Role of Sphingolipids in the Pathobiology of Lung Inflammation

Abstract

Sphingolipid bioactivities in the respiratory airways and the roles of the proteins that handle them have been extensively investigated. Gas or inhaled particles or microorganisms come into contact with mucus components, epithelial cells, blood barrier, and immune surveillance within the airways. Lung structure and functionality rely on a complex interplay of polar and hydrophobic structures forming the surfactant layer and governing external-internal exchanges, such as glycerol-phospholipids sphingolipids and proteins. Sphingolipids act as important signaling mediators involved in the control of cell survival and stress response, as well as secreted molecules endowed with inflammation-regulatory activities. Most successful respiratory infection and injuries evolve in the alveolar compartment, the critical lung functional unit involved in gas exchange. Sphingolipid altered metabolism in this compartment is closely related to inflammatory reaction and ceramide increase, in particular, favors the switch to pathological hyperinflammation. This short review explores a few mechanisms underlying sphingolipid involvement in the healthy lung (surfactant production and endothelial barrier maintenance) and in a selection of lung pathologies in which the impact of sphingolipid synthesis and metabolism is most apparent, such as acute lung injury, or chronic pathologies such as cystic fibrosis and chronic obstructive pulmonary disease.

Plasma metabolomics in adults with cystic fibrosis during a pulmonary exacerbation: A pilot randomized study of high-dose vitamin D 3 administration

“…Sphingolipids play an important role in the inflammatory response and are known to be dysregulated in CF (44). Phosphatidylcholine metabolites were also generally elevated compared to healthy controls, in contrast to previous studies indicating lower levels in clinically-stable CF (45,46), and may reflect the acutely ill state of our hospitalized subjects.…”

Mogroside IIIE Attenuates LPS‐Induced Acute Lung Injury in Mice Partly Through Regulation of the TLR4/MAPK/NF‐κB Axis via AMPK Activation

“…Acute lung injury (ALI) is characterized by the infiltration of inflammatory cells, production of inflammatory mediators and diffuse lung inflammation (Shi et al, ), leading to a high mortality rate (Sun et al, ; Ghidoni et al, ; Sharp et al, ). A variety of clinical syndromes, such as pneumonia, sepsis, major trauma, gastric content aspiration and acute pancreatitis, can induce the occurrence of ALI (Feng et al, ).…”

The bidirectional relationship between CFTR and lipids

“…Importantly, this imbalance was found regardless of whether the mice were fed the liquid Peptamen diet or the standard chow diet like the non-CF control mice, indicating that altered diet was not the cause of ceramide imbalance. This ceramide imbalance could contribute to the chronic inflammation seen in CF patient lungs as long-chain ceramides are pro-inflammatory while very-long-chain ceramides are anti-inflammatory (see Ghidoni et al 40 , for details on ceramide's involvement in the pathophysiology of CF and other inflammatory lung diseases). Importantly, total lung homogenate includes much more than just epithelial cells, so these data must be considered carefully since it is unclear what cell types are contributing to this imbalance.…”