Resolution of inflammation: state of the art, definitions and terms

Abstract

A recent focus meeting on Controlling Acute Inflammation was held in London, April 27-28, 2006, organized by D.W. Gilroy and S.D. Brain for the British Pharmacology Society. We concluded at the meeting that a consensus report was needed that addresses the rapid progress in this emerging field and details how the specific study of resolution of acute inflammation provides leads for novel anti-inflammatory therapeutics, as well as defines the terms and key components of interest in the resolution process within tissues as appreciated today. The inflammatory response protects the body against infection and injury but can itself become dysregulated with deleterious consequences to the host. It is now evident that endogenous biochemical pathways activated during defense reactions can counter-regulate inflammation and promote resolution. Hence, resolution is an active rather than a passive process, as once believed, which now promises novel approaches for the treatment of inflammation-associated diseases based on endogenous agonists of resolution.

Figure 1

Schematic depicting the cellular and molecular components of the inflammatory response and the requirements for resolution. A) (adapted from Cotran; see ref. 1) depicts the cellular and histological changes that occur in tissues following an inflammatory insult. Acute inflammation is characterized by the extravascular accumulation of neutrophils (PMN) and edema formation early in the response. Later during the response, mononuclear cells and macrophages accumulate and help prepare the tissue for resolution. B, C) Represent the role that specific molecular mediators play in these events. In (B), we highlight that early on in the inflammatory response, immediate and early sequential pre-dominately pro-inflammatory mediators are released, which initiate and augment the acute-phase of the response (green lights). However, this is counterbalanced by endogenous anti-inflammatory signals such as corticosterone, which serve to temper the severity and limit the duration of the early onset phase. As inflammation progresses, certain “stop signals” at appropriate “checkpoints” prevent further leukocyte traffic into tissue. These stop signals include the lipoxins, Resolvins, and prostaglandins (PGs) of the D series and pave the way for monocyte migration and their differentiation to phagocytosing macrophages, which remove dead cells and then exit the site of inflammation. Stromal cells such as fibroblasts also contribute to the resolution of inflammation by the withdrawal of survival signals and the normalization of chemokine gradients, thereby allowing infiltrating leukocytes to undergo apoptosis or leave the tissue through the draining lymphatics. This sequential set of responses leads to complete resolution and, importantly, the restoration of the inflamed tissue to its prior physiological functioning. This is the ideal sequence of events in physiological inflammation, which contrast to the situation in pathological inflammation (B) where some of the factors that initiate the resolution program lead to the inappropriate accumulation of leukocytes in the wrong place at the wrong time.