Abstract
BackgroundLysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3). We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation.MethodsWild type, LPA1 heterozygous knockout mice (LPA1+/-), and LPA2 heterozygous knockout mice (LPA2+/-) were sensitized with inactivated Schistosoma mansoni eggs and local antigenic challenge with Schistosoma mansoni soluble egg Ag (SEA) in the lungs. Bronchoalveolar larvage (BAL) fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA.ResultsBAL fluids from Schistosoma mansoni egg-sensitized and challenged wild type mice (4 days of challenge) showed increase of LPA level (~2.8 fold), compared to control mice. LPA2+/- mice, but not LPA1+/- mice, exposed to Schistosoma mansoni egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA2+/- and LPA1+/- mice showed decreases in bronchial goblet cells. LPA2+/- mice, but not LPA1+/- mice showed the decreases in prostaglandin E2 (PGE2) and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA2+/- mice. These results suggest that LPA and LPA receptors are involved in Schistosoma mansoni egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.
Highlights
Lysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3)
Airway epithelial cells isolated from LPA2+/- mice exhibited reduced COX-2 expression and prostaglandin E2 (PGE2) release compared to cells from wild type mice. These results show for the first time a role for LPA2 in the development of airway inflammation and pathogenesis of asthma
Unsaturated molecular species of LPA (18:1, 20:4, 22:5, and 22:6) were detected in bronchoalveolar lavage (BAL) fluids of control mice, which increased significantly after soluble egg Ag (SEA) challenge. These results show for the first time, to our knowledge, increase in LPA during allergic lung inflammation in a murine model of asthma
Summary
Lysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA1-3). In addition to its anti-inflammatory effect, LPA regulated E-cadherin intracellular trafficking and airway epithelial barrier integrity and intratracheal posttreatment with LPA reduced neutrophil influx, protein leak, and E-cadherin shedding in bronchoalveolar lavage (BAL) fluids in a murine model of LPS-induced acute lung injury [27]. These data suggest a protective role of administrated LPA in airway inflammatory diseases
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