LYSOPHOSPHATIDIC ACID RECEPTOR TARGETING FOR SCLERODERMA AND OTHER FIBROTIC DISEASES

摘要

LPA signaling through LPA1, but not LPA2, has been shown to be involved in the development of bleomycin-induced dermal fibrosis effecting both myofibroblast accumulation and TGF-ß-Smad signaling. In addition, genetic deletion, preventive pharmacological inhibition, and therapeutic pharmacological inhibition of LPA1 protected mice from dermal fibrosis. For example, a selective LPA1 receptor antagonist, AM095, attenuates dermal fibrosis when initiated after tissue injury onset in a therapeutic regimen. Consequently, antagonism of LPA1 may be effective in the treatment of patients with already existing fibrosis, as would be needed for clinically useful anti-fibrotic drugs. LPA-LPA1 inhibition has the potential to be an effective new therapeutic strategy for dermal fibrosis, and that LPA1 represents a viable target for pharmacological intervention.