Glucocorticoids are potent anti-inflammatory agents. Endogenous glucocorticoid action is modulated by 11β-hydroxysteroid dehydrogenase (11β-HSD) which interconverts active (cortisol, corticosterone) and intrinsically inert glucocorticoids (cortisone, 11-dehydrocorticosterone). 11β-HSD type 1 regenerates active glucocorticoids. 11β-HSD 1 highly expressed in the lung but its role is little explored.
Immunohistochemical staining of mouse lung localised 11β-HSD1 to the cytoplasm of fusiform cells in alveolar walls, in a multivesicular pattern characteristic of interstitial fibroblasts and consistent with 11β-HSD1 activity measurements in primary cultured lung fibroblasts (35 pmol cortisol/h per 106 cells). 11β-HSD1 expression was increased in the alveolar walls with strong staining of interstitial fibroblasts 7d and 14d following intratracheal instillation of 0.025 U (low dose) bleomycin to induce inflammation and fibrosis. At 7d, strong staining was also seen in mononuclear cells, a population which was reduced at 14d. However, there were no changes in 11β-HSD1 mRNA level in wild type (WT) mice. Comparison of WT and 11β-HSD1 knockout (KO) mice showed similar numbers of inflammatory cells recovered in Bronchoalveolar Lavage Fluid at 2d, 7d or 14d following bleomycin exposure. Histological assessment showed interstitial inflammatory cell infiltration 7d following bleomycin but no major differences between genotypes. However, 14d following bleomycin the fibrotic response was more marked in KO mice, with increased collagen deposition, revealed by picro-sirius red staining and Massons Trichrome staining. Real-time PCR carried out on lung RNA showed increased expression of Haemoxygenase-1 (HO-1), Transforming growth factor-β1, α-smooth muscle actin 2, Hypoxia inducible factor-1α following bleomycin treatment, both in WT and KO mice. The induction of HO-1 was significantly greater in KO mice 14d following installation of bleomycin (WT: 1.52±0.5 vs KO: 2.26±0.13, Arbitrary Units; P<0.05).
We suggest that glucocorticoid regeneration by 11β-HSD1 in lung fibroblasts limits fibroblast proliferation and/or collagen synthesis, and its deficiency or inhibition may lead to greater fibrosis following lung injury.