R&D program on inflammation and its resolution

Ambiotis is the first CRO worldwide specializing in the process OF resolution.

Inflammation is a common host response to injury, irritation or infection.

The process is divided into 3 main steps: onset or initiation, amplification and resolution.

When correctly controlled, inflammation is supposed to end and lead to the complete restoration of the targeted tissue.

Various cell and biochemical effectors from in particular innate and adaptive system are indeed involved throughout the process and are tightly regulated.

The metabolization of pro-inflammatory mediators into inactive compounds is not sufficient to allow the tissue to come back to initial state.

Non Steroidal Anti Inflammatory Drugs (NSAIDs) were built on this hypothesis: they inhibit the inflammatory process by inhibiting cyclooxygenases and thus of PGE2 synthesis. They show a strong efficiency for the treatment of acute inflammation and a weaker efficiency for the treatment of chronic inflammation. Furthermore, unpleasant side effects have been reported.

Over the last decade, it has been shown that specific mediators are actually secreted in a timely coordinated manner all along the inflammatory response, including resolution phase.

 

Resolution is an active process, involving specific mediators that are biologically active and that CAN be used as biomarkers of homeostasis.

These biomarkers are issued from the omega-6 and the omega-3 polyunsaturated fatty acid (PUFA) metabolism and are termed lipoxins, resolvins, maresins and protectins, which are collectively referred to as SPMs (Specialized Pro-resolving Mediators)

Those molecules control physiological mechanisms involved in the end of the inflammatory process from the decrease of inflammatory cell recruitment, the elimination of pathogens and cell debris to the healing of the tissue and the decrease of pain. This offers promising perspectives for new drug development applications against chronic inflammatory diseases.

Indeed, a new branch of pharmacology has recently emerged: resolution pharmacology. Inflammation pharmacology aims at inhibiting mediators that are responsible for bad effects on tissues. By contrast resolution pharmacology focuses on the activation, the increase or improvement of cellular processes involved in the return to initial state (limit/repair damages, clean inflammatory site from debris…)


« The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation, or to the resolution thereof, as well as to potential, resolution-based immunopharmacological therapies. »

(Serhan CN, Am J Pathol 2010)

« In the past decade, a new paradigm in our understanding of the inflammatory process has emerged with the appreciation of genetic, molecular, and cellular mechanisms that are engaged to actively resolve inflammation. The ‘resolution of acute inflammation’ is enabled by counter-regulatory checkpoints to terminate the inflammatory reaction, promoting healing and repair. It may be possible to harness this knowledge for innovative approaches to the treatment of inflammatory pathologies. Here we discuss current translational attempts to develop agonists at proresolving targets as a strategy to rectify chronic inflammatory status. We reason this new approach will lead to the identification of better drugs that will establish a new branch of pharmacology, ‘resolution pharmacology’ »

(Perretti M, Trends in Pharmacological Science,2015)

« it has been proposed that some diseases that are associated with chronic inflam­ mation may be underpinned by dysregulated resolution as much as driven by ongoing pro­inflammatory processes, and that therapy based on rectifying these defects will help to guide ongoing inflammation down a pro­resolution pathway. »

(Fullerton JM, Nature Rev Drug discovery, 2016)

Become a partner : our commitment is to make our innovations your future development

Since its creation, Ambiotis leads R&D programs and investigate the naturally occurring mechanisms involved in the end of the inflammatory process in the aim of favouring them thanks to new molecules.

The company has thus built a thorough experience and expertise in this area to be able to propose finely tuned models in tight concomitance with a robust analytical approach.

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Publications


In Vitro and in Vivo Anti-Inflammatory Effect of a Biotechnologically Modified Borage Seed Extract: Evidence for Lipid Pro-Resolving Mediators’ Implication in the Enhancement of Psoriatic and Atopic Dermatitis Lesions
Chene G,  Baillif V, Van Goethem E, et al - JCDSA -2015 - DOI: 10.4236/jcdsa.2015.52018

A role for 12/15-lipoxygenase-derived proresolving mediators in postoperative ileus: protectin DX-regulated neutrophil extravasation.
Stein K, Stoffels M, Lysson M, Schneiker B, Dewald O, Krönke G, Kalff JC, Wehner S. - J Leukoc Biol. 2015 Aug 20. PMID: 2629297

Quantification and Potential Functions of Endogenous Agonists of Transient Receptor Potential Channels in Patients With Irritable Bowel Syndrome.
Cenac N,..., Dubourdeau M,et al. - Gastroenterology. 2015 Apr 21. PMID: 25911511

Molecular and cellular profiles of the resolution phase in a damage-associated molecular pattern-mediated peritonitis model and revelation of leukocyte persistence in peritoneal tissues.
Lastrucci C, Baillif V, ..., Dubourdeau M, et al. FASEB J. 2015 Jan 21.  PMID: 25609430

Protective effects of n-6 fatty acids-enriched diet on intestinal ischaemia/reperfusion injury involve lipoxin A4 and its receptor.
Gobbetti T, ..., Dubourdeau M, et al. - Br J Pharmacol. 2015 Feb; PMID: 25296998

Polyunsaturated fatty acid metabolism signature in ischemia differs from reperfusion in mouse intestine.
Gobbetti T, ..., Dubourdeau M, et al. - PLoS One. 2013 Sep 20 PMID: 24073272

LC-MS/MS method for rapid and concomitant quantification of pro-inflammatory and pro-resolving polyunsaturated fatty acid metabolites.
Le Faouder P, Baillif V, ..., Chêne G, Guigné C, ..., Dubourdeau M, et al. - J Chromatogr B Analyt Technol Biomed Life Sci. 2013 Aug  PMID: 23831705

Relevance of the cyclophosphamide-induced cystitis model for pharmacological studies targeting inflammation and pain of the bladder.
Augé C, Chene G, Dubourdeau M, et al. - Eur J Pharmacol. 2013 May 5 PMID: 23541724

Oral communications

2017

Monitoring of Pneumocystis jirovecii acquired pneumonia by specialized pro-resolving mediators

World Congress on Inflammation


Beta Glucans Are Reinforcing the Immune System Through the Mobilization of Resolution Pathways

International Scientific Conference on Probiotics and Prebiotics


2016

Long chain fatty acids and their related oxylipins in preterm human milk during the first month of lactation (Collaborative work with Daniel T Robinson from Northwestern University Feinberg School of Medicine, Chicago, US)

6th European Workshop on Lipid Mediators


Glutaminyl cylase (QC) inhibition in a mouse peritonitis model effects eosinophil and macrophage recruitment and levels of resolution molecules (Co-authorship with Torsten Hoffmann & Inge Lues from Probiodrug AG, Germany)

Summer Frontiers Symposium 2016 ‘Systems Biology of Innate Immunity’,


Specialized proresolving mediators and transcriptomic signatures in bleomycin-induced lung fibrosis

ERS International Congress


Development of a primary human M1 and M2 macrophage model and phagocytosis evaluation of Candida albicans in the presence of lipoxin A4, resolvin D1 and D5

Miami Symposium on Inflammation 2016 – Best poster prize


2015


To be filled soon