Suppression of lung inflammation in rats by prevention of NF-kappa B activation in the liver

Activation of NF-kappaB and production of NF-kappaB-dependent chemokines ar e thought to be involved in the pathogenesis of neutrophilic lung inflammat ion. Calpain-1inhibitor (Cl-1 blocks activation of NF-kappaB by preventing proteolysis of the inhibitory protein I kappaB-alpha by the ubiquitin/prote asome pathway. We hypothesized that inhibition of proteasome function with CI-1would block NF-kappaB activation in vivo after intrapcritoneal (IP) tre atment with bacterial lipopolysaccharide (LPS), and that NF-kappaB inhibiti on would be associated with suppression of chemokine gene expression and at tenuation of neutrophilic alveolitis. We treated rats with a single IP inje ction of CI-1 (10 mg/kg) two hours prior to IP LPS (7 mg/kg). Treatment wit h CI-1 prevented degradation of I kappaB-alpha and activation of NF-kappaB in the liver in response to LPS; however, CI-1 treatment had no detected ef fect on NF-kappaB activation in lung tissue. CI-1 treatment prior to LPS re sulted in 40tib lower MIP-2 concentration in lung lavage fluid compared to rats treated with vehicle prior to LPS (502 +/- 112 pg/ml vs. 859 +/- 144 p g/ml, P < 0.05). In addition, CI-I treatment substantially inhibited LPS-in duced neutrophilic alveolitis (2.7 <plus/minus> 1.2 x 10(5) vs. 43.7 +/- 12 .2 x 10(5) lung lavage neutrophils, P < 0.01). These data indicate that NF- <kappa>B inhibition in the liver can alter lung inflammation induced by sys temic LPS treatment and suggest that a liver-lung interaction contributes t o the inflammatory response of the lung.