Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:145

Article

Baernthaler, Thomas¹  Theiler, Anna¹  Zabini, Diana^2,3  Trautmann, Sandra⁴  Stacher-Priehse, Elvira²  Lanz, Ilse¹  Klepetko, Walter⁵  Sinn, Katharina⁵  Flick, Holger⁶  Scheidl, Stefan⁶  Thomas, Dominique⁴  Olschewski, Horst^3,6  Kwapiszewska, Grazyna^2,3  Schuligoi, Rufina¹  Heinemann, Akos¹ 

[1] Med Univ Graz, Otto Loewi Res Ctr, Div Pharmacol, Graz, Austria

[2] Med Univ Graz, Otto Loewi Res Ctr, Div Physiol, Graz, Austria

[3] Ludwig Boltzmann Inst Lung Vasc Res, Graz, Austria

[4] Goethe Univ Frankfurt, Inst Clin Pharmacol, Pharmazentrum Frankfurt ZAFES, Frankfurt, Germany

[5] Med Univ Vienna, Div Thorac Surg, Dept Surg, Vienna, Austria

[6] Med Univ Graz, Div Pulmonol, Dept Internal Med, Graz, Austria

关键词: PGE(2);    15-PGDH;    idiopathic pulmonary fibrosis;    fibrocytes;   

DOI  :  10.1016/j.jaci.2019.11.032

来源: Elsevier

【 摘 要 】

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with high 5-year mortality and few therapeutic options. Prostaglandin (PG) E-2 exhibits antifibrotic properties and is reduced in bronchoalveolar lavage from patients with IPF. 15-Prostaglandin dehydrogenase (15-PGDH) is the key enzyme in PGE(2) metabolism under the control of TGF-beta and microRNA 218. Objective: We sought to investigate the expression of 15-PGDH in IPF and the therapeutic potential of a specific inhibitor of this enzyme in a mouse model and human tissue. Methods: In vitro studies, including fibrocyte differentiation, regulation of 15-PGDH, RT-PCR, and Western blot, were performed using peripheral blood from healthy donors and patients with IPF and A549 cells. Immunohistochemistry, immunofluorescence, 15-PGDH activity assays, and in situ hybridization as well as ex vivo IPF tissue culture experiments were done using healthy donor and IPF lungs. Therapeutic effects of 15-PGDH inhibition were studied in the bleomycin mouse model of pulmonary fibrosis. Results: We demonstrate that 15-PGDH shows areas of increased expression in patients with IPF. Inhibition of this enzyme increases PGE(2) levels and reduces collagen production in IPF precision cut lung slices and in the bleomycin model. Inhibitor-treated mice show amelioration of lung function, decreased alveolar epithelial cell apoptosis, and fibroblast proliferation. Pulmonary fibrocyte accumulation is also decreased by inhibitor treatment in mice, similar to PGE2 that inhibits fibrocyte differentiation from blood of healthy donors and patients with IPF. Finally, microRNA 218-5p, which is downregulated in patients with IPF, suppressed 15-PGDH expression in vivo and in vitro. Conclusions: These findings highlight the role of 15-PGDH in IPF and suggest 15-PGDH inhibition as a promising therapeutic approach.

【 授权许可】

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