Abstract
Fibrosis characterizes many chronic diseases that result in end-stage organ failure, causing major morbidity and mortality. Fibrosis in many of these diseases appears to result from aberrant or over-exuberant wound-healing responses to chronic injury, producing excessive accumulation of fibroblasts and extracellular matrix that disrupt normal tissue homeostasis. The potent bioactive lipid lysophosphatidic acid (LPA), signaling through one of its receptors LPA1, mediates numerous fundamental cell behaviors involved in wound healing responses, including cell contraction, migration, survival, proliferation, and gene expression. Recent studies indicate that the LPA-LPA1 pathway regulates many of the aberrant wound-healing responses that have been implicated in fibrotic diseases. This pathway has been shown to exert pro-fibrotic effects on multiple cell types: LPA-LPA1 signaling promotes epithelial cell apoptosis and fibroblast migration, proliferation and resistance to apoptosis, and impairs endothelial cell barrier function. Consistent with its broad pro-fibrotic activities, inhibition of the LPA-LPA1 pathway has recently been demonstrated to have profound anti-fibrotic effects. Targeting LPA-LPA1 signaling has been demonstrated to be an effective therapeutic strategy in mouse models of fibrotic diseases affecting multiple different organs, including the lung, kidney, skin and peritoneum. The breadth of these effects suggest that LPA and LPA1 represent a core pathway in fibrosis, and make these molecules attractive targets for the development of new therapies with the potential to be effective for multiple human fibrotic diseases.
