Surfactant Lipids at the Host-Environment Interface. Metabolic Sensors, Suppressors, and Effectors of Inflammatory Lung Disease

Abstract

The lipid composition of pulmonary surfactant is unlike that of any other body fluid. This extracellular lipid reservoir is also uniquely susceptible by virtue of its direct and continuous exposure to environmental oxidants, inflammatory agents, and pathogens. Historically, the greatest attention has been focused on those biophysical features of surfactant that serve to reduce surface tension at the air-liquid interface. More recently, surfactant lipids have also been recognized as bioactive molecules that maintain immune quiescence in the lung but can also be remodeled by the inhaled environment into neolipids that mediate key roles in inflammation, immunity, and fibrosis. This review focuses on the roles in inflammatory and infectious lung disease of two classes of native surfactant lipids, glycerophospholipids and sterols, and their corresponding oxidized species, oxidized glycerophospholipids and oxysterols. We highlight evidence that surfactant composition is sensitive to circulating lipoproteins and that the lipid milieu of the alveolus should thus be recognized as susceptible to diet and common systemic metabolic disorders. We also discuss intriguing evidence suggesting that oxidized surfactant lipids may represent an evolutionary link between immunity and tissue homeostasis that arose in the primordial lung. Taken together, the emerging picture is one in which the unique environmental susceptibility of the lung, together with its unique extracellular lipid requirements, may have made this organ both an evolutionary hub and an engine for lipid-immune cross-talk.

Keywords: cholesterol; innate immunity; lung; phospholipid; surfactant.

Figure 1.

Representative structures of lipid species found in pulmonary surfactant. For glycerophospholipids and cardiolipin, fatty acyl side chains are depicted in pink, the glycerol backbone is shown in black, and polar head groups are located on the far right side of the structure. Structures shown were generated using the online structure drawing tools from LIPID MAPS (132).

Figure 2.

Roles of native and oxidized surfactant glycerophospholipids in inflammatory lung responses to the environment. The complex immune interactions that occur in the alveolus between native surfactant glycerophospholipids (PLs) and environmental agents are depicted. Surfactant PLs, including dipalmitoylphosphatidylcholine (DPPC), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylinositol (PI), phosphatidylethanolamine (PE), and 1-palmitoyl-2-arachidonoyl-phosphatidylcholine (PAPC) are synthesized by alveolar epithelial type 2 cells and released as lamellar bodies that unravel to form the surfactant layer. Various lipids are depicted in the surfactant monolayer inset, but native surfactant is DPPC predominant. Inhaled agents and reactive oxygen species (ROS) derived from host cells oxidize PAPC and PE into oxidized PLs (oxPLs), as shown. Native PLs antagonize delivery of pathogens and pathogen-associated molecules to cellular receptors, and oxPL species act on multiple receptors on alveolar macrophages, both promoting and suppressing inflammation. Plasma lipoproteins, including high-density lipoprotein (HDL), low-density lipoprotein (LDL), and very LDL (VLDL), deliver and receive lipids to/from alveolar epithelial cells, influencing PL synthesis. ABCA1, ATP binding cassette A1 transporter; CCT, cytidyltransferase; EP2, prostaglandin E2 receptor; IAV, influenza A virus; KETE, 15-ketoeicosatetraenoic acid; MALP-2, macrophage-activating lipopeptide-2; MARCO, macrophage receptor with collagenous structure; Nrf2, nuclear factor E2-related factor 2; oxPAPC, oxidized PAPC; PEIPC, 1-palmitoyl-2-(5,6-epoxyisoprostane E2)-sn-glycero-3-phosphocholine; PPAR, peroxisome proliferator-activated receptor; RSV, respiratory syncytial virus; SARS, severe acute respiratory syndrome; SR-BI, scavenger receptor class B member I; TGF, transforming growth factor; TLR, Toll-like receptor.