The Yin and Yang of Tyrosine Kinase Inhibition During Experimental Polymicrobial Sepsis

Abstract

Neutrophils are the first cells of our immune system to arrive at the site of inflammation. They release cytokines, e.g., chemokines, to attract further immune cells, but also actively start to phagocytose and kill pathogens. In the case of sepsis, this tightly regulated host defense mechanism can become uncontrolled and hyperactive resulting in severe organ damage. Currently, no effective therapy is available to fight sepsis; therefore, novel treatment targets that could prevent excessive inflammatory responses are warranted. Src Family tyrosine Kinases (SFK), a group of tyrosine kinases, have been shown to play a major role in regulating immune cell recruitment and host defense. Leukocytes with SFK depletion display severe spreading and migration defects along with reduced cytokine production. Thus, we investigated the effects of dasatinib, a tyrosine kinase inhibitor, with a strong inhibitory capacity on SFKs during sterile inflammation and polymicrobial sepsis in mice. We found that dasatinib-treated mice displayed diminished leukocyte adhesion and extravasation in tumor necrosis factor-α-stimulated cremaster muscle venules in vivo. In polymicrobial sepsis, sepsis severity, organ damage, and clinical outcome improved in a dose-dependent fashion pointing toward an optimal therapeutic window for dasatinib dosage during polymicrobial sepsis. Dasatinib treatment may, therefore, provide a balanced immune response by preventing an overshooting inflammatory reaction on the one side and bacterial overgrowth on the other side.

Omega-9 Oleic Acid, the Main Compound of Olive Oil, Mitigates Inflammation during Experimental Sepsis

“…Interestingly, we also detected increased bacterial clearance in the peritoneal lavage in omega-9-treated septic animals. Similar results have been obtained recently by our group using low dose dasatinib treatment in septic mice [ 72 ]. Neutrophils increase their ability to produce ROS after treatment with omega-9 [ 73 ].…”

Src kinase inhibition with dasatinib impairs neutrophil function and clearance of Escherichia coli infection in a murine model of acute lung injury

“…These data are in contrast to the beneficial effects of src kinase inhibition with dasatinib in the CLP sepsis model, where the lower dose of 1 mg/kg dasatinib administered 30 min before, 6 h and 24 h after CLP (compared with our own time course of 30 min before and 12 h after i.t. E. coli ), improved survival and sepsis severity, as well as reduced intraperitoneal bacterial growth and spread [ 18 ]. Possible explanations for these differences are the timings of dasatinib administration after the acute inflammatory stimulus in the CLP model and the differing stimulus intensity between the two models.…”

“…A key consideration is whether our findings are compatible with existing literature. In particular, the elegant study by Gonçalves-de-Albuquerque et al showed that dasatinib reduced lung infection in a CLP model [ 18 ]. There were fundamental differences between the studies including strain of mouse, route of administration of dasatinib (gavage versus our i.p.…”

“…In a murine lipopolysaccharide (LPS)-induced model of acute lung injury, dasatinib attenuated lung inflammation but its effect was dependent on the dose and the method of LPS delivery [ 17 ]. In the caecal ligation and puncture (CLP) model of sepsis, pre- and post-CLP administration of low dose dasatinib (1 mg/kg) improved survival by 50% whereas survival was worsened by a higher dose (10 mg/kg) [ 18 ].…”

Mediterranean Diet: Lipids, Inflammation, and Malaria Infection

“…In this regard, an immune response is linked to the severity of malaria as well as sepsis. The immune checkpoint blockade is a striking success in specific diseases, suggesting that it would be useful for preventing and treating a range of infectious diseases [ 34 ].…”