There has been great recent interest in the bioactive lipid mediator lysophosphatidic acid (LPA) in the pathogenesis of fibrotic diseases, from both academic laboratories and pharmaceutical companies. Investigators have demonstrated critical roles for LPA signaling through one of its receptors, LPA1, in animal models of fibrosis of multiple organs, including the lung (1, 2), skin (3), and kidney (4, 5). Building on these pre-clinical studies, pharmaceutical companies will be evaluating LPA1 antagonism in upcoming clinical trials as a new therapeutic strategy for human fibrotic diseases, including idiopathic pulmonary fibrosis (IPF) and scleroderma. In this issue of the Journal, Oikonomou and colleagues (pp. 566–574) demonstrate that genetic deletion or pharmacological inhibition of autotaxin, the enzyme responsible for generating most extracellular LPA, also limits the development of lung fibrosis in the bleomycin model (6). These investigators demonstrate increased expression of autotaxin in the lungs of patients with IPF and fibrotic nonspecific interstitial pneumonia (NSIP), identifying this enzyme as an exciting new addition to the growing list of rationale drug targets for IPF and other fibrotic diseases. LPA is the common name for acyl-hydroxy-glycero-3-phosphates, all consisting of a glycerol phosphate backbone esterified to a single fatty acid (Figure 1), and signaling through specific G protein–coupled receptors. Five high-affinity LPA receptors have been definitively established and designated LPA1 to LPA5 (Figure 1); P2Y5 is a lower-affinity receptor that is likely to join the LPA receptor family as LPA6 (7). By signaling through these receptors, LPA mediates multiple fundamental responses to tissue injury, including responses that may be aberrant or aberrantly excessive when injury leads to fibrosis rather than to repair. LPA signaling specifically through LPA1 has pro-fibrotic effects on epithelial cells, endothelial cells, and fibroblasts: genetic deletion of this receptor reduces epithelial cell apoptosis, vascular leak, and fibroblast accumulation in the bleomycin model of lung fibrosis (1, 8). LPA1-deficient mice are consequently dramatically protected from fibrosis and mortality in this model (1). Pharmacological inhibition of LPA1 abrogates fibroblast migration in response to the bronchoalveolar lavage (BAL) of patients with IPF, demonstrating that LPA–LPA1 signaling is responsible for fibroblast recruitment in this disease (1).

The study by Oikonomou and colleagues demonstrates that, as does LPA1 antagonism, limiting LPA synthesis by inhibiting autotaxin limits the development of pulmonary fibrosis (6). Although LPA can be produced from membrane phospholipids of cells or platelets, or from surfactant phospholipids, by at least three pathways (9), the majority of LPA in vivo appears to be produced by autotaxin, since plasma LPA concentrations in mice heterozygous