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Publications (2)14.15 Total impact

  • Daniel Abraha · Seong H Cho · Devendra K Agrawal · Jae M Park · Chad K Oh ·
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    ABSTRACT: Racemic formoterol is an equimolar mixture of (R,R)- and (S,S)-formoterol. Several studies have shown (S,S)-formoterol to have proinflammatory effects. We previously reported that (S)-albuterol increased the secretion of histamine and interleukin (IL)-4 in murine mast cells. We thus hypothesized that (S,S)-formoterol promotes asthma by enhancing IL-4 production in mast cells of the asthmatic airway. Murine and human mast cells were stimulated by high affinity IgE receptor (Fc epsilon RI) cross-linking or with phorbol myristate acetate/calcium ionophore A23187 (PMA/A23187). Jurkat T cells were stimulated with PMA. Cells were pretreated with either (R,R)- or (S,S)-formoterol. Ovalbumin (OVA)-sensitized BALB/c mice were pretreated with (R,R)- or (S,S)-formoterol before each intranasal OVA challenge for 10 days. Bronchoalveolar lavage fluid was obtained from the mice. The levels of IL-4, histamine and PGD(2) were measured. Early and late allergic responses (EAR and LAR, respectively) to OVA challenge and airway hyperresponsiveness (AHR) were measured. (S,S)-formoterol enhanced the production of IL-4, histamine, and PGD(2) in mast cells, whereas (R,R)-formoterol had no effect. Neither (S,S)- nor (R,R)-formoterol had effect on IL-4 production in Jurkat T cells. In OVA-challenged mice, (S,S)-formoterol increased IL-4 secretion, whereas (R,R)-formoterol had no effect. Finally, (S,S)-formoterol enhanced the inflammatory changes in the peribronchial and perivascular areas without affecting EAR, LAR or AHR, whereas (R,R)-formoterol reduced EAR, LAR and AHR as well as cellular infiltration in the lung tissue of these mice. (S,S)-formoterol may exert adverse effects in asthma control by activating mast cells to produce proinflammatory mediators such as IL-4.
    International Archives of Allergy and Immunology 05/2004; 133(4):380-8. DOI:10.1159/000077358 · 2.67 Impact Factor
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    ABSTRACT: Asthma represents a chronic inflammatory process of the airways. The plasminogen activator inhibitor I gene (PAI1) has an essential role in promoting fibrosis after inflammation. The tissue-type, plasminogen activator and urokinase-type plasminogen activator convert plasminogen to plasmin, which enhances proteolytic degradation of the extracellular matrix (ECM). Among the inhibitors of plasminogen activators, PAI-I is the most important in the process of lunar fibrosis(1) PAI-1-overexpressing mice underwent severe lung injury and deposition of ECM after bleomycin challenge, whereas PAI-1-deficient mice were protected against such fibrotic reactions.(2) these reactions.2 These findings show that PAI-1 is closely associated with fibrosis and the accumulation of ECM after lung injury or inflammation. We previously reported that the PAT1 gene is induced in lung mast cells in asthmatic subjects.(3) These findings suggest that PAI-1 could contribute to tissue remodeling and subsequent fibrosis in asthma. The PAI1 gene has variation in the promoter region on the basis. of a single guanosine insertion-deletion (5G or 4G);(4,5) and the *4G allele, is, correlated with increased plasma PAI-1 levels.(5,6) In vitro experiments have initially shown that the *5G allele contains an additional binding site for a protein likely related to the nuclear factor KB group of transcription factors, and this binding site is absent in the *4G allele.(4) After stimulation with IL-1, HepG2 cells. transfected with the *4G allele produce 6 times more PAI-1 mRNA than these with the *5G allele. These data suggest a functional role of the. 4G/5G polymorphism in the response to cytokines, with the,*4G allele being associated with enhanced gene expression. In the present study we demonstrate that the *4G allele is preferentially transmitted to asthmatic children. These data suggest a possible role of the PAI1 gene and the 4G polymorphism in the pathophysiology of asthma.
    Journal of Allergy and Clinical Immunology 09/2001; 108(2):212-4. DOI:10.1067/mai.2001.117260 · 11.48 Impact Factor