PMID- 17707916
OWN - NLM
STAT- MEDLINE
DCOM- 20071025
LR  - 20190104
IS  - 0165-2478 (Print)
IS  - 0165-2478 (Linking)
VI  - 112
IP  - 1
DP  - 2007 Sep 15
TI  - Modulation of human lung fibroblast functions by ciclesonide: evidence for its 
      conversion into the active metabolite desisobutyryl-ciclesonide.
PG  - 39-46
AB  - BACKGROUND: Ciclesonide, an inhaled corticosteroid administered as inactive 
      compound with almost no binding affinity for the glucocorticoid receptor, is 
      clinically effective in asthma being converted by airway epithelial cells into 
      its active metabolite desisobutyryl-(des)-ciclesonide. AIM: To evaluate whether 
      ciclesonide could directly modulate in vitro bronchial fibroblast functions being 
      converted into des-ciclesonide by these pluripotent cells involved in the 
      regulation of airway inflammation and remodelling. METHODS: Ciclesonide (0.09-9.0 
      microM) was added to a human adult lung fibroblast cell line (CCL-202), seeded in 
      medium in the presence of the following cytokines and growth factors: (a) basic 
      fibroblast growth factor (bFGF) for cell proliferation, measured by tritiated 
      thymidine ([3H]TdR) incorporation; (b) tumour necrosis factor (TNF)-alpha, to 
      stimulate intercellular adhesion molecule (ICAM)-1 expression and monocyte 
      chemoattractant protein-1 (MCP-1) and eotaxin release, evaluated by flow 
      cytometry and ELISA, respectively; (c) transforming growth factor (TGF)-beta1, 
      for induction of alpha smooth muscle actin (alpha-SMA) protein expression and 
      modification of the organization of alpha-SMA stress fibres, evaluated by Western 
      blot analysis and fluorescence microscopy. RESULTS: The presence of ciclesonide 
      in cell cultures induced a significant downregulation of: (a) bFGF-induced 
      fibroblast proliferation and TNF-alpha-induced ICAM-1 expression, at the 0.3-9.0 
      microM concentrations (p<0.05); (b) TNF-alpha-induced MCP-1 release, at all the 
      concentrations tested (p<0.05); (c) TNF-alpha-induced eotaxin release, at the 
      three highest concentrations (0.9-9.0 microM) (p<0.05); (d) TGF-beta1-induced of 
      alpha-SMA protein expression at the 0.3-3.0 microM concentrations, associated 
      with a reduction in the organization of alpha-SMA stress fibres. CONCLUSIONS: 
      These data show at cellular level an effective anti-inflammatory activity of 
      ciclesonide on human lung fibroblasts and support the hypothesis that also these 
      cells, in addition to airway epithelial cells, may be involved in converting the 
      parental compound into its active metabolite in the airways.
FAU - Boero, Silvia
AU  - Boero S
AD  - Pulmonary Disease Unit, G. Gaslini Institute, Largo G. Gaslini 5, 16147 Genoa, 
      Italy.
FAU - Sabatini, Federica
AU  - Sabatini F
FAU - Silvestri, Michela
AU  - Silvestri M
FAU - Petecchia, Loredana
AU  - Petecchia L
FAU - Nachira, Antonio
AU  - Nachira A
FAU - Pezzolo, Annalisa
AU  - Pezzolo A
FAU - Scarso, Lucia
AU  - Scarso L
FAU - Rossi, Giovanni A
AU  - Rossi GA
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20070801
PL  - Netherlands
TA  - Immunol Lett
JT  - Immunology letters
JID - 7910006
RN  - 0 (Actins)
RN  - 0 (Anti-Asthmatic Agents)
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (CCL11 protein, human)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL11)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Chemokines, CC)
RN  - 0 (Pregnenediones)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 103107-01-3 (Fibroblast Growth Factor 2)
RN  - 126547-89-5 (Intercellular Adhesion Molecule-1)
RN  - 8DL7FH77SF (desisobutyrylciclesonide)
RN  - S59502J185 (ciclesonide)
SB  - IM
MH  - Actins/metabolism
MH  - Anti-Asthmatic Agents/metabolism/*pharmacology
MH  - Anti-Inflammatory Agents/metabolism/*pharmacology
MH  - Biotransformation
MH  - Cell Differentiation/drug effects
MH  - Cell Line
MH  - Cell Proliferation/drug effects
MH  - Chemokine CCL11
MH  - Chemokine CCL2/metabolism
MH  - Chemokines, CC/metabolism
MH  - Dose-Response Relationship, Drug
MH  - Fibroblast Growth Factor 2/metabolism
MH  - Fibroblasts/*drug effects/metabolism
MH  - Humans
MH  - Intercellular Adhesion Molecule-1/metabolism
MH  - Lung/cytology/*drug effects/metabolism
MH  - Pregnenediones/metabolism/*pharmacology
MH  - Stress Fibers/drug effects/metabolism
MH  - Transforming Growth Factor beta1/metabolism
MH  - Tumor Necrosis Factor-alpha/metabolism
EDAT- 2007/08/21 09:00
MHDA- 2007/10/27 09:00
CRDT- 2007/08/21 09:00
PHST- 2007/05/23 00:00 [received]
PHST- 2007/06/21 00:00 [revised]
PHST- 2007/06/26 00:00 [accepted]
PHST- 2007/08/21 09:00 [pubmed]
PHST- 2007/10/27 09:00 [medline]
PHST- 2007/08/21 09:00 [entrez]
AID - S0165-2478(07)00144-7 [pii]
AID - 10.1016/j.imlet.2007.06.010 [doi]
PST - ppublish
SO  - Immunol Lett. 2007 Sep 15;112(1):39-46. doi: 10.1016/j.imlet.2007.06.010. Epub 
      2007 Aug 1.