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Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1β) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1β, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in angiotensin-converting enzyme-2 (ACE-2) following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.

Acute lung injury caused by sepsis remains one of the most difficult challenges faced by patients in intensive care units and is associated with a high mortality rate. The aim of the present study was to investigate whether programmed cell death (PD)-1/programmed cell death-ligand 1 (PD-L1) inhibitors reduce alveolar macrophage apoptosis, reduce inflammatory factor release and relieve inflammation. For this purpose, murine alveolar macrophages, MH-S, were cultured and divided into control, lipopolysaccharide (LPS) and LPS+BMS-1 (PD-1/PD-L1 inhibitors) groups. LPS (10 ng/ml) was added to the LPS and LPS+BMS-1 groups for 24 h and PD-1/PD-L1 inhibitor BMS-1 (1 µmol/l) was added to the LPS+BMS-1 group for 72 h. PD-1 mRNA expression was detected using reverse transcription-quantitative PCR and PD-1 protein expression was detected using western blotting in the control, LPS and LPS+BMS-1 groups of macrophages. MH-S apoptosis was detected using flow cytometry with Annexin V/PI staining. The levels of the inflammatory factors interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α and IL-10 were detected by ELISA. Murine alveolar macrophages expressed PD-1 at both the molecular and protein levels and PD-1 expression was increased in MH-S cells stimulated with LPS. Compared with the LPS group, the expression of PD-1 in the LPS+BMS-1 group was significantly decreased. Flow cytometry demonstrated that there was increased apoptosis of alveolar macrophages in the LPS group compared with the control group, whereas, alveolar macrophages notably decreased apoptosis in the LPS+BMS-1 group compared with the LPS group. There was no statistical difference between the control group and the LPS+BMS-1 group. IL-1β, IL-6, TNF-α and IL-10 were increased in the LPS group compared with the control group. The levels of IL-1β, IL-6 and TNF-α in the LPS+BMS-1 group were lower compared with those in the LPS group whereas IL-10 was further increased. In vitro , the PD-1/PD-L1 inhibitor, BMS-1, decreases alveolar macrophage apoptosis compared with the LPS group to maintain effective immune clearance and reduce inflammatory factor release. This decreased the inflammatory response and reduced acute lung injury caused by sepsis. Therefore, PD-1/PD-L1 inhibitors may be a potential therapeutic target for acute lung injury in patients with sepsis., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Jia et al.)

Background: Acute lung injury (ALI) is a type of severe pulmonary inflammatory disease with high rates of morbidity and mortality. Now, an increasing number of studies suggest that lncRNAs may act as key regulators of the inflammatory response and play a crucial role in the pathogenesis of many inflammatory diseases. Our study firstly explored the function and underlying mechanism of lncRNA metastasis-associated lung adenocarcinoma transcription 1 (MALAT1) in regulating the inflammatory response of lipopolysaccharide (LPS)-induced ALI in rats., Methods: The ALI rats were constructed by intratracheal instillation with LPS. Hematoxylin and eosin (HE) for histological examination were performed to detect histopathological changes in the lung tissues. Enzyme-linked immunosorbent assay (ELISA) was used to determine the concentrations of cytokines TNF-α, IL-6, and IL-1β in the supernatants of the bronchoalveolar lavage fluid (BALF). Quantitative real-time PCR (qRT-PCR) analysis was employed to assess the expression of MALAT1, miR-146a, TNF-α, IL-6, and IL-1β in lung tissues. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were used to detect the relationship between MALAT1 and miR-146a., Results: The results revealed that MALAT1 knockdown played a protective role in the LPS-induced ALI rat model. In addition, knockdown of MALAT1 in vitro inhibited LPS-induced inflammatory response in murine alveolar macrophages cell line MH-S and murine alveolar epithelial cell line MLE-12. This study found that MALAT1 acts as a molecular sponge for miR-146a and MALAT1 negatively regulated miR-146a expression. Mechanistically, MALAT1 overexpression alleviated the inhibitory effect of miR-146a on LPS-induced inflammatory response in MH-S., Conclusions: Together, our study provided the first evidence that MALAT1 knockdown could suppress inflammatory response by up-regulating miR-146a in LPS-induced ALI, which provided a potential therapeutic target for the treatment of ALI.