Abstrakt

Inflammatory pulmonary fibrosis is associated with pulmonary autotaxin expression

Vassilis Aidinis

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive, fibrotic form of diffuse lung disease occurring mainly in older adults and characterized by a progressive worsening of lung function and a poor prognosis. To date, no management approach has proven efficacious. The disease is largely unresponsive to corticosteroid and immunosuppressive therapy. To study the pathogenetic mechanisms that govern disease activation and perpetuation, a number of animal models have been developed. Among them, the bleomycin (BLM) model is the most widely used and best characterized. Current research suggests that the mechanisms driving IPF reflect abnormal wound healing in response to pulmonary epithelial damage, involving increased activity and possibly exaggerated responses by a spectrum of proinflammatory and profibrogenic factors. Lysophos Phatidic Acid (LPA) is a phospholipid mediator that evokes growth-factor?like responses in almost all cell types, including pulmonary fibroblasts, smooth muscle cells, and epithelial cells. Its diverse functions are attributed to at least six LPA receptors (LPARs) with overlapping specificities and widespread tissue distribution, including the lung. LPARs couple to more than three distinct G proteins, which in turn feed into multiple effector systems. LPA concentrations were found to be increased in the bronchoalveolar lavage fluids (BALFs) of IPF patients and a BLM murine model, and were shown to mediate fibroblast recruitment and vascular leakage. Moreover, the genetic or pharmacological inhibition of LPAR1 attenuated the development of BLM-induced pulmonary fibrosis, suggesting a primary role for LPA in disease pathogenesis.