Chemical mediators and the resolution of airway inflammation

Abstract

Asthma pathobiology is remarkable for chronic airway inflammation that fails to spontaneously resolve. No curative therapy is currently available. A growing body of evidence indicates that, in health, inflammation resolution is an active process orchestrated by specific chemical mediators that are elaborated to restore tissue homeostasis. Activated cell membranes release polyunsaturated fatty acids from phospholipids for enzymatic conversion to biologically active mediators with profound regulatory effects on innate and adaptive immunity. Some of these mediators carry anti-inflammatory and pro-resolving actions that are transduced in a cell-type specific manner via specific recognition sites that initiate regulatory intracellular signals, such as presqualene diphosphate remodeling, to limit pro-phlogistic cell activation. Some of these counter-regulatory lipid mediators have been identified in the airway during asthma and defects in their production are associated with disease severity. In this review, we describe the biosynthesis and bioactions of pro-resolving chemical mediators and provide examples of select mediators and their structural analogs with particular relevance to asthma.

Figure 1

Illustration of cellular PSDP remodeling. Activation of PMNs results in the rapid and transient conversion of PSDP to PSMP concurrent with functional responses, such as superoxide anion generation, PLD and PI3K activity. PSDP remodeling is mediated by polyisoprenyl diphosphate phosphatase 1 (PDP1) and PSDP dephosphorylation is blocked by LX signaling. PSDP and PSMP are drawn with Chem3D Pro. The color scheme is as follows: red-oxygen, pink-phosphorus, blue-hydrogen, and grey-carbon.

Figure 2

Evolutionary dendrogram based on sequence similarity among the lipid phosphate/phosphotransferase family members. Adapted from reference .