Deletion of Lysophosphatidic acid Receptors 1 and 2 Protects Against Lipopolysaccharide‐Induced Acute Lung Injury in Mice

Abstract

Lysophosphatidic acid (LPA), a bioactive phospholipid, exhibits both pro‐ and anti‐inflammatory responses in the airway. LPA activates intracellular signaling pathways by ligating to G‐protein‐coupled LPA receptors (LPA‐Rs). Here, we have evaluated the role of LPA and LPA‐Rs in a LPS‐induced murine model of acute lung injury (ALI). Wild type and genetically engineered LPA1 and LPA2 knockout (LPA1−/− and LPA2−/−) mice were intratracheally challenged with LPS, and after 24 h, bronchoalveolar lavage (BAL) fluids and lung tissues were collected. LPS challenge increased LPA1–3 protein expression in the lung and LPA levels in BAL fluids, as measured by LC‐MS/MS. LPA1−/− and LPA2−/− mice reduced lung inflammation after LPS challenge as determined by IL‐6 levels, and infiltration of neutrophils in BAL fluids. Further, intratracheal administration of Ki16425, an antagonist of LPA1&3, prior to LPS challenge attenuated LPS‐induced IL‐6 release and interstitial infiltration of neutrophils without altering total protein concentration in BAL fluids. Taken together, these results show that inhibition of LPA receptors protects against LPS‐induced lung inflammation, but not pulmonary microvascular injury. These studies identify LPA‐Rs as novel pro‐inflammatory components in LPS‐induced ALI. This work was supported by NIH grant HL 091916 to Y.Z.