For the treatment of severe COVID-19, supplementation with human plasma-purified α-1 antitrypsin (AAT) to patients is currently considered. AAT inhibits host proteases that facilitate viral entry and possesses broad anti-inflammatory and immunomodulatory activities. Researchers have demonstrated that an interaction between SARS-CoV-2 spike protein (S) and lipopolysaccharides (LPS) enhances pro-inflammatory responses in vitro and in vivo. Hence, we wanted to understand the potential anti-inflammatory activities of plasma-derived and recombinant AAT (recAAT) in a model of human total peripheral blood mononuclear cells (PBMCs) exposed to a combination of CHO expressed trimeric spike protein and LPS, ex vivo. We confirmed that cytokine production was enhanced in PBMCs within six hours when low levels of LPS were combined with purified spike proteins (“spike”). In the presence of 0.5 mg/mL recAAT, however, LPS/spike-induced TNF-α and IL-1β mRNA expression and protein release were significantly inhibited (by about 46–50%) relative to LPS/spike alone. Although without statistical significance, recAAT also reduced production of IL-6 and IL-8. Notably, under the same experimental conditions, the plasma-derived AAT preparation Respreeza (used in native and oxidized forms) did not show significant effects. Our findings imply that an early pro-inflammatory activation of human PBMCs is better controlled by the recombinant version of AAT than the human plasma-derived AAT used here. Considering the increasing clinical interest in AAT therapy as useful to ameliorate the hyper-inflammation seen during COVID-19 infection, different AAT preparations require careful evaluation.

To explore the relationship between cancer cell SREBF1 expression, lipid droplets (LDs) formation, and the sensitivity to chemotherapies, we cultured lung adenocarcinoma cells H1299 (with LD) and H1563 (without LD) in a serum-free basal medium (BM) or neutrophil degranulation products containing medium (NDM), and tested cell responses to cisplatin and etoposide. By using the DESeq2 Bioconductor package, we detected 674 differentially expressed genes (DEGs) associated with NDM/BM differences between two cell lines, many of these genes were associated with the regulation of sterol and cholesterol biosynthesis processes. Specifically, SREBF1 markedly declined in both cell lines cultured in NDM or when treated with chemotherapeutics. Despite the latter, H1563 exhibited LD formation and resistance to etoposide, but not to cisplatin. Although H1299 cells preserved LDs, these cells were similarly sensitive to both drugs. In a cohort of 292 patients with non-small-cell lung cancer, a lower SREBF1 expression in tumors than in adjacent nontumor tissue correlated with overall better survival, specifically in patients with adenocarcinoma at stage I. Our findings imply that a direct correlation between SREBF1 and LD accumulation can be lost due to the changes in cancer cell environment and/or chemotherapy. The role of LDs in lung cancer development and response to therapies remains to be examined in more detail.

Lung cancer is one of the main causes of cancer deaths in the world, and adenocarcinoma (ADC) subtype accounts for more than 50% of the cases. Cancer cells exhibit abilities for lipid uptake and can store them as lipid droplets (LDs). Lipids and lipid metabolism-related genes widely participate in the regulation of cancer cell viability, response and resistance to chemotherapy. In this study, we compared transcriptomic profiles from two lung ADC cell lines: i) H1299, containing LDs and expressing phospholipid transfer protein (PLTP), which facilitates the transfer of various lipid molecules; and ii) H1563 having no LDs and very low PLTP expression; and tested the responses of these cells to chemotherapeutic drugs- staurosporin, cisplatin and etoposide. According to the Annexin V-PE apoptosis detection assays, H1299 and H1563 cells revealed similar resistance to staurosporin (50 nM) but H1299 were more resistant (by 50%) to cisplatin (70 µM). The cell behavior was totally different in response to etoposide because a higher concentration (100µM) of this drug induced LDs formation in H1563, and these cells were more resistant (by 40%) to etoposide-induced apoptosis than H1299 cells. According to RNA-seq data, H1563 show higher expression of LPL (12-fold), FABP4 (9-fold) and CD36 (4-fold) than H1299 cells. Via LPL, cancer cells are able to acquire fatty acids (FA) from the circulation and CD36 facilitates cellular FA uptake. An anti-apoptotic and LPL-linked gene BCL2 (4-fold higher in H1563) may increase resistance to DNA-damage-inducing drugs, like etoposide. Hence, a better understanding of lipid role in carcinogenesis is crucial for advancements in diagnostic and treatment strategies in lung cancer.