Anionic Pulmonary Surfactant Phospholipids Inhibit Inflammatory Responses from Alveolar Macrophages and U937 Cells by Binding the Lipopolysaccharide-interacting Proteins CD14 and MD-2

Abstract

Lipopolysaccharide (LPS), derived from Gram-negative bacteria, is a major cause of acute lung injury and respiratory distress syndrome. Pulmonary surfactant is secreted as a complex mixture of lipids and proteins onto the alveolar surface of the lung. Surfactant phospholipids are essential in reducing surface tension at the air-liquid interface and preventing alveolar collapse at the end of the respiratory cycle. In the present study, we determined that palmitoyl-oleoyl-phosphatidylglycerol and phosphatidylinositol, which are minor components of pulmonary surfactant, and synthetic dimyristoylphosphatidylglycerol regulated the inflammatory response of alveolar macrophages. The anionic lipids significantly inhibited LPS-induced nitric oxide and tumor necrosis factor-␣ production from rat and human alveolar macrophages and a U937 cell line by reducing the LPS-elicited phosphorylation of multiple intracellular protein kinases. The anionic lipids were also effective at attenuating inflammation when administered intratracheally to mice challenged with LPS. Binding studies revealed high affinity interactions between the palmitoyl-oleoylphosphatidylglycerol and the Toll-like receptor 4-interacting proteins CD14 and MD-2. Our data clearly identify important antiinflammatory properties of the minor surfactant phospholipids at the environmental interface of the lung.

Pulmonary surfactant phosphatidylglycerol inhibits respiratory syncytial virus–induced inflammation and infection

“…Previous studies have provided evidence that the antagonism of LPS activation through LBP/CD14/MD2/TLR4 is dependent upon the molecular class and species of phospholipid used as an antagonist (17)(18)(19)(20). We examined the molecular specificity of the POPG effect on RSV-elicited cytokine production by comparing the effects of POPG with a phospholipid counterpart containing a choline polar moiety, palmitoyl-oleoylphosphatidylcholine (POPC).…”

“…In human pulmonary surfactant, POPG is the most abundant molecular species present within the PG class of phospholipid. Recent findings now indicate that selected surfactant lipids and proteins may complement each other in the homeostatic suppression of inflammation in the lung (17,21,22).We have undertaken a comprehensive examination of the role of POPG in regulating multiple aspects of innate immunity. As part of this endeavor we focused upon the interrelationships between CD14, POPG, and RSV.…”

“…Recently, we found that POPG inhibits proinflamamtory cytokine production induced by LPS in vitro and in vivo through direct interactions with CD 14 and MD2 (17). Additional studies have identified phosphatidylglycerol (PG) as an antagonist of LPS binding protein (LBP), and CD14 (18)(19)(20).…”

“…In human pulmonary surfactant, POPG is the most abundant molecular species present within the PG class of phospholipid. Recent findings now indicate that selected surfactant lipids and proteins may complement each other in the homeostatic suppression of inflammation in the lung (17,21,22).…”

Giving RSV some POP(G)

“…4 Now, his team has shown that POPG directly binds RSV in vitro and reduces viral infection and lung pathology in vivo. 1 In RSV-infected epithelial cell lines, POPG liposomes prevented both viral spread to neighboring cells and cell death.…”