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. 2022 Dec 14;12(12):1878.
doi: 10.3390/biom12121878.

Lipidomic Profile Analysis of Lung Tissues Revealed Lipointoxication in Pulmonary Veno-Occlusive Disease

Spiro Khoury  1 , Antoine Beauvais  2   3   4 , Jenny Colas  1   5 , Anaïs Saint-Martin Willer  2   3 , Frédéric Perros  2   3 , Marc Humbert  2   3   4 , Clarisse Vandebrouck  1   5 , David Montani  2   3   4 , Thierry Ferreira  1   5 , Fabrice Antigny  2   3
Affiliations

Lipidomic Profile Analysis of Lung Tissues Revealed Lipointoxication in Pulmonary Veno-Occlusive Disease

Spiro Khoury et al. Biomolecules. .

Abstract

Pulmonary veno-occlusive disease (PVOD) is a rare form of pulmonary arterial hypertension (PAH) occurring in a heritable form (hPVOD) due to biallelic inactivating mutations of EIF2AK4 (encoding GCN2, general control nonderepressible 2) or in a sporadic form in older age (sPVOD), following exposure to chemotherapy or organic solvents. In contrast to PAH, PVOD is characterized by a particular remodeling of the pulmonary venous system and the obliteration of small pulmonary veins by fibrous intimal thickening and patchy capillary proliferation. The pathobiological knowledge of PVOD is poor, explaining the absence of medical therapy for PVOD. Lung transplantation remains the only therapy for eligible PVOD patients. As we recently demonstrated, respiratory diseases, chronic obstructive pulmonary disease, or cystic fibrosis exhibit lipointoxication signatures characterized by excessive levels of saturated phospholipids contributing to the pathological features of these diseases, including endoplasmic reticulum stress, pro-inflammatory cytokines production, and bronchoconstriction. In this study, we investigated and compared the clinical data and lung lipid signature of control (10 patients), idiopathic PAH (7 patients), heritable PAH (9 BMPR2 mutations carriers), hPVOD (10 EIF2AK4 mutation carriers), and sPVOD (6 non-carriers) subjects. Mass spectrometry analyses demonstrated lung lipointoxication only in hPVOD patients, characterized by an increased abundance of saturated phosphatidylcholine (PC) at the expense of the polyunsaturated species in the lungs of hPVOD patients. The present data suggest that lipointoxication could be a potential player in the etiology of PVOD.

Keywords: PVOD; lysophosphatidylcholine; phospholipids.

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Conflict of interest statement

The sponsors had no role in the design, collection, analysis, or interpretation of data, the writing of this article, or the decision to submit it for publication. M.H. and D.M. have relationships with specific drug companies, including Actelion, Bayer, GSK, Novartis, and Pfizer. In addition to being investigators in trials involving these companies, other relationships include consultancy services and memberships on scientific advisory boards. The other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Relative abundance of phosphatidylcholine (PC) species in lungs from control. After total lipids were extracted, the relative abundance of phosphatidylcholine (PC) species was analyzed by mass spectrometry.
Figure 2
Figure 2
hPVOD lung tissues are characterized by lipointoxication. (A) PC32:0; (B) PC34:2; (C) PC34:4; (D) PC34:1. (E) PC36:4/PC32:0 ratio in lungs from control, iPAH, hPAH, hPVOD, and sPVOD patients. (F) LPC16:0/PC36:4 ratio in lungs from control, iPAH, hPAH, hPVOD, and sPVOD patients. ns: non-significant, * p < 0.05, ** p < 0.001.
See this image and copyright information in PMC

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