Resolving the problem of persistence in the switch from acute to chronic inflammation
- Oliver Haworth* and
- Christopher D. Buckley†,‡
- *Pulmonary and Critical Care Medicine, Brigham and Women's Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115; and
- †Rheumatology Research Group, Medical Research Council Centre for Immune Regulation, Institute for Biomedical Research, University of Birmingham, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom
The rapid induction of an inflammatory response is crucial for effective host defense. A wide range of proinflammatory agents ensure that this response occurs. Prominent among these are members of the prostaglandin and leukotriene family that are enzymatically derived from arachidonic acid (AA, C20:4) (1). At the onset of inflammation, AA is metabolized via either cyclooxygenases (COX) to produce prostaglandins (PGs) and thromboxanes or lipoxygenases to generate leukotrienes (LTs) (1). These ecicosanoids induce and help establish the inflammatory infiltrate. However, at some point during the inflammatory cascade, inhibition and ultimately resolution of the inflammatory response must occur; otherwise, tissue homeostasis cannot occur and inflammation persists.
Until relatively recently, the resolution of inflammation was thought to occur mainly as a result of the passive withdrawal of proinflammatory mediators. It is now clear that the inflammatory program contains key checkpoints as well as temporal and spatial switches that regulate its onset, maintenance, and resolution (2). A key finding in recent years is that the biosynthetic pathways required for inflammation to resolve often require the prior production of lipid mediators produced during the induction phase of inflammation. In particular, PGE2 and PGD2, which are responsible for inflammation induction, subsequently stimulate antiinflammatory circuits by inducing the lipoxin-producing enzyme 15-lipoxygenase in neutrophils. This class switch in eicosanoid production, from LTs and PGs to lipoxins (3), provides temporal and spatial checkpoints during the inflammatory cascade (see Fig. 1). In this issue of PNAS, Rajakariar et al. (4) provide yet another twist in the resolution story with the demonstration that class switching may not always be required for resolution to be initiated. They provide compelling evidence that, within a single eicosanoid family pathway initiated by COX-2 and subsequently regulated by the enzyme hematopoietic PGD2 synthase …
‡To whom correspondence should be addressed. E-mail: c.d.buckley{at}bham.ac.uk
