Abstract
Lysophosphatidic acid (LPA) plays a dual-function in lung inflammatory diseases. LPA receptors contribute to the pathogenesis of asthma, acute lung injury, and fibrosis. Here, we investigate the role of LPA receptor type 2 (LPA2) in sepsis-induced lung inflammation and injury. Sepsis was induced using cecal ligation and single puncture (CLP) with 27 gauge needle. Plasma interleukin-6 (IL-6) and KC levels were elevated in septic wild type and LPA2-/- mice, while septic LPA2-/- mice reduces plasma KC, not IL-6 levels, compared to septic wild type mice. Bronchoalveolar lavage (BAL) KC levels increased in septic wild type and LPA2-/- mice, while the sepsis had no effect on BAL IL-6 levels, protein leak, and inflammatory cell infiltration in the lungs in wild type and LPA2-/- mice. Hematoxylin and eosin (H&E) staining revealed that septic LPA2-/- mice aggravated alveolar space enlargement. Western blotting analysis of lung tissues demonstrate that the level of cortactin, an F-actin binding protein, was decreased in septic LPA2-/- mice, when compared to wild type mice. The level of immunoglobulin G (IgG) in BAL fluids significantly increased in septic LPA2-/- mice, when compared to septic wild type mice and sham mice. Furthermore, we found that sham and septic LPA2-/- mice increased surfactant proteins B, C, and D (SP-B, SP-C, and SP-D) expression in lungs, while SP-A levels in lungs was decreased in sham and septic LPA2-/- mice. These results suggest LPA2 may regulate cortactin and surfactant protein expression in the lung. LPA2 and its downstream signaling may play a protective role against sepsis induced emphysema like disease.
Highlights
Lysophospholipids have been known as vital components in the organization of membrane structure; the increasing evidences suggest that lysophospholipids induce various cellular responses through ligation to their receptors on cell surface
LPA receptor type 2 (LPA2) mRNA was not changed after cecal ligation and single puncture (CLP). These results suggest that sepsis by CLP with a 27-gauge needle increased KC levels in bronchoalveolar larvage (BAL) fluids, but the procedure has limited effects on inflammatory cells influx into lung and lung leak in wild type and LPA2-/- mice
These results suggest that LPA2 and its downstream signaling protect against alveolar space enlargement
Summary
Lysophospholipids have been known as vital components in the organization of membrane structure; the increasing evidences suggest that lysophospholipids induce various cellular responses through ligation to their receptors on cell surface. Evidence of the pro-inflammatory effect of LPA has been observed by it increasing interleukin-8 (IL-8) production and secretion in lung epithelial cells [5,6,7]. This study is the first report to demonstrate that LPA2 deficient mice show alveolar space enlargement with a reduction of cortactin, an increase in the BAL IgG level, and changes of surfactant proteins in the lungs of a murine model of cecal ligation and puncture (CLP)-induced sepsis. These findings may provide a new therapeutic target against septic lung injury
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