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Therapeutic targeting of 15-PGDH in murine pulmonary fibrosis.
Smith, Julianne N P; Witkin, Matthew D; Jogasuria, Alvin P; Christo, Kelsey F; Raffay, Thomas M; Markowitz, Sanford D; Desai, Amar B.
Afiliación
  • Smith JNP; Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Witkin MD; Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Jogasuria AP; Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Christo KF; Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Raffay TM; Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • Markowitz SD; Department of Medicine, and Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, 44106, USA. sxm10@case.edu.
  • Desai AB; University Hospitals Seidman Cancer Center, Cleveland, OH, 44106, USA. sxm10@case.edu.
Sci Rep ; 10(1): 11657, 2020 07 15.
Article en En | MEDLINE | ID: mdl-32669620
Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by interstitial remodeling and pulmonary dysfunction. The etiology of IPF is not completely understood but involves pathologic inflammation and subsequent failure to resolve fibrosis in response to epithelial injury. Treatments for IPF are limited to anti-inflammatory and immunomodulatory agents, which are only partially effective. Prostaglandin E2 (PGE2) disrupts TGFß signaling and suppresses myofibroblast differentiation, however practical strategies to raise tissue PGE2 during IPF have been limited. We previously described the discovery of a small molecule, (+)SW033291, that binds with high affinity to the PGE2-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) and increases PGE2 levels. Here we evaluated pulmonary 15-PGDH expression and activity and tested whether pharmacologic 15-PGDH inhibition (PGDHi) is protective in a mouse model of bleomycin-induced pulmonary fibrosis (PF). Long-term PGDHi was well-tolerated, reduced the severity of pulmonary fibrotic lesions and extracellular matrix remodeling, and improved pulmonary function in bleomycin-treated mice. Moreover, PGDHi attenuated both acute inflammation and weight loss, and decreased mortality. Endothelial cells and macrophages are likely targets as these cell types highly expressed 15-PGDH. In conclusion, PGDHi ameliorates inflammatory pathology and fibrosis in murine PF, and may have clinical utility to treat human disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Tiofenos / Dinoprostona / Hidroxiprostaglandina Deshidrogenasas / Inhibidores Enzimáticos / Fibrosis Pulmonar Idiopática / Antiinflamatorios Límite: Animals / Female / Humans Idioma: En Revista: Sci Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Piridinas / Tiofenos / Dinoprostona / Hidroxiprostaglandina Deshidrogenasas / Inhibidores Enzimáticos / Fibrosis Pulmonar Idiopática / Antiinflamatorios Límite: Animals / Female / Humans Idioma: En Revista: Sci Rep Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido