Tocilizumab attenuates acute lung and kidney injuries and improves survival in a rat model of sepsis via down-regulation of NF-κB/JNK: a possible role of P-glycoprotein.

Abstract

Acute lung injury (ALI) and acute kidney injury (AKI) are major causes of sepsis-induced mortality. The objective of the study is to evaluate the effect of tocilizumab (TCZ), an IL-6 receptor inhibitor, in sepsis-induced ALI and AKI using the cecal ligation and puncture (CLP) rat model of sepsis. Clinical and experimental studies have demonstrated the importance of IL-6 in sepsis; however, the role of TCZ has not been investigated. Rats subjected to CLP developed histological evidence of ALI and AKI at 24h. We found that TCZ alleviated sepsis-induced ALI and AKI as evidenced by improvements in various pathological changes, a significant reduction in the lung wet/dry weight ratio and total protein content in bronchoalveolar lavage fluid (BALF), and a significant decrease in the elevated serum level of creatinine (CR) and blood urea nitrogen (BUN). TCZ induced an increase in the survival rate of treated rats. Additionally, TCZ markedly inhibited sepsis-induced pulmonary and renal inflammatory responses. Moreover, we found that treatment with TCZ inhibited oxidative stress and apoptosis in lung and kidney tissue. TCZ treatment significantly inhibited NF-κB activation, attenuating JNK signaling pathway and significantly up-regulated P-glycoprotein (P-gp) expression in pulmonary as well as in renal tissues. Our data provide novel evidence that TCZ has a protective effect against sepsis-induced ALI and AKI by blocking IL-6 receptor signaling. This could provide a molecular basis for a new medical treatment for sepsis-induced ALI and AKI.