Ultramicronized Palmitoylethanolamide in the Management of Sepsis-Induced Coagulopathy and Disseminated Intravascular Coagulation

Abstract

Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.

Keywords: coagulation; disseminated intravascular coagulation; inflammation; sepsis; ultramicronized palmitoylethanolamide.

Figure 1

Blood coagulation parameters: platelet (PLT) counts (A); fibrinogen (Fib) levels (B); prothrombin time (PT) (C); activated partial thromboplastin time (APTT) (D); D-dimer levels (E). *** p < 0.001 vs. sham; # p < 0.05 vs. LPS; ## p < 0.01 vs. LPS; ### p < 0.001 vs. LPS.

Figure 2

Cytokine levels in plasma: IL-1β (A); IL-6 (B); TNF-α (C); IFN-γ (D). *** p < 0.001 vs. sham; ## p < 0.01 vs. LPS; ### p < 0.001 vs. LPS.

Figure 3

Cytokine levels in lung samples: IL-1β (A); IL-6 (B); TNF-α (C); IFN-γ (D). *** p < 0.001 vs. sham; ## p < 0.01 vs. LPS; ### p < 0.001 vs. LPS.

Figure 4

Western blot and, respectively, quantification of IκB-α (A) and NF-κB (B) in lung tissues. *** p < 0.001 vs. sham; ### p < 0.001 vs. LPS.

Figure 5

Macroscopic observation: sham (A), LPS (B), LPS + um-PEA (C). H/E staining: sham (D), LPS (E), LPS + um-PEA (F). PTAH staining: sham (G), LPS (H), LPS + um-PEA (I). Histological score (J) and wet/dry weight (K). A 10× magnification is shown (250-µm scale bar) for H/E staining; a 40× magnification is shown (75-µm scale bar) for PTAH staining. * p < 0.05 vs. sham; *** p < 0.001 vs. sham; # p < 0.05 vs. LPS; ## p < 0.01 vs. LPS.

Figure 6

Toluidine blue staining: sham (A), LPS (B), LPS + um-PEA (C), mast cell count (D). A 40× magnification is shown (75-µm scale bar). *** p < 0.001 vs. sham; ### p < 0.001 vs. LPS.

Figure 7

Immunohistochemical evaluation for chymase expression: sham (A), LPS (B), LPS + um-PEA (C); and tryptase expression: sham (D), LPS (E), LPS + um-PEA (F). Graphical quantification of chymase (G) and tryptase (H) expression in lung. A 40× magnification is shown (75-µm scale bar). *** p < 0.001 vs. sham; ## p < 0.01 vs. LPS.