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Biomedical subjects

Edward S Chen

Publications and source records attributed to Edward S Chen.

8 recordsLinked to original sources

Expression profiling in granulomatous lung disease.

Granulomatous lung diseases, such as sarcoidosis, hypersensitivity pneumonitis, Wegener's granulomatosis, and chronic beryllium disease, along with granulomatous diseases of known infectious etiologies, such as tuberculosis, are major causes of morbidity and mortality throughout the world. Clinical manifestations of these diseases are highly heterogeneous, and the determinants of disease susceptibility and clinical course (e.g., resolution vs. chronic, progressive fibrosis) are largely unknown. The underlying pathogenic mechanisms of these diseases also remain poorly understood. Within this context, these diseases have been approached using genomic and proteomic technologies to allow us to identify patterns of gene/protein expression that track with clinical disease or to identify new pathways involved in disease pathogenesis. The results from these initial studies highlight the potential for these "-omics" approaches to reveal novel insights into the pathogenesis of granulomatous lung disease and provide new tools to improve diagnosis, clinical classification, course prediction, and response to therapy. Realizing this potential will require collaboration among multidisciplinary groups with expertise in the respective technologies, bioinformatics, and clinical medicine for these complex diseases.

Gene Expression Profiling↗

Pluripotent allospecific CD8+ effector T cells traffic to lung in murine obliterative airway disease.

Long-term success in lung transplantation is limited by obliterative bronchiolitis, whereas T cell effector mechanisms in this process remain incompletely understood. Using the mouse heterotopic allogeneic airway transplant model, we studied T cell effector responses during obliterative airways disease (OAD). Allospecific CD8+ IFN-gamma+ T cells were detected in airway allografts, with significant coexpression of TNF-alpha and granzyme B. Therefore, using IFN-gamma as a surrogate marker, we assessed the distribution and kinetics of extragraft allo-specific T cells during OAD. Robust allospecific IFN-gamma was produced by draining the lymph nodes, spleen, and lung mononuclear cells from allograft, but not isograft recipients by Day 14, and significantly decreased by Day 28. Although the majority of allospecific T cells were CD8+, allospecific CD4+ T cells were also detected in these compartments, with each employing distinct allorecognition pathways. An influx of pluripotent CD8+ effector cells with a memory phenotype were detected in the lung during OAD similar to those seen in the allografts and secondary lymphoid tissue. Antibody depletion of CD8+ T cells markedly reduced airway lumen obliteration and fibrosis at Day 28. Together, these data demonstrate that allospecific CD8+ effector T cells play an important role in OAD and traffic to the lung after heterotopic airway transplant, suggesting that the lung is an important immunologic site, and perhaps a reservoir, for effector cells during the rejection process.

Animals↗

ACAT1 deletion in murine macrophages associated with cytotoxicity and decreased expression of collagen type 3A1.

In contrast to some published studies of murine macrophages, we previously showed that ACAT inhibitors appeared to be anti-atherogenic in primary human macrophages in that they decreased foam cell formation without inducing cytotoxicity. Herein, we examined foam cell formation and cytotoxicity in murine ACAT1 knockout (KO) macrophages in an attempt to resolve the discrepancies. Elicited peritoneal macrophages from normal C57BL6 and ACAT1 KO mice were incubated with DMEM containing acetylated LDL (acLDL, 100 microg protein/ml) for 48h. Cells became cholesterol enriched and there were no differences in the total cholesterol mass. Esterified cholesterol mass was lower in ACAT1 KO foam cells compared to normal macrophages (p<0.04). Cytotoxicity, as measured by the cellular release of [(14)C]adenine from macrophages, was approximately 2-fold greater in ACAT1 KO macrophages as compared to normal macrophages (p<0.0001), and this was independent of cholesterol enrichment. cDNA microarray analysis showed that ACAT1 KO macrophages expressed substantially less collagen type 3A1 (26-fold), which was confirmed by RT-PCR. Total collagen content was also significantly reduced (57%) in lung homogenates isolated from ACAT1 KO mice (p<0.02). Thus, ACAT1 KO macrophages show biochemical changes consistent with increased cytotoxicity and also a novel association with decreased expression of collagen type 3A1.

Acetyl-CoA C-Acetyltransferase↗

Mycobacterial catalase-peroxidase is a tissue antigen and target of the adaptive immune response in systemic sarcoidosis.

Sarcoidosis is a disease of unknown etiology characterized by noncaseating epithelioid granulomas, oligoclonal CD4(+) T cell infiltrates, and immune complex formation. To identify pathogenic antigens relevant to immune-mediated granulomatous inflammation in sarcoidosis, we used a limited proteomics approach to detect tissue antigens that were poorly soluble in neutral detergent and resistant to protease digestion, consistent with the known biochemical properties of granuloma-inducing sarcoidosis tissue extracts. Tissue antigens with these characteristics were detected with immunoglobulin (Ig)G or F(ab')(2) fragments from the sera of sarcoidosis patients in 9 of 12 (75%) sarcoidosis tissues (150-160, 80, or 60-64 kD) but only 3 of 22 (14%) control tissues (all 62-64 kD; P = 0.0006). Matrix-assisted laser desorption/ionization time of flight mass spectrometry identified Mycobacterium tuberculosis catalase-peroxidase (mKatG) as one of these tissue antigens. Protein immunoblotting using anti-mKatG monoclonal antibodies independently confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues but in none of 14 control tissues (P = 0.0037). IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 (48%) sarcoidosis patients compared with 0 of 11 (0%) purified protein derivative (PPD)(-) (P = 0.0059) and 4 of 10 (40%) PPD(+) (P = 0.7233) control subjects, suggesting that remnant mycobacterial catalase-peroxidase is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.

Antigens, Bacterial↗

Electron attachment to C(2)Cl(4) and Trojan horse ionization.

In a recent study of tetrachloroethylene, the anion yield curves were analyzed using three published negative-ion Morse potentials. Unexpected ions at zero electron energy were explained by the "Trojan horse" mechanism. This communication also attributes formation of Cl(2)(-) at higher energies to a Trojan horse mechanism. Six new Morse potentials are calculated to account for the observed anion states. These combine all extant electron impact and attachment data. The electron affinity of the C(2)Cl(3) radical, 3.1(1) eV, and the C-Cl bond dissociation energy 4.0(1) eV are reported.

Letter↗

Electron-capture detector and multiple negative ions of aromatic hydrocarbons.

Multiple electron affinities are identified in the temperature dependence of the electron-capture detector: naphthalene, 0.16, 0.13+/-0.01, anthracene, 0.69, 0.60, 0 53+/-0.01; tetracene 1.1, 0.88+/-0.03, 0.53+/-0.05; pyrene, 0.61, 0.50+/-0.02; azulene 0.90, 0.80, 0.70+/-0.02, 0.65, 0.55+/-0.05; acenaphthylene, 0.80, 0.69, 0.60, 0.50+/-0.05; and c-C8H8, 0.80, 0.70, 0.55+/-0.02; (all in eV). These are obtained from a rigorous least squares procedure incorporating literature values and uncertainties. The adiabatic electron affinities for about 40 hydrocarbons listed in the US National Institute of Standards and Technology (NIST) tables are evaluated. The adiabatic electron affinity values not listed in NIST are biphenylene, 0.45+/-0.05 eV and coronene. 0.8+/-0.05 eV. Morse potential energy curves in the C-H dimensions illustrate multiple states for benzene and naphthalene.

Chromatography, Gas↗

What causes sarcoidosis?

Limited but encouraging progress has been made over the last several years in our understanding of the etiology of sarcoidosis as a result of recent investments in epidemiologic, immunologic, and molecular biologic studies. A recent US multicenter study of sarcoidosis found few environmental or occupational exposures associated with a two-fold or higher risk of development of sarcoidosis, suggesting noninfectious exposures play a small, if any, role in causing systemic sarcoidosis. In contrast, recent studies have linked infectious agents including mycobacterial and propionibacterial organisms with sarcoidosis. The association of sarcoidosis with the use of Th1-promoting biologic response modifiers is consistent with a central role for enhanced Th1 immune responses in the pathogenesis of sarcoidosis. Given evidence for a genetic predisposition to sarcoidosis, these findings suggest that the etiology of systemic sarcoidosis is linked to genetically determined enhanced Th1 immune responses to a limited number of microbial pathogens.

Environmental Exposure↗