The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak

Abstract

Aberrant wound-healing responses to injury have been implicated in the development of pulmonary fibrosis, but the mediators directing these pathologic responses have yet to be fully identified. We show that lysophosphatidic acid levels increase in bronchoalveolar lavage fluid following lung injury in the bleomycin model of pulmonary fibrosis, and that mice lacking one of its receptors, LPA1, are markedly protected from fibrosis and mortality in this model. The absence of LPA1 led to reduced fibroblast recruitment and vascular leak, two responses that may be excessive when injury leads to fibrosis rather than to repair, whereas leukocyte recruitment was preserved during the first week after injury. In persons with idiopathic pulmonary fibrosis, lysophosphatidic acid levels in bronchoalveolar lavage fluid were also increased, and inhibition of LPA1 markedly reduced fibroblast responses to the chemotactic activity of this fluid. LPA1 therefore represents a new therapeutic target for diseases in which aberrant responses to injury contribute to fibrosis, such as idiopathic pulmonary fibrosis.

Discovery of ONO-7300243 from a Novel Class of Lysophosphatidic Acid Receptor 1 Antagonists: From Hit to Lead

“…4 Furthermore, these physiological functions can be related to a number of pathophysiological responses, such as cancer, 5 neuropathic pain, 6 and fibrosis. 7 The biological effects of LPAs are mediated through G protein-coupled receptors (GPCRs). Six LPA receptors (LPA 1−6 ) have been identified and characterized to date.…”

Cellular and Molecular Mechanisms of Chronic Inflammation-Associated Organ Fibrosis

“…On the contrary, prostaglandin E 2 (PGE 2 ), which has well established anti-inflammatory activities, may suppress fibrosis by inhibiting the proliferation, migration, and differentiation of myofibroblasts (Kohyama et al, 2001;Lama et al, 2002;Thomas et al, 2007). Recent studies have demonstrated that PGF2a receptor deficient mice are resistant against bleomycininduced lung fibrosis (Oga et al, 2009), and that LTB4 receptor inhibitors and LPA1 inhibitors suppress bleomycin-induced lung fibrosis (Tager et al, 2008). Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are liberated from stored lipid precursors through enzymatic activation and provide migration, proliferation, and differentiation signals to a variety of cells through the LPA receptors (LPA 1-8 ) and S1P receptors (S1P 1-5 ), respectively (Pattanaik and Postlethwaite, 2010).…”

“…Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are liberated from stored lipid precursors through enzymatic activation and provide migration, proliferation, and differentiation signals to a variety of cells through the LPA receptors (LPA 1-8 ) and S1P receptors (S1P 1-5 ), respectively (Pattanaik and Postlethwaite, 2010). LPA 1 deficient mice are protected from bleomycin-induced lung fibrosis and unilateral ureteral ligation induced-renal fibrosis (Tager et al, 2008). The pro-fibrotic role of LPA is reportedly mediated in part by www.frontiersin.org the induction of fibroblast-to-myofibroblast differentiation (Yin et al, 2008).…”

Possible Role of Lysophosphatidic Acid in Rat Model of Hypoxic Pulmonary Vascular Remodeling

“…10 However, little is known about the effect of increased LPA concentration in the blood, although indirect data suggest that high LPA is deleterious. 11,12 This lipid was also shown to enhance production and secretion of cytokines in lymphocytes. 13 In the cardiovascular system, LPA alters endothelial barrier functions and initiates and perpetuates pathophysiological processes such as inflammation and atherogenesis.…”