Kallistatin, a
plasma protein, has been shown to exert multi-factorial functions including inhibition of
inflammation, oxidative stress and apoptosis in animal models and cultured cells.
Kallistatin levels are reduced in patients with
sepsis and in
lipopolysaccharide (LPS)-induced septic mice. Moreover, transgenic mice expressing
kallistatin are more resistant to LPS-induced mortality. Here, we investigated the effects of human
kallistatin on organ injury and survival in a mouse model of polymicrobial
sepsis. In this study, mice were injected intravenously with recombinant
kallistatin (KS3, 3 mg/kg; or KS10, 10 mg/kg
body weight) and then rendered septic by caecal
ligation and
puncture 30 min later.
Kallistatin administration resulted in a > 10-fold reduction of peritoneal bacterial counts, and significantly decreased serum tumour
necrosis factor-α,
interleukin-6 and high mobility group box-1 (
HMGB1) levels.
Kallistatin also inhibited
HMGB1 and toll-like receptor-4 gene expression in the lung and kidney. Administration of
kallistatin attenuated renal damage and decreased blood
urea nitrogen and serum
creatinine levels, but increased
endothelial nitric oxide synthase and
nitric oxide levels in the kidney. In cultured endothelial cells, human
kallistatin via its
heparin-binding site inhibited HMGB1-induced nuclear factor-κB activation and inflammatory gene expression. Moreover,
kallistatin significantly reduced apoptosis and
caspase-3 activity in the spleen. Furthermore,
kallistatin treatment markedly improved the survival of septic mice by 23% (KS3) and 41% (KS10). These results indicate that
kallistatin is a unique protecting agent in
sepsis-induced organ damage and mortality by inhibiting
inflammation and apoptosis, as well as enhancing bacterial clearance in a mouse model of polymicrobial
sepsis.