Autotaxin signaling, purinergic receptors and lung damage

Abstract

ATX is a secreted enzyme that produces lysophosphatindic acid (LPA) in plasma. For several years investigators have characterize endogenous factors that regulate ATX expression and compartmentalization. However many questions remain unanswered and this article highlights our recent finding that autotaxin (ATX) is readily induced by toxic environmental chemicals. LPA binds G-protein coupled receptors that affect basic cell functions. The interest in the ATX-LPA axis stems from its role in embryogenesis and its association to diseases such as allergic asthma, idiopathic lung fibroses, rheumatoid arthritis, wound healing and several common types of cancer. In our study we used toluene diisocyanate (TDI) and other diisocyanates. Diisocyanates are low-molecular weight industrial chemicals notorious for being respiratory sensitizers and lung toxicants. Mechanisms behind these effects are not sufficiently characterized. We mainly used TDI and found that TDI in the nM range induced a rapid secretion of ATX from respiratory epithelial cells. Two purinergic recptors, P2X4 and P2X7, were implicated in this effect of TDI, suggesting that there is a “P2X-ATX axis” in bronchial epithelium that is sensitive to diisocyanates. We also showed associations between TDI exposures, LPA levels in plasma and symptoms reported by exposed individuals. Thus, our data support a role for the ATX-LPA axis in TDI toxicity. Furthermore, they suggest novel ways to study the regulation of ATX expression. Of particular interest is to understand how ATX expression is affected by purinergic receptors, and to investigate a possible involvement of ATX in asthma induced by diisocyanates and perhaps other low-molecular weight environmental chemicals. Our study also raises questions about current occupational exposure limits for diisocyanates.