Suppression of lung inflammation in rats by prevention of NF-kappaB activation in the liver.

Lancaster LH, Christman JW, Blackwell TR, Koay MA, Blackwell TS
Inflammation. 2001 25 (1): 25-31

PMID: 11293663

Activation of NF-kappaB and production of NF-kappaB-dependent chemokines are thought to be involved in the pathogenesis of neutrophilic lung inflammation. Calpain-1 inhibitor (CI-1) blocks activation of NF-kappaB by preventing proteolysis of the inhibitory protein IkappaB-alpha by the ubiquitin/proteasome pathway. We hypothesized that inhibition of proteasome function with CI-1 would block NF-kappaB activation in vivo after intraperitoneal (i.p.) treatment with bacterial lipopolysaccharide (LPS), and that NF-kappaB inhibition would be associated with suppression of chemokine gene expression and attenuation of neutrophilic alveolitis. We treated rats with a single i.p. injection of CI-1 (10 mg/kg) two hours prior to i.p. LPS (7 mg/kg). Treatment with Cl-1 prevented degradation of IkappaB-alpha and activation of NF-kappaB in the liver in response to LPS; however, Cl-1 treatment had no detected effect on NF-kappaB 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 x 10(5) vs. 43.7 +/- 12.2 x 10(5) lung lavage neutrophils, P < 0.01). These data indicate that NF-kappaB 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.

MeSH Terms (26)

Animals Bronchoalveolar Lavage Fluid Chemokine CXCL2 Chemokines Cysteine Endopeptidases DNA-Binding Proteins Endotoxemia Gene Expression Regulation Glycoproteins I-kappa B Proteins Lipopolysaccharides Liver Lung Macrophages, Alveolar Male Multienzyme Complexes Neutrophils NF-kappa B NF-KappaB Inhibitor alpha Phosphorylation Pneumonia Protease Inhibitors Proteasome Endopeptidase Complex Protein Processing, Post-Translational Rats Rats, Sprague-Dawley

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