Sphingolipids in Lung Pathology in the Coronavirus Disease Era: A Review of Sphingolipid Involvement in the Pathogenesis of Lung Damage

Abstract

Sphingolipids are bioactive lipids involved in the regulation of cell survival, proliferation, and the inflammatory response. The SphK/S1P/S1PR pathway (S1P pathway) is a driver of many anti-apoptotic and proliferative processes. Pro-survival sphingolipid sphingosine-1-phosphate (S1P) initiates its signaling cascade by interacting with various sphingosine-1-phosphate receptors (S1PR) through which it is able to exert its pro-survival or inflammatory effects. Whereas sphingolipids, including ceramides and sphingosines are pro-apoptotic. The pro-apoptotic lipid, ceramide, can be produced de novo by ceramide synthases and converted to sphingosine by way of ceramidases. The balance of these antagonistic lipids and how this balance manifests is the essence of the sphingolipid rheostat. Recent studies on SARS-CoV-2 have implicated the S1P pathway in the pathogenesis of novel coronavirus disease COVID-19-related lung damage. Accumulating evidence indicates that an aberrant inflammatory process, known as “cytokine storm” causes lung injury in COVID-19, and studies have shown that the S1P pathway is involved in signaling this hyperinflammatory response. Beyond the influence of this pathway on cytokine storm, over the last decade the S1P pathway has been investigated for its role in a wide array of lung pathologies, including pulmonary fibrosis, pulmonary arterial hypertension (PAH), and lung cancer. Various studies have used S1P pathway modulators in models of lung disease; many of these efforts have yielded results that point to the potential efficacy of targeting this pathway for future treatment options. Additionally, they have emphasized S1P pathway’s significant role in inflammation, fibrosis, and a number of other endothelial and epithelial changes that contribute to lung damage. This review summarizes the S1P pathway’s involvement in COVID-19 and chronic lung diseases and discusses the potential for targeting S1P pathway as a therapeutic option for these diseases.

S1P-Induced TNF-α and IL-6 Release from PBMCs Exacerbates Lung Cancer-Associated Inflammation

“…An ever-growing body of evidence has now confirmed S1P involvement in inflammatory signaling(s) associated with the development of lung disorders [ 13 ], although the mechanism(s) is/are still elusive. Therefore, we stimulated PBMCs isolated from the blood of healthy volunteers (H) and lung cancer patients (LK) with S1P (10 nM), and the release of pro-inflammatory cytokines was evaluated.…”

Network-based integrative multi-omics approach reveals biosignatures specific to COVID-19 disease phases

“…We identified Sphingolipid metabolism processes to be common across all disease states. It has been suggested that the virus hijacks sphingolipid metabolism and dysregulates the metabolism activities to promote its replication and to evade the host immune response, aligning with the involvement of these processes in the pathogenesis of severe disease patients ( Supplementary File 4 Tables 5, 6, and 12 ) (72). We also identified other pathways linked with metabolic pathways discriminating moderate and severe disease states including, but not limited to, phenylalanine, tyrosine, and tryptophan biosynthesis pathways, and the pentose phosphate pathway.…”

In silico analysis of genomic landscape of SARS-CoV-2 and its variant of concerns (Delta and Omicron) reveals changes in the coding potential of miRNAs and their target genes

“…For the Omicron strain, we got 4 enriched genes (ROCK2, KRAS, FYN, and GNAI1) related to the sphingolipid signaling pathway. The role of sphingolipids in COVID1-19 related lung damage has been recently reviewed by Khan et al ( Khan et al, 2021 ) shows that disruption in the sphingolipid pathway induces the hyperinflammatory response known as cytokine storm.…”