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A role for mast cells in geographic atrophy.
Ogura, Shuntaro; Baldeosingh, Rajkumar; Bhutto, Imran A; Kambhampati, Siva P; Scott McLeod, Donald; Edwards, Malia M; Rais, Rana; Schubert, William; Lutty, Gerard A.
Afiliação
  • Ogura S; Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.
  • Baldeosingh R; Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.
  • Bhutto IA; Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.
  • Kambhampati SP; Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.
  • Scott McLeod D; Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.
  • Edwards MM; Wilmer Ophthalmological Institute, Johns Hopkins Hospital, Baltimore, MD, USA.
  • Rais R; Johns Hopkins Drug Discovery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Schubert W; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Lutty GA; Bayer AG Pharmaceuticals, Wuppertal, Germany.
FASEB J ; 34(8): 10117-10131, 2020 08.
Article em En | MEDLINE | ID: mdl-32525594
Mast cells (MCs) are the initial responders of innate immunity and their degranulation contribute to various etiologies. While the abundance of MCs in the choroid implies their fundamental importance in the eye, little is known about the significance of MCs and their degranulation in choroid. The cause of geographic atrophy (GA), a progressive dry form of age-related macular degeneration is elusive and there is currently no therapy for this blinding disorder. Here we demonstrate in both human GA and a rat model for GA, that MC degranulation and MC-derived tryptase are central to disease progression. Retinal pigment epithelium degeneration followed by retinal and choroidal thinning, characteristic phenotypes of GA, were driven by continuous choroidal MC stimulation and activation in a slow release fashion in the rat. Genetic manipulation of MCs, pharmacological intervention targeting MC degranulation with ketotifen fumarate or inhibition of MC-derived tryptase with APC 366 prevented all of GA-like phenotypes following MC degranulation in the rat model. Our results demonstrate the fundamental role of choroidal MC involvement in GA disease etiology, and will provide new opportunities for understanding GA pathology and identifying novel therapies targeting MCs.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Atrofia Geográfica / Mastócitos Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Atrofia Geográfica / Mastócitos Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2020 Tipo de documento: Article