Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat.
OBJECTIVE
11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11beta-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11beta-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation.


METHODS
Controlled laboratory study.


METHODS
University research laboratory.


METHODS
Adult Sprague-Dawley rats (n = 66).


METHODS
Rats were intraperitoneally injected with carbenoxolone (2 x 10 mg.kg(-1).day(-1) for 3 days) and allowed free access to water and food. Rats were further challenged with endotoxin instillation (1 mg/kg).


RESULTS
We discovered that carbenoxolone significantly increased messenger RNA expression of all three epithelial sodium channel subunits in distal lung tissues (two-fold increase of alpha-subunit, four-fold increase of beta-subunit, and two-fold increase of gamma-subunit) as well as in trachea. Carbenoxolone increased the amiloride-sensitive alveolar fluid clearance significantly. When rats were further challenged by endotoxin instillation (1 mg/kg), pretreatment with carbenoxolone significantly inhibited endotoxin-induced increase in lung neutrophils as well as tumor necrosis factor-alpha and cytokine-induced neutrophil chemoattractant-1 concentrations in serum and bronchoalveolar lavage fluid.


CONCLUSIONS
These beneficial effects of carbenoxolone on lung fluid balance and inflammation are very similar to those expected when glucocorticoids are introduced exogenously. We conclude that carbenoxolone increased the actions of endogenous bioactive glucocorticoids on lung cells by reducing local steroid breakdown.
Suzuki
Satoshi
S
Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, Japan.
Matsuda
Yasushi
Y
Sugawara
Takafumi
T
Tabata
Toshiharu
T
Ishibashi
Hironori
H
Hoshikawa
Yasushi
Y
Kubo
Hiroshi
H
Kondo
Takashi
T
D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2 / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D000818:Animals; D002229:Carbenoxolone / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D008297:Male; D009504:Neutrophils / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012128:Respiratory Distress Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D020545:Respiratory Mucosa / Q000187:drug effects / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D016207:Cytokines; D015222:Sodium Channels; D043209:11-beta-Hydroxysteroid Dehydrogenase Type 2; D002229:Carbenoxolone