Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat

Satoshi Suzuki, Yasushi Matsuda, Takafumi Sugawara, Toshiharu Tabata, Hironori Ishibashi, Yasushi Hoshikawa, Hiroshi Kubo, Takashi Kondo

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

Objectives: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11β-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11β-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation. Design: Controlled laboratory study. Setting: University research laboratory. Subjects: Adult Sprague-Dawley rats (n = 66). Interventions: Rats were intraperitoneally injected with carbenoxolone (2 × 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). Measurements and Main 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 α-subunit, four-fold increase of β-subunit, and two-fold increase of γ-subunit) as well as in trachea. Carbanoxolone 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-α 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.

Original languageEnglish
Pages (from-to)1910-1915
Number of pages6
JournalCritical Care Medicine
Volume32
Issue number9
DOIs
Publication statusPublished - 01-09-2004

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Carbenoxolone
Pneumonia
Lung
Glucocorticoids
Endotoxins
11-beta-Hydroxysteroid Dehydrogenases
Water-Electrolyte Balance
Neutrophils
Inflammation
Epithelial Sodium Channels
Amiloride
Chemotactic Factors
Bronchoalveolar Lavage Fluid
Trachea
NAD
Sprague Dawley Rats
Tumor Necrosis Factor-alpha
Epithelial Cells
Steroids
Cytokines

All Science Journal Classification (ASJC) codes

  • Critical Care and Intensive Care Medicine

Cite this

Suzuki, Satoshi ; Matsuda, Yasushi ; Sugawara, Takafumi ; Tabata, Toshiharu ; Ishibashi, Hironori ; Hoshikawa, Yasushi ; Kubo, Hiroshi ; Kondo, Takashi. / Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat. In: Critical Care Medicine. 2004 ; Vol. 32, No. 9. pp. 1910-1915.
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abstract = "Objectives: 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which requires oxidized nicotinamide adenine dinucleotide as a cofactor, metabolizes endogenous glucocorticoids. Since 11β-HSD2 has been detected in lung epithelial cells, we examined whether carbenoxolone, a potent inhibitor of 11β-HSD, would enhance endogenous glucocorticoid action on lung fluid balance and inflammation. Design: Controlled laboratory study. Setting: University research laboratory. Subjects: Adult Sprague-Dawley rats (n = 66). Interventions: Rats were intraperitoneally injected with carbenoxolone (2 × 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). Measurements and Main 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 α-subunit, four-fold increase of β-subunit, and two-fold increase of γ-subunit) as well as in trachea. Carbanoxolone 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-α 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.",
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Suzuki, S, Matsuda, Y, Sugawara, T, Tabata, T, Ishibashi, H, Hoshikawa, Y, Kubo, H & Kondo, T 2004, 'Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat', Critical Care Medicine, vol. 32, no. 9, pp. 1910-1915. https://doi.org/10.1097/01.CCM.0000139621.74965.FB

Effects of carbenoxolone on alveolar fluid clearance and lung inflammation in the rat. / Suzuki, Satoshi; Matsuda, Yasushi; Sugawara, Takafumi; Tabata, Toshiharu; Ishibashi, Hironori; Hoshikawa, Yasushi; Kubo, Hiroshi; Kondo, Takashi.

In: Critical Care Medicine, Vol. 32, No. 9, 01.09.2004, p. 1910-1915.

Research output: Contribution to journalArticle

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AU - Suzuki, Satoshi

AU - Matsuda, Yasushi

AU - Sugawara, Takafumi

AU - Tabata, Toshiharu

AU - Ishibashi, Hironori

AU - Hoshikawa, Yasushi

AU - Kubo, Hiroshi

AU - Kondo, Takashi

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