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Review
. 2022 Apr 3;11(7):1209.
doi: 10.3390/cells11071209.

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

Olivier Burgy  1   2 , Sabrina Loriod  1   2 , Guillaume Beltramo  1   2   3 , Philippe Bonniaud  1   2   3
Affiliations
Review

Extracellular Lipids in the Lung and Their Role in Pulmonary Fibrosis

Olivier Burgy et al. Cells. .

Abstract

Lipids are major actors and regulators of physiological processes within the lung. Initial research has described their critical role in tissue homeostasis and in orchestrating cellular communication to allow respiration. Over the past decades, a growing body of research has also emphasized how lipids and their metabolism may be altered, contributing to the development and progression of chronic lung diseases such as pulmonary fibrosis. In this review, we first describe the current working model of the mechanisms of lung fibrogenesis before introducing lipids and their cellular metabolism. We then summarize the evidence of altered lipid homeostasis during pulmonary fibrosis, focusing on their extracellular forms. Finally, we highlight how lipid _targeting may open avenues to develop therapeutic options for patients with lung fibrosis.

Keywords: extracellular lipids; idiopathic pulmonary fibrosis; lipid metabolism.

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Conflict of interest statement

O.B. and S.L. declare no conflict of interest. G.B. and P.B. received support from Boeringher Ingelheim and Roche for attending medical and research meetings and serving in advisory board.

Figures

Figure 1
Figure 1
Altered lipid metabolism during fibrosis contributes to the activation of alveolar epithelial cells. Under physiological conditions, the elongation enzyme ELOVL6 allows fatty acid elongation and therefore promotes high intracellular stearic acid vs. palmitic acid. Stearic acid interferes with pro-fibrotic TGF-β/Smad signaling (red inhibition arrow). In parallel, ATII cells produce surfactant lipids (mainly PCs) which will be stocked in lamellar bodies and exported in the extracellular milieu in an ABCA3-dependant mechanism. During pulmonary fibrosis, ELOVL6 expression is decreased, favoring the accumulation of palmitic acid. High intracellular palmitic acid induces oxidative and ER stress, thus promoting TGF-β/Smad signaling and cell activation. This is enhanced by the accumulation of cholesterol and its derivates during fibrosis, which activates the expression of collagen and other ECM components. In addition, surfactant lipids accumulate within the cell due to decreased expression of ABCA3 under fibrotic conditions. This also leads to impaired surfactant formation in pulmonary fibrosis.
Figure 2
Figure 2
The role of extracellular lipids in the pathogenesis of pulmonary fibrosis. During pulmonary fibrosis, (1) impaired secretion of the surfactant lipids, mainly phosphatydil-choline (PC) promotes the accumulation of oxidized phospholipids, mainly oxidized-PC (OxPC). (2) PC are also a source of lysophosphate acid (LPA) after processing by autotaxin, which is increased during fibrosis. (3) The accumulation of palmitic acid in alveolar epithelial cells results in major oxidative stress and ultimately apoptosis. (4) Sphingosine-1-phosphate (S1P) accumulates in the extracellular space and promotes the EMT of ATII cells. Further, (5) activated ATII cells produce large amount of phosphatydil-glycerol. All these lipids contribute to the polarization of local macrophages towards a profibrotic M2-phenotype or the activation of ATII cells. In addition, S1P has a supplemental role in the activation of aberrant ATII cells. Altogether, cell activation turns fibroblasts into pathological (myo)fibroblasts which (6) produce high levels of arachidonic acid derivatives with a high leukotriene to prostaglandin ratio. Of note, (7) inflammation-primed fibroblasts also secrete extracellular vesicles carrying prostaglandins. The increase in pulmonary lipids during fibrosis is linked to increased circulating PC. In normal conditions, (8) lower levels of blood PC are likely to be found with increased circulating HDL, and (9) arachidonic acid metabolism in fibroblasts results in leukotriene overproduction. (10) ATII cells produce surfactant-forming lipids (mainly PCs) to participate in lung surfactant homeostasis. Cell types (black) and lipids (light green) are labeled.
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