The COVID-19 pandemic, promoted by the SARS-CoV-2 respiratory virus, has resulted in widespread global morbidity and mortality. The immune response against this pathogen has shown a thin line between protective effects and pathological reactions resulting from the massive release of cytokines and poor viral clearance. The latter is possibly caused by exhaustion, senescence, or both of TCD8+ cells and reduced activity of natural killer (NK) cells. The imbalance between innate and adaptive responses during the early stages of infection caused by SARS-CoV-2 contributes to the ineffective control of viral spread. The present study evaluated the tissue immunoexpression of the tissue biomarkers (Arginase-1, CCR4, CD3, CD4, CD8, CD20, CD57, CD68, CD138, IL-4, INF-α, INF-γ, iNOS, PD-1, Perforin and Sphingosine-1) to understand the cellular immune response triggered in patients who died of COVID-19. We evaluated twenty-four paraffin-embedded lung tissue samples from patients who died of COVID-19 (COVID-19 group) and compared them with ten lung tissue samples from patients who died of H1N1pdm09 (H1N1 group) with the immunohistochemical markers mentioned above. In addition, polymorphisms in the Perforin gene were genotyped through Real-Time PCR. Significantly increased tissue immunoexpression of Arginase, CD4, CD68, CD138, Perforin, Sphingosine-1, and IL-4 markers were observed in the COVID-19 group. A significantly lower immunoexpression of CD8 and CD57 was also found in this group. It is suggested that patients who died from COVID-19 had a poor cellular response concerning viral clearance and adaptive response going through tissue repair.
Oxidative stress (OS) is essential in uremia‐associated comorbidities, including renal anemia. Complications experienced by hemodialysis (HD) patients, such as hypoxemia and uremic toxins accumulation, induce OS and premature death of red blood cells (RBC). We aimed to characterize reactive oxygen species (ROS) production and antioxidant pathways in HD‐RBC and RBC from healthy controls (CON‐RBC) and evaluate the role of uremia and hypoxia in these pathways. ROS production, xanthine oxidase (XO) and superoxide dismutase (SOD) activities, glutathione (GSH), and heme oxygenase‐1 (HO‐1) levels were measured using flow cytometry or spectrophotometry in CON‐RBC and HD‐RBC (pre‐ and post‐HD), at baseline and after 24 h incubation with uremic serum (S‐HD) and/or under hypoxic conditions (5% O2). Ketoprofen was used to inhibit RBC uremic toxins uptake. HD‐RBC showed higher ROS levels and lower XO activity than CON‐RBC, particularly post‐HD. GSH levels were lower, while SOD activity and HO‐1 levels of HD‐RBC were higher than control. Hypoxia per se triggered ROS production in CON‐RBC and HD‐RBC. S‐HD, on top of hypoxia, increased ROS levels. Inhibition of uremic toxins uptake attenuated ROS of CON and HD‐RBC under hypoxia and uremia. CON‐RBC in uremia and hypoxia showed lower GSH levels than cells in normoxia and non‐uremic conditions. Redox mechanisms of HD‐RBC are altered and prone to oxidation. Uremic toxins and hypoxia play a role in unbalancing these systems. Hypoxia and uremia participate in the pathogenesis of OS in HD‐RBC and might induce RBC death and thus compound anemia.
Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, shares structural similarities with the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). We explored the hypothesis that CMPF at a concentration seen in uremia activates Piezo1 located on red blood cells (RBC). We incubated RBC from five healthy individuals with either Jedi1 or CMPF (both 87 μM), with or without the Piezo1 inhibitor GsMTx-4 (2 μM), and quantified the cells osmotic fragility. Our results indicate that compared to controls (i.e., RBC incubated with buffer), both Jedi1 and CMPF increase the osmotic fragility of RBC (i.e., reduce their resistance to osmotic stress). Effects of Jedi1 and CMPF were reversed to the control level by GsMTx-4. These results indicate a role of Piezo1 in augmenting RBC osmotic fragility and modulation of this effect by Jedi1 and CMPF. Our findings open the possibility that CMPF may act as an endogenous chemical activator of Piezo1.
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