Lipid plays an important role in lung pathology and physiology. Although the composition and involvement of the lipidome in various disease is still poorly understood, abnormal lipid metabolism has been reported in pulmonary diseases including asthma, COPD and lung cancer (Li WJ et al.2021; Liu D et al. 2020; Zhu Z et al.2020). Lipids comprise diverse classes of components which are critically involved in cellular structure, signaling and energy storage (Zehethofer N et al. 2015). However, the potential role of lipid in pneumoconiosis pathogenesis remains unclear.
We observed that most of pneumoconiosis patients have poor nutritional status and bodies. We assume that it is related to hypoxia and poor lung function. We analyzed the possible reasons as follow: (1) Long-term hypoxia and chronic inflammatory infiltration may lead to gastrointestinal congestion. Recurrent pneumonia and dyspnea with antibiotics and theophylline and other drugs may reduce the absorption, transformation and synthesis of exogenous cholesterol and triglyceride in small intestinal mucosa cells (Mc GT et al. 2018); (2) liver cell hypoxia leads to energy dysmetabolism and decreasing the source of cholesterol and triglyceride synthesis raw materials, such as fatty acid, Acetyl coenzyme A, ATP, NADPH +, H +, and the synthesis rate of endogenous cholesterol and triglyceride decreased (Xiao W et al. 2018); (3) The lipid decomposition of pneumoconiosis increases, due to lung fibrosis. Thus, it causes a large amount of ATP consumption and increased body catabolism, and lipolysis (Nambiar S et al. 2021).
Lipidomic profiles between health and pneumoconiosis had never been defined before, although a majority of pneumoconiosis patients had decreased levels of serum CHO, TAG, HDL and LDL. With the rapid development of biotechnology on analytical chemistry, lipidomics has been used as a tool to define the lipid profiling of lung tissue and plasma, and the relationship between lipid characterization and lung function (Zhu Z et al.2020; Gao D et al. 2019). We investigated the plasma lipidomic profiles of patients with pneumoconiosis. Our study showed that PEs and FFAs were significantly higher in pneumoconiosis than healthy control, whereas some of PCs, lyso PCs were significantly lower.
PCs and PEs are the most abundant phospholipids in cell membranes and play essential structural and signaling roles. PCs play significant roles in lung surfactant phospholipid metabolism and is the major phospholipid comprising around 80% of surfactant lipid. Alterations in their composition can cause reduced elasticity, leading to an overall decrease in lung compliance (Agudelo CW et al. 2020; Agassandian M et al. 2013). Changes in the component phospholipids, including PCs have been described increased in plasma of patients with pulmonary fibrosis (Nambiar S et al. 2021). Lv et al demonstrated that plasma levels of PC and lysoPC were increased while PE and lysoPE were decreased in patient with lung cancer (Lv J et al. 2021). Gao et al also found that there was an increase of PC and lysoPC in acute exacerbation of chronic pulmonary (AECOPD), acute pulmonary embolism (APE) and sever acute pneumonia (SAP) (Gao D et al. 2019). However, the trend of PE, PC and lysoPC in patient with pneumoconiosis were different from the results of the above researches in other pulmonary diseases. The up-regulated PE and down-regulated PC in this study might be a potential criterion to distinguish the pneumoconiosis from healthy and even other lung diseases. Although the reason and mechanism of changed lipidomics in pneumoconiosis are not clear, it may be of great significance to find the pathogenesis of pneumoconiosis.
In our study, we also found that FFA (22:4) was significantly higher in pneumoconiosis than healthy control. Guenther et al. reported that elevated plasma FFA levels resulted in increased activation of the classic proinflammatory IKK/IκB/NF-κB pathway and increased expression of inflammatory cytokines (tumor necrosis fator-α, interleukin-1β and interleukin-6) (Boden G et al. 2005). Rudi et al. reported that activation of FFA, a member of the G protein-coupled receptor family, FFA, that responded to FFA, resulted in a decrease in lung resistance (Prihandoko R et al. 2020). At present, researches on FFA and FFA receptors are mostly focused on metabolic disorders such as diabetes and obesity, but few on respiratory diseases. Recent study found that FFA4 was highly expressed in lung epithelial cells (Miyauchi S et al. 2009), and that FFA acting via FFA4 receptors might have some beneficial effects on airway epithelial repair after naphthalene-induced airway injury (Lee KP et al. 2017). These researches suggested that it may also be a potential target for understanding pathogenesis and treating respiratory diseases including pneumoconiosis.
There was lack of research in linking the lipidome data with clinical phenomes. Like other omics analysis, most genomic data were not tied with clinical information, which showed limited value for clinical precision medicine (Rubin MA et al. 2015). In order to integrate lipid profiles with clinical phenomes, clinical lipidomics is a novel extension of lipidomics to study lipid profiles, pathways and networks by characterizing and quantifying the total lipidomes in patients, and to link the lipidomics components to clinical phenomics (Lv J et al. 2018). Our study made the descriptive clinical phenomes scored by DESS system (Shi L et al. 2018), converting descriptive information of clinical phenomes into digital information (Chen H et al. 2012) and had performed in patients with pulmonary embolism, acute pneumonia, and AECOPD, based on clinical tran-somics principle (Gao D et al. 2019).
In this study, through eQTL model and integrated lipidomic and phenomic profiles, we discovered clinical phenotypes can be associated with a variety of altered lipid elements. Lipidomic profiles with about 426 lipids in 11 classes in pneumoconiosis, were correlated with clinical phenotypes, and it turned out that all altered lipids (VIP>1.0) had strong correlations with pH, FEV1, mediastinal lymph node calcification and complications. Furthermore, we also found that PE was corresponded to pH, smoking history and mediastinal lymph node calcification and PC was corresponded to BMI, dust exposure history and mediastinal lymph node calcification separately.
The pathophysiological characteristics were macrophage accumulation. Recent studies had showed that macrophages were fundamental for the repair of organs that were injured due to ischemia. In response to hypoxia, acute-phase macrophages activate hypoxia-inducible transcription factors that adjust cellular metabolism. This occurs through glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, lipids, amino acids pathways leading to metabolic acidosis and decreased pH (Thorp EB. 2021).
1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), is a lipid marker of alveolar type 2 epithelial cells. Recently a study revealed SiO2 exposure could result in decreased DPPC secretion, affecting the normal function of alveoli, and lung function potentially (Liu S et al. 2021). There were studies confirmed that altered lipid metabolism (PCs and lysoPCs) is associated with decreased lean body mass (Papandreou C et al. 2021). These studies were consistent with our experimental results.
There was a research indicating that PEs were higher expressed in smokers with COPD, compared with smokers without COPD. Altered lipids with a high fold change between smokers with and without COPD showed high correlations with lower lung function and inflammation in sputum (Telenga ED et al. 2014). In our study, PEs were highly expressed in smoking patients. The mechanism and the diagnostic and therapeutic value of elevated PE was not clear now. Wu et al found that phospholipid remodeling was critical forstem cell pluripotency by facilitating mesenchymal-to-epithelial transition and also showed that PE binding to Pebp1 enhanced the interaction of Pebp1 with IKKα/β and reduced the phosphorylation of IKKα/β and NF-κB signaling. Collectively, studies reveal an unforeseen connection between phospholipids and cell pluripotency and also highlights the importance of phospholipids in diseases (Wu Y et al. 2019).
Calcification of mediastinal and hilar lymph nodes was commonly found in pneumoconiosis. Although the mechanism of calcification of mediastinal lymph nodes was not clear, it might because macrophage accumulation and altered lipid metabolism in pneumoconiosis present with similar dystrophic calcification. But further clinical trials are needed (Bargagli E et al. 2017).
There were also limitations in this study. First, the sample size was small. Second,
therapeutic factors were not explored, and most corresponding groups of patients should be studied in future to explore medical influence on lipidomics. Third, it is not clear whether the correlation is positive or negative by the eQTL model for trans-omics.
In conclusion, we found that altered lipid panels between pneumoconiosis patients and healthy people by qualitatively and quantitatively measured plasma lipidomic profiles. Levels of PE and FFA elements meaningfully improved while PC and lysoPC reduced in patients with pneumoconiosis. Clinical trans-omics analyses demonstrated that some phenomes have strong correlation with lipids, although those needed to be further confirmed by bigger studies including large population of patients in multicenters. Consequently, our data suggested that trans-omic profiles between clinical phenomes and lipidomes might have the potential value to reveal the heterogeneity of lipid metabolism among pneumoconiosis patients and to identify meaningful phenome-based lipid panels as biomarkers.