Abstract 9795: Deficiency of Phospholipase A2 Receptor Exacerbates Airway Inflammation and Pulmonary Vessel Remodeling After Ovalbumin Treatment Through Impaired Clearance of Secretory Phospholipase A2
Secretory phospholipase A2 (sPLA2) plays a critical role in the genesis of various inflammatory diseases through pro-inflammatory eicosanoids. We previously discovered a cell surface receptor for sPLA2 (PLA2R) and showed that PLA2R as well as its ligands, sPLA2 groups IB and X, were expressed in the lung, but the pathogenic role of PLA2R in the lung is unknown. This study examined the role of PLA2R in the pathogenesis of inflammation of the airway and pulmonary vessels using PLA2R knockout (KO) mice.
Methods and Results: Allergic lung inflammation was induced by immuno-sensitization with ovalbumin (OVA). In immunohistochemical analysis, PLA2R was detected in airway smooth muscle cells in PLA2R wild type (WT) lung. PLA2R KO mice showed a significantly greater infiltration of inflammatory cells around the airways and blood vessels (1.7 fold greater than WT mice) and a greater wall thickness of blood vessels (1.3 fold greater than WT mice) after OVA-treatment. PLA2R KO mice had significantly higher levels of sPLA2-IB and -X in bronchoalveolar lavage fluid (BALF) after OVA treatment than WT mice (sPLA2-IB, 34.4 ± 3.2 pg/mL vs. 13.5 ± 1.8 pg/mL; sPLA2-X, 9.8 ± 2.4 pg/mL vs. 3.9 ± 0.9 pg/mL; respectively, p < 0.05 for both). This difference was associated with greater levels of eicosanoids (LTB4, CysLTs and PGD2), and Th2 cytokines (IL-4 and IL-5) and higher numbers of eosinophils and neutrophils in OVA-treated BALF of PLA2R KO mice than WT mice. When 125I-labeled sPLA2-IB was endotracheally instilled into the lung, 125I-sPLA2-IB was cleared much more slowly from BALF of PLA2R KO mice than from WT mice (instilled 125I-sPLA2-IB remaining in BALF at 2 hrs; 40% vs. 10%, respectively). Degradation of instilled 125I-sPLA2-IB, assessed by TCA-soluble radioactivity in BALF, was lower in PLA2R KO mice (70% of WT mice at 4 hr). In experiments using cultures of airway smooth muscle cells, binding, internalization and degradation of 125I-sPLA2-IB were lower in PLA2R KO cells than WT cells, supporting the impaired clearance of sPLA2 from lungs of PLA2R KO mice.
Conclusions: PLA2R-deficiency increased sPLA2-IB and -X levels in the lungs due to impaired clearance from the lung, leading to exaggeration of airway inflammation and pulmonary vessel remodeling after OVA treatment in a mouse model.
- © 2013 by American Heart Association, Inc.