Endotoxin Tolerance Inhibits Lipopolysaccharide-Initiated Acute Pulmonary Inflammation and Lung Injury in Rats by the Mechanism of Nuclear Factor-κB

Abstract

In this study, the effect of endotoxin tolerance on lipopolysaccharide (LPS)-initiated pulmonary inflammation, the local production of tumour necrosis factor-α (TNF-α) and the cytokine-induced neutrophil attractant (CINC), as well as the activation of nuclear factor-κB (NF-κB) and its subunit composition, were examined in vivo. Endotoxin tolerance was reproduced by four consecutive daily intraperitoneal injections of 0.6 mg/kg of Escherichia coli 055:B5 LPS. Compared with control rats, endotoxin-tolerant rats failed to increase the permeability of pulmonary microvascular or recruit neutrophil to lung tissue upon restimulation with 6 mg/kg of LPSs. Pretreatment with LPSs inhibited the protein level of TNF-α in bronchoalveolar lavage fluid (BALF) and mRNA expression of CINC in lung tissue in response to subsequent LPS stimulation. These changes were accompanied by the suppression of activation of NF-κB, including the low level of total amount of DNA-binding activity and high percentage of non-transactive p50 homodimers. These data demonstrate that endotoxin tolerance can alleviate the LPS-induced acute neutrophilic pulmonary inflammation in rats and can inhibit the proinflammatory cytokines in lung and suggest that endotoxin tolerance might result from the unresponsiveness of NF-κB and persistent high percentage of p50 homodimers. Therefore, the phenomenon of endotoxin tolerance might be used as a strategy for the prevention or treatment of LPS-associated acute respiratory distress syndrome in which excessive or dysregulated inflammation leads to acute lung injury.