Abstract
Activation of NF-κB and production of NF-κB-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (Cl-1) blocks activation of NF-κB by preventing proteolysis of the inhibitory protein IκB-α by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-κB activation in vivo after intraperitoneal (IP) treatment with bacterial lipopolysaccharide (LPS), and that NF-κB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. We treated rats with a single IP injection of CI-1 (10 mg/kg) two hours prior to IP LPS (7 mg/kg). Treatment with CI-1 prevented degradation of IκB-α and activation of NF-κB in the liver in response to LPS; however, CI-1 treatment had no detected effect on NF-κB activation in lung tissue. CI-1 treatment prior to LPS resulted in 40% lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/− 112 pg/ml vs. 859 +/− 144 pg/ml, P < 0.05). In addition, CI-1 treatment substantially inhibited LPS-induced neutrophilic alveolitis (2.7 +/− 1.2 × 105 vs. 43.7 +/− 12.2 × 105 lung lavage neutrophils, P < 0.01). These data indicate that NF-κB inhibition in the liver can alter lung inflammation induced by systemic LPS treatment and suggest that a liver-lung interaction contributes to the inflammatory response of the lung.
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Lancaster, L.H., Christman, J.W., Blackwell, T.R. et al. Suppression of Lung Inflammation in Rats by Prevention of NF-κB Activation in the Liver. Inflammation 25, 25–31 (2001). https://doi.org/10.1023/A:1007071527408
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DOI: https://doi.org/10.1023/A:1007071527408