2016 Ross Prize in Molecular Medicine: Resolution of Inflammation

Agenda

* Presentation times are subject to change.

Abstracts

Resolution Pharmacology: Innovation in the Treatment of Chronic Diseases
Mauro Perretti, PhD, William Harvey Research Institute at Queen Mary University of London

It is now appreciated that a coordinated inflammatory reaction requires a pro-inflammatory phase followed by a resolution phase with the consequence that an effective resolution program prevents progression from acute inflammation to persistent chronic inflammation. How can we harness this knowledge to improve the clinical management of inflammatory diseases? We propose that innovation exploiting the science of resolution of inflammation would lead to the development of novel anti-inflammatory drugs with the establishment of Resolution Pharmacology: such therapeutics could complement, if not represent, an alternative to current therapies (all developed by assessing their ability to block specific pro-inflammatory mediators) and—we predict—be burdened by a much lower degree of side effects. It is plausible that pro-resolving based therapeutics might be suitable for subsets of patients, perhaps where expression of specific receptors is augmented or specific mediators are deficient. We propose that definition of cell-specific pro-resolving signaling and downstream phenotypic responses would and should guide the development of novel molecules that act as agonists at pro-resolving receptor or therapeutic approaches that elevate the expression of endogenous pro-resolving mediators.
 
Resolution Pharmacology will enable the development of innovative therapeutics leading to an improved way on how we manage the complex, multi-morbidity, markedly debilitating and highly impacting diseases.

Structural Elucidation of Novel Mediators in Resolution of Infectious Inflammation and Tissue Regeneration in Human Tissues
Charles N. Serhan, PhD, DSc, Harvard Institutes of Medicine, BWH and Harvard Medical School

Uncontrolled inflammation is a component of many widely occurring chronic diseases. Using a systems approach with self-limited inflammatory infectious exudates to map tissue events, cell traffic and identification of protein and chemical mediators, we identified 3 structurally distinct families of potent essential fatty acid-derived (EPA, DPA, DHA) novel mediators, termed resolvins, protectins and maresins. Each family member is chemically unique and functions as a pro-resolving mediator that controls the duration and magnitude of acute inflammatory responses in pico- to nanogram range. The biosynthetic pathways and potent mediators from resolvin, protectin and maresin bioactive-metabolomes are coined specialized pro-resolving mediators (SPM). Mapping of these resolution circuits provides new avenues to probe the molecular basis of many diseases (CN Serhan, Nature 2014). This presentation will give an overview of our recent advances on SPM biosynthesis and functions. We use LC-MS-MS mediator-metabololipidomics targeted to profile SPM in human tissues (serum, plasma, breast milk, adipose and brain), which uncovered new pathways that stimulate tissue regeneration and bacterial clearance. Several SPM are in clinical development and in ongoing human trials. Identification of SPM during inflammation-resolution indicates that resolution is an active programmed process challenging the old concept that resolution is passive, where chemotactic molecules dilute and simply wane to resolve exudates. These findings indicate that resolution pathways may underlie prevalent diseases as failed resolution and open the potential for resolution physiology and resolution-based pharmacology. The author acknowledges support of NIH grants P01GM095467, R01GM38765, P01HL108801 and R01DE025020.

Inflammation, Homeostasis and Disease
Ruslan Medzhitov, PhD, Howard Hughes Medical Institute (HHMI), Yale University School of Medicine

Inflammation is an adaptive response to infection, tissue injury and other alterations of normal tissue function and homeostasis. The inflammatory response consists of four universal components: inflammatory triggers, sensors, mediators and target tissues. The inflammatory trigger can be an infectious agent, damaged or malfunctioning tissue. Inflammatory sensors are receptors and cell types that express them, including TLRs expressed on macrophages and other tissue resident cells. Inflammatory mediators comprise a large class of molecules that includes inflammatory cytokines, chemokines, bioactive amines and eicosanoids. Finally, the targets of the inflammatory response are the tissues responsive to a particular set of inflammatory mediators under a given condition. Depending on the nature of the inflammatory trigger, different combinations and quantities of the inflammatory mediators are produced by sensor cells. The inflammatory pathway is regulated at the level of all four components of the pathway. The principles of inflammatory regulation and their implications for normal physiology and pathology will be the focus of this presentation.

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