Sordi, R. | Search bioRxiv

bioRxiv2021

Inhibition of Bruton's tyrosine kinase activity attenuates trauma-induced multiple organ dysfunction in rats

ObjectiveThe aim of this study was to investigate (a) the potential of the Brutons tyrosine kinase (BTK) inhibitors (BTKi) acalabrutinib and fenebrutinib to reduce multiple organ dysfunction syndrome (MODS) in acute and chronic hemorrhagic shock (HS) rat models and (b) whether treatment with either acalabrutinib or fenebrutinib attenuates BTK, NF-{kappa}B and NLRP3 activation in HS. BackgroundThe MODS caused by an excessive systemic inflammatory response following trauma is associated with a high morbidity and mortality. The protein BTK is known to play a role in the activation of the NLRP3 inflammasome, which is a key component of the innate inflammatory response. However, its role in trauma-hemorrhage is unknown. MethodsAcute and chronic HS rat models were performed to determine the influence of acalabrutinib or fenebrutinib on MODS. The activation of BTK, NF-{kappa}B and NLRP3 pathways were analyzed by western blot in the kidney. ResultsWe demonstrated that (a) HS caused organ injury and/or dysfunction and hypotension (post resuscitation) in rats, while (b) treatment of HS-rats with either acalabrutinib or fenebrutinib attenuated the organ injury and dysfunction in acute and chronic HS models and (c) reduced the activation of BTK, NF-{kappa}B and NLRP3 pathways in the kidney. ConclusionOur results point to a role of BTK in the pathophysiology of organ injury and dysfunction caused by trauma/hemorrhage and indicate that BTK inhibitors may be repurposed as a potential therapeutic approach for MODS after trauma and/or hemorrhage. MINI-ABSTRACTThis study evaluated the role of Brutons tyrosine kinase (BTK) in trauma/hemorrhage. Patients with trauma had elevated gene expression of BTK. The BTK inhibitors acalabrutinib (irreversible) and fenebrutinib (reversible) attenuated the trauma-induced multiple organ dysfunction in rats with hemorrhagic shock, indicating that BTK could be a potential therapeutic target.

pharmacology and toxicology↗

bioRxiv2020

Neuraminidase inhibitors rewire neutrophil function in murine sepsis and COVID-19 patient cells

Neutrophil overstimulation plays a crucial role in tissue damage during severe infections. Neuraminidase (NEU)-mediated cleavage of surface sialic acid has been demonstrated to regulate leukocyte responses. Here, we report that antiviral NEU inhibitors constrain host NEU activity, surface sialic acid release, ROS production, and NETs released by microbial-activated human neutrophils. In vivo, treatment with Oseltamivir results in infection control and host survival in peritonitis and pneumonia models of sepsis. Single-cell RNA sequencing re-analysis of publicly data sets of respiratory tract samples from critical COVID-19 patients revealed an overexpression of NEU1 in infiltrated neutrophils. Moreover, Oseltamivir or Zanamivir treatment of whole blood cells from severe COVID-19 patients reduces host NEU-mediated shedding of cell surface sialic acid and neutrophil overactivation. These findings suggest that neuraminidase inhibitors can serve as host-directed interventions to dampen neutrophil dysfunction in severe infections. At a GlanceIn a severe systemic inflammatory response, such as sepsis and COVID-19, neutrophils play a central role in organ damage. Thus, finding new ways to inhibit the exacerbated response of these cells is greatly needed. Here, we demonstrate that in vitro treatment of whole blood with the viral neuraminidase inhibitors Oseltamivir or Zanamivir, inhibits the activity of human neuraminidases as well as the exacerbated response of neutrophils. In experimental models of severe sepsis, oseltamivir decreased neutrophil activation and increased the survival rate of mice. Moreover, Oseltamivir or Zanamivir ex vivo treatment of whole blood cells from severe COVID-19 patients rewire neutrophil function.

immunology↗