-UTR polymorphisms may improve predictive power within the context of β 2 -AR haplotypes in pharmacogenetic studies.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00277.2007
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2008
    detail.hit.zdb_id: 1477300-4
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  • 9
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    Online Resource
    Exhaled breath condensate identifies metabolic dysregulation in patients with radiation-induced lung injury
    American Physiological Society ; 2023
    In:  American Journal of Physiology-Lung Cellular and Molecular Physiology Vol. 324, No. 6 ( 2023-06-01), p. L863-L869
    Details
    In: American Journal of Physiology-Lung Cellular and Molecular Physiology, American Physiological Society, Vol. 324, No. 6 ( 2023-06-01), p. L863-L869
    Abstract: Radiation-induced lung injury (RILI) is a consequence of therapeutic thoracic irradiation (TR) for many cancers, and there are no FDA-approved curative strategies. Studies report that 80% of patients who undergo TR will have CT-detectable interstitial lung abnormalities, and strategies to limit the risk of RILI may make radiotherapy less effective at treating cancer. Our lab and others have reported that lung tissue from patients with idiopathic pulmonary fibrosis (IPF) exhibits metabolic defects including increased glycolysis and lactate production. In this pilot study, we hypothesized that patients with radiation-induced lung damage will exhibit distinct changes in lung metabolism that may be associated with the incidence of fibrosis. Using liquid chromatography/tandem mass spectrometry to identify metabolic compounds, we analyzed exhaled breath condensate (EBC) in subjects with CT-confirmed lung lesions after TR for lung cancer, compared with healthy subjects, smokers, and cancer patients who had not yet received TR. The lung metabolomic profile of the irradiated group was significantly different from the three nonirradiated control groups, highlighted by increased levels of lactate. Pathway enrichment analysis revealed that EBC from the case patients exhibited concurrent alterations in lipid, amino acid, and carbohydrate energy metabolism associated with the energy-producing tricarboxylic acid (TCA) cycle. Radiation-induced glycolysis and diversion of lactate to the extracellular space suggests that pyruvate, a precursor metabolite, converts to lactate rather than acetyl-CoA, which contributes to the TCA cycle. This TCA cycle deficiency may be compensated by these alternate energy sources to meet the metabolic demands of chronic wound repair. Using an “omics” approach to probe lung disease in a noninvasive manner could inform future mechanistic investigations and the development of novel therapeutic targets. NEW & NOTEWORTHY We report that exhaled breath condensate (EBC) identifies cellular metabolic dysregulation in patients with radiation-induced lung injury. In this pilot study, untargeted metabolomics revealed a striking metabolic signature in EBC from patients with radiation-induced lung fibrosis compared to patients with lung cancer, at-risk smokers, and healthy volunteers. Patients with radiation-induced fibrosis exhibit specific changes in tricarboxylic acid (TCA) cycle energy metabolism that may be required to support the increased energy demands of fibroproliferation.
    Type of Medium: Online Resource
    ISSN: 1040-0605 , 1522-1504
    URL: Article
    DOI: 10.1152/ajplung.00439.2022
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1477300-4
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