M. G. Rice, J. R. McRae, D. R. Storm, R. P. Robertson

N2 - Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E 2 (PGE 2) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE 2 synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE 2 axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless ofchallenge number, exhibited no defect in the ability of PGE 2 or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP 2 receptor, which is pivotal for PGE 2 responsiveness. However, cytokine-induced upregulation of PGE 2 biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX- 2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE 2 acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE 2 generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma.

 / Nakanishi, Masako; Perret, Christine; Rosenberg, Daniel W.

It is sold under the trade name of Cervidil (by Forest Laboratories, Inc.), Prostin E2 (by Pfizer Inc.), Propess (by Ferring Pharmaceuticals) and Glandin (by Nabiqasim Pharmaceuticals Pakistan) as a vaginal suppository, to prepare the cervix for labour; it is used to induce labour.


/ Rice, M. G.; McRae, J. R.; Storm, D. R.; Robertson, R. P.

Themost homogeneous sulfide composition is a (Fe,Ni)1 - xS monosulfide with 5 wt % Ni and 1-sigma variations in34S-normalized noble metal count rates of


T2 - Bioorganic and Medicinal Chemistry

AB - Prostaglandin (PG)E 2 is a major cyclooxygenase (COX) product that is important in human physiology and pathophysiology. Quantification of systemic PG production in humans is best assessed by measuring excreted urinary metabolites. Accurate and easy-to-perform assays to quantify the major urinary metabolite of PGE 2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor- prostane-1,20-dioic acid (PGE-M), do not exist. We now report the development of a robust and facile method to measure urinary PGE-M excretion in humans using stable isotope dilution techniques employing liquid chromatography/tandem mass spectrometry (LC/MS/MS). Concentrations of the metabolite in urine from healthy humans are nearly twofold greater in men than in women (10.4 ± 1.5 vs. 6.0 ± 0.7 ng/mg creatinine). Levels of PGE-M in healthy humans are suppressed significantly not only by the nonselective COX inhibitor ibuprofen but also by the COX-2 selective inhibitor rofecoxib, suggesting that the majority of PGE 2 formed in vivo is derived from COX-2. Increased COX-2 expression and increased PGE 2 production are associated with malignancy. Levels of PGE-M were found to be greatly increased in humans with unresectable non-small cell cancer of the lung, and this increase is dramatically reduced by administration of the COX-2 inhibitor celecoxib, implying that COX-2 contributes significantly to the overproduction of PGE 2. In summary, quantification of PGE-M using LC/MS/MS provides a facile and accurate method to assess PGE 2 formation in human physiological and pathophysiological processes.

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N2 - Prostaglandin (PG)E 2 is a major cyclooxygenase (COX) product that is important in human physiology and pathophysiology. Quantification of systemic PG production in humans is best assessed by measuring excreted urinary metabolites. Accurate and easy-to-perform assays to quantify the major urinary metabolite of PGE 2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor- prostane-1,20-dioic acid (PGE-M), do not exist. We now report the development of a robust and facile method to measure urinary PGE-M excretion in humans using stable isotope dilution techniques employing liquid chromatography/tandem mass spectrometry (LC/MS/MS). Concentrations of the metabolite in urine from healthy humans are nearly twofold greater in men than in women (10.4 ± 1.5 vs. 6.0 ± 0.7 ng/mg creatinine). Levels of PGE-M in healthy humans are suppressed significantly not only by the nonselective COX inhibitor ibuprofen but also by the COX-2 selective inhibitor rofecoxib, suggesting that the majority of PGE 2 formed in vivo is derived from COX-2. Increased COX-2 expression and increased PGE 2 production are associated with malignancy. Levels of PGE-M were found to be greatly increased in humans with unresectable non-small cell cancer of the lung, and this increase is dramatically reduced by administration of the COX-2 inhibitor celecoxib, implying that COX-2 contributes significantly to the overproduction of PGE 2. In summary, quantification of PGE-M using LC/MS/MS provides a facile and accurate method to assess PGE 2 formation in human physiological and pathophysiological processes.