A striking histological characteristic of a healthy gut mucosa is the general absence of neutrophils; however, these acute inflammatory cells are capable of rapid influx into the mucosa and are necessary for controlling infection. This innate immune process depends upon the classical sequence of neutrophil recruitment: adhesion, extravasation, chemotaxis, and terminal transepithelial migration of assembled neutrophils from the basement membrane of the epithelial monolayer to the apical surface, where they are positioned to intercept luminal pathogens. While neutrophil influx into the intestinal lumen is a critical response to enteric infection that mediates the phagocytosis and killing of bacteria, this influx is also universally recognized as a double-edged sword, as the products of neutrophil degranulation and oxidative burst tightly associate with collateral cellular and macromolecular damage (1). Chronic neutrophilic inflammation in the gut, such as that seen in ulcerative colitis and certain enteric infections, can result in scarring, functional alterations, and increased risk of neoplasia. Thus, it is clear that the mucosa requires fine-tuned strategies to rapidly summon acute inflammatory cells when needed and to counteract proinflammatory signaling to rapidly clear inflammatory cells and stimulate restitution. Understandably, mechanisms involved in the resolution of inflammation are a current topic of intense interest, given the obvious potential of these pathways for therapeutic exploitation.

An important area of investigation is the identification and characterization of numerous bioactive lipid compounds, often eicosanoid mediators, which can play varying roles in inflammatory processes. For example, the lipid chemoattractant hepoxilin A 3 (HxA 3 ) is an eicosanoid that is secreted from intestinal epithelial cells by the apically restricted efflux pump multidrug resistance protein 2 (MRP2) and that mediates terminal translocation of recruited neutrophils across the epithelial monolayer (2). Conversely, lipid mediators, including lipoxin A 4 and the resolvins, also possess important antiinflammatory and restitutive functions (3). Thus, lipid mediators represent a fruitful source of potentially novel inflammatory-modulating agents.

In this issue, Szabady et al. describe a bioactive lipid-mediated mechanism that serves to counterbalance activation of the HxA 3 /MRP2 proinflammatory pathway (4). Interestingly, the antiinflammatory mediators identified are endocannabinoids (ECs), which are part of a biochemical system that is gaining increased attention as both an endogenous signaling pathway and as a potential mechanism for therapeutic properties imputed to exogenous phytocannabinoids (5). Szabady and colleagues sought to discover inflammation-suppressing molecules by evaluating the P-glycoprotein–dependent (P-gp–dependent) secreted lipidome of unstimulated epithelial monolayers. P-gp is a multidrug transporter known to efflux small hydrophobic compounds that is encoded on the Mdr1 gene. Mice lacking the Mdr1a gene develop spontaneous colitis (6), and polymorphisms in the human MDR1 gene are known risk alleles for inflammatory bowel disease (IBD) (7); therefore, compounds secreted by this pathway may play a role in antiinflammatory and/or homeostatic functions.