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. A Brief Overview on Sphingolipids within the Lung Environment The interest in sphingolipid presence and bioactivities in the respiratory airways has produced a steady number of reports since the 1970s. However, a host of publications in the last few years have provided an increasingly detailed picture of the role played in the lungs by this class of lipids and by the proteins that handle them. As vital respiratory organs that mediate air-blood gas exchanges, lungs must undergo delicate and tightly controlled developmental transitions. Antenatally, a 20-week human fetus displays lungs that have branched to generate all airways, but it is not before ∼28 weeks of gestation that alveolarization begins from primordial saccular structures and type I alveolar cells differentiate from the cuboidal epithelium. Concomitantly, at this stage endothelial cells shape the alveolar capillary bed and type II alveolar cells appear, to demarcate alveolar septal junctions. Type II cells start producing surfactant, which accumulates to increasing concentrations by term. The initiation of autonomous ventilation at birth represents a dramatic switch in postnatal lung function. While throughout gestation a chloride-ion driven liquid secretion creates a positive pressure that distends the lungs and stimulates growth, a sudden reversal from net secretion to net adsorption takes place at birth under the effect of O 2 and hormones (epinephrine, glucocorticoids, and thyroid hormones), enabling the rapid elimination of lung liquid. From this moment on, lung lumen will maintain a low-level chloride-ion based liquid secretion to generate a surface liquid layer, known as surfactant and formed by specific secreted lipids and proteins, and a robust absorptive capacity will prevent alveolar flooding and edema. Equally important, being permanently exposed to inhaled particles and microorganisms from birth, pulmonary immunity must be tuned to effectively dispose of them, while minimizing immunopathology to preserve appropriate gas exchange. Thus, the first-line lung defenses, prior to immunity, are based on mechanical weapons including cilia, mucus, and the cough reflex, which concur to prevent pathogen access to the lower airways and in so doing avoid an overt inflammatory response. This is one of the major reasons why lungs are particularly sensitive to the sphingolipid (and Hindawi Publishing Corporatio