Protective Effect of Ketotifen on Cardiac Dysfunction in Septic Rats Induced by LPS through Regulation of the PD-1/PD-L1 Pathway

Abstract

Background: Ketotifen is a leukotriene receptor antagonist that exerts anti-inflammatory effects primarily by antagonizing leukotriene B4 receptors. While the effect of ketotifen on sepsis-induced cardiac dysfunction remains to be further explored and its underlying mechanisms remain unclear. Hence, this study aimed to investigate the role and mechanisms of ketotifen in sepsis-induced cardiac dysfunction. Methods: Rats were divided into five groups (n = 5 each group): control group, sepsis group, sepsis + low-dose ketotifen (1 mg/kg) group, sepsis + high-dose ketotifen (10 mg/kg) group and Healthy control group (HC group). Sepsis was induced by intraperitoneal injection of Lipopolysaccharide (LPS) at a dosage of 5 mg/kg and controls received Phosphoric acid buffer solution (PBS) injections instead. Ketotifen was intraperitoneally injected immediately before sepsis induction at doses of 1 or 10 mg/kg. The serum levels of inflammatory cytokines were determined and myocardial tissues were harvested. Results: Compared to sepsis model group, ketotifen administration significantly alleviated sepsis-induced cardiac dysfunction, manifested as reduced serum levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), interleukin 17 (IL-17), tumor necrosis factor α (TNF-α), receptor for advanced glycation end products (RAGE) and soluble receptor for advanced glycation end products (sRAGE) (p < 0.05), increased left ventricular fractional (LVFS) (%) and left ventricular ejection fraction (LVEF) (%) detected by echocardiography (p < 0.05), improved myocardial structure shown by electron microscopy and reduced expression of transient receptor potential ankyrin 1 (TRPA1) in myocardial tissues of septic rats (p < 0.05). By western blotting, our results showed that the expressions of programmed cell death protein 1 (PD-1), programmed cell death-ligand 1 (PD-L1), V-domain Ig suppressor of T cell activation (VISTA) as well as Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) were remarkably elevated in sepsis model group (p < 0.05), and administration of ketotifen significantly downregulate the expressions of them. Conclusion: Ketotifen exerted beneficial effects against cardiac dysfunction induced by sepsis in rats. The cardioprotective effect of ketotifen was possibly attributed to inhibiting PD-1/PD-L1 pathway in myocardial tissues of septic rats.