Lysophosphatidic acid enhances pulmonary epithelial barrier integrity and protects endotoxin-induced epithelial barrier disruption and lung injury.

Abstract

Lysophosphatidic acid (LPA), a bioactive phospholipid, induces a wide range of cellular effects, including gene expression, cytoskeletal rearrangement, and cell survival. We have previously shown that LPA stimulates secretion of pro- and anti-inflammatory cytokines in bronchial epithelial cells. This study provides evidence that LPA enhances pulmonary epithelial barrier integrity through protein kinase C (PKC) delta- and zeta-mediated E-cadherin accumulation at cell-cell junctions. Treatment of human bronchial epithelial cells (HBEpCs) with LPA increased transepithelial electrical resistance (TER) by approximately 2.0-fold and enhanced accumulation of E-cadherin to the cell-cell junctions through Galpha(i)-coupled LPA receptors. Knockdown of E-cadherin with E-cadherin small interfering RNA or pretreatment with EGTA (0.1 mm) prior to LPA (1 microm) treatment attenuated LPA-induced increases in TER in HBEpCs. Furthermore, LPA induced tyrosine phosphorylation of focal adhesion kinase (FAK) and overexpression of the FAK inhibitor, and FAK-related non-kinase-attenuated LPA induced increases in TER and E-cadherin accumulation at cell-cell junctions. Overexpression of dominant negative protein kinase delta and zeta attenuated LPA-induced phosphorylation of FAK, accumulation of E-cadherin at cell-cell junctions, and an increase in TER. Additionally, lipopolysaccharide decreased TER and induced E-cadherin relocalization from cell-cell junctions to cytoplasm in a dose-dependent fashion, which was restored by LPA post-treatment in HBEpCs. Intratracheal post-treatment with LPA (5 microm) reduced LPS-induced neutrophil influx, protein leak, and E-cadherin shedding in bronchoalveolar lavage fluids in a murine model of acute lung injury. These data suggest a protective role of LPA in airway inflammation and remodeling.

• Authors: Donghong He, Yanlin Su, Peter V Usatyuk, Ernst Wm Spannhake, Paul Kogut, Julian Solway, Viswanathan Natarajan, Yutong Zhao
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 284 Issue 36 Pg. 24123-32 (Sep 04 2009) ISSN: 0021-9258 [Print] United States
• PMID: 19586906 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Cadherins
• Cytokines
• Lipopolysaccharides
• Lysophospholipids
• Receptors, Lysophosphatidic Acid
• Focal Adhesion Kinase 1
• PTK2 protein, human
• Ptk2 protein, mouse
• Protein Kinase C-delta
• Protein Kinase C-epsilon
• lysophosphatidic acid

Topics

• Animals
• Cadherins (genetics, metabolism)
• Cytokines (genetics, metabolism)
• Dose-Response Relationship, Drug
• Epithelial Cells (metabolism, pathology)
• Focal Adhesion Kinase 1 (genetics, metabolism)
• Humans
• Lipopolysaccharides (toxicity)
• Lung Injury (chemically induced, genetics, metabolism, pathology, prevention & control)
• Lysophospholipids (pharmacology)
• Mice
• Phosphorylation (drug effects, genetics)
• Protein Kinase C-delta (genetics, metabolism)
• Protein Kinase C-epsilon (genetics, metabolism)
• Receptors, Lysophosphatidic Acid (genetics, metabolism)
• Respiratory Mucosa (metabolism, pathology)