Signaling lipids as diagnostic biomarkers for ocular surface cicatrizing conjunctivitis

Antonio Di Zazzo,Alessandra Micera,Amy C Harms,Isabelle Kohler,Wei Yang,Fabrizio Piccinni,Marco Antonini,Thomas Hankemeier,Marco Coassin,Maria De Piano,Alireza Mashaghi,Stefano Boinini

doi:10.1007/s00109-020-01907-w

Abstract

Metabolomics has been applied to diagnose diseases, predict disease progression, and design therapeutic strategies in various areas of medicine. However, it remains to be applied to the ocular surface diseases, where biological samples are often of limited quantities. We successfully performed proof-of-concept metabolomics assessment of volume-limited cytology samples from a clinical form of chronic inflammatory cicatrizing conjunctivitis, i.e., ocular MMP and discovered metabolic changes of signaling lipid mediators upon disease onset and progression. The metabolomics assessment revealed active oxylipins, lysophospholipids, fatty acids, and endocannabinoids alterations, from which potential biomarkers linked to inflammatory processes were identified. Possible underlying mechanisms such as dysregulated enzyme activities (e.g., lipoxygenases, cytochrome P450, and phospholipases) were suggested which may be considered as potential therapeutic targets in future studies.Key messagesMetabolic profile of the ocular surface can be measured using impression cytology samples.Metabolomics analysis of ocular pemphigoid is presented for the first time.The metabolomics assessment of OCP patients revealed active oxylipins, lysophospholipids, fatty acids, and endocannabinoids alterations.Several oxylipins are identified as diagnostic biomarkers for OCP.

Highlights

Antonio Di Zazzo and Wei Yang contributed to this work.Ophthalmology Complex Operative Unit, University Campus Bio-Medico, Rome, ItalyLeiden Academic Centre for Drug Research, Faculty of Science, Leiden University, 2333 CC Leiden, The NetherlandsResearch laboratories in Ophthalmology, IRCCS Fondazione Bietti, Rome, ItalyAmsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam, The NetherlandsChronic cicatrizing conjunctivitis (CCC) include 35 immunological and neoplastic entities which lead to ocular surface scarring, often causing ocular surface dysfunction and loss of visual ability [1]
We investigated whether a targeted metabolomics-based approach targeting signaling lipid mediators harvested by non-invasive conjunctival impression cytology could serve as sensitive and objective diagnostic biomarkers of active chronic inflammation which leads to ocular surface fibrosis in ocular membrane pemphigoid (MMP)
Those two metabolites were exclusively detected, and at considerable abundance, in all patients’ conjunctival biopsies analyzed, as illustrated in Fig. 5, while not detected in control conjunctival biopsies. This suggests that 9(S)HOTrE and (±)5-HEPE were both only produced in ocular MMP patients, which makes them potential specific disease biomarker candidates

Summary

Introduction

Ophthalmology Complex Operative Unit, University Campus Bio-Medico, Rome, Italy. Leiden Academic Centre for Drug Research, Faculty of Science, Leiden University, 2333 CC Leiden, The Netherlands. Research laboratories in Ophthalmology, IRCCS Fondazione Bietti, Rome, Italy. Ocular mucous membrane pemphigoid (MMP) is the most common form of CCC and the high risk among the causes of blindness in western countries [2]. MMP is an autoimmune chronic inflammatory mucous disease characterized by subepithelial blistering, with an estimated incidence between 1:12000 and 1:60000 [3]. The ocular surface has the second highest approximate frequency of involvement, namely, circa 70% of cases [4]. A substantial proportion of cases, i.e., 27%, has ocular-only disease without any other mucous involvement [5].

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