Modulation of human lung fibroblast functions by ciclesonide: Evidence for its conversion into the active metabolite desisobutyryl-ciclesonide

Boero, Silvia; Sabatini, Federica; Silvestri, Michela; Petecchia, Loredana; Nachira, Antonio; Pezzolo, Annalisa; Scarso, Lucia; Rossi, Giovanni A.

doi:10.1016/j.imlet.2007.06.010

Cited by 19 publications

(13 citation statements)

References 28 publications

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“…bFGF has been shown to induce cell proliferation in quiescent cultures of human lung fibroblasts [34,35], a finding which we also confirmed (Figure 4). Although bFGF is a milder stimulus for lung fibroblasts than classical mitogens such as EGF and PDGF [35], exposure to conditioned media of RV-infected epithelial cells containing bFGF at much lower levels than our positive control (approx.…”

Section: Discussionsupporting

confidence: 88%

Rhinovirus‐induced basic fibroblast growth factor release mediates airway remodeling features

Skevaki

Psarras

Volonaki

et al. 2012

Clinical & Translational All

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BackgroundHuman rhinoviruses, major precipitants of asthma exacerbations, induce lower airway inflammation and mediate angiogenesis. The purpose of this study was to assess the possibility that rhinoviruses may also contribute to the fibrotic component of airway remodeling.MethodsLevels of basic fibroblast growth factor (bFGF) mRNA and protein were measured following rhinovirus infection of bronchial epithelial cells. The profibrotic effect of epithelial products was assessed by DNA synthesis and matrix metalloproteinase activity assays. Moreover, epithelial cells were exposed to supernatants from cultured peripheral blood mononuclear cells, obtained from healthy donors or atopic asthmatic subjects and subsequently infected by rhinovirus and bFGF release was estimated. bFGF was also measured in respiratory secretions from atopic asthmatic patients before and during rhinovirus-induced asthma exacerbations.ResultsRhinovirus epithelial infection stimulated mRNA expression and release of bFGF, the latter being positively correlated with cell death under conditions promoting rhinovirus-induced cytotoxicity. Supernatants from infected cultures induced lung fibroblast proliferation, which was inhibited by anti-bFGF antibody, and demonstrated increased matrix metalloproteinase activity. Rhinovirus-mediated bFGF release was significantly higher in an in vitro simulation of atopic asthmatic environment and, importantly, during rhinovirus-associated asthma exacerbations.ConclusionsRhinovirus infection induces bFGF release by airway epithelium, and stimulates stroma cell proliferation contributing to airway remodeling in asthma. Repeated rhinovirus infections may promote asthma persistence, particularly in the context of atopy; prevention of such infections may influence the natural history of asthma.

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Section: Discussionsupporting

confidence: 88%

Rhinovirus‐induced basic fibroblast growth factor release mediates airway remodeling features

Skevaki

Psarras

Volonaki

et al. 2012

Clinical & Translational All

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“…CIC is a "pro-drug" with almost no affinity for the glucocorticoid receptor, and consequently was added to cell cultures as an inactive compound. Therefore the results here reported demonstrate that, as already shown for airway epithelial cells [16,20] and lung fibroblasts [17], also blood mononuclear cells are able to convert the parent compound in the active principle des-CIC, to exert anti-inflammatory functions on the same cells. This is a relevant information considering both the key role that mononuclear cells, i.e.…”

Section: Discussionsupporting

confidence: 84%

“…Administered as a parent compound with almost no binding affinity for the glucocorticoid receptor, CIC is rapidly converted in the airway mucosa into the active metabolite, desisobutyryl-ciclesonide (des-CIC) known to have a remarkable anti-inflammatory activity [14,15]. In in vitro cellular models CIC is highly effective in downregulating within 3 h the pro-inflammatory activities of airway epithelial cells and fibroblasts when converted by these cells into the active metabolite desisobutyryl (des)-CIC [16,17]. However it is not known whether: (a) conversion of CIC into des-CIC may occur also at human mononuclear cell level, resulting in an effective downregulation of allergeninduced T-lymphocyte activation and (b) the inhibitory activity of CIC could be higher for a Th2 response than for a Th1 response.…”

Section: Introductionmentioning

confidence: 99%

Ciclesonide modulates in vitro allergen-driven activation of blood mononuclear cells and allergen-specific T-cell blasts

et al. 2012

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“…Fluorescein isothiocyanateconjugate goat anti-mouse immunoglobulin G (Immunotech, Beckman Coulter Company, Milan, Italy) was used to visualise a-SMA. Quantification of the myofibroblast number in each experimental condition was performed at 206 magnification, as previously described [16][17][18]. Only cells clearly showing positive staining for a-SMA or F-actin were counted in a blinded manner in a minimum of three randomly chosen microscopic fields.…”

Section: Experiments Designmentioning

confidence: 99%

“…Electrophoresis of protein extracts and subsequent blotting were performed as previously described [18,19]. Blots were incubated with a mouse anti-a-SMA antibody (Dako cytomation), anti-MLC kinase antibody (Sigma), anti-MLC antibody (Sigma) or anti-diphospho-MLC (Thr-18/Ser-19; Santa Cruz Biotechnology, Santa Cruz, CA, USA) and visualised using the enhanced chemiluminescence system (Pierce Biotechnology, Inc., Rockford, IL, USA).…”

Section: Western Blot Analysismentioning

confidence: 99%

Mechanisms of bradykinin-induced contraction in human fetal lung fibroblasts

Petecchia

Sabatini

Usai³

et al. 2010

Eur Respir J

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Bradykinin (BK) induces fibroblast contraction but the structural changes and intracellular mechanisms involved have not been completely explored.We stimulated HFL-1 fibroblasts with BK to assess: 1) fibroblast contractility; 2) the role of asmooth muscle actin (SMA) in contraction by small interfering RNA (siRNA); 3) a-SMA protein expression; 4) a-SMA and F-actin structure; 5) intracellular calcium concentration ([Ca 2+ ] i ); and 6) phosphorylated myosin light-chain (pMLC) and MLC kinase (MLCK) expression. BK triggered concentration-and time-dependent fibroblast gel contraction in conjunction with a-SMA over expression, but not in a-SMA-siRNA-treated cells. BK also increased a-SMA + and Factin + cell number and stress fibre polymerisation (detectable at 5-60 min). These BK-induced changes were associated with an increase in [Ca 2+ ] i , which peaked within 15 s, and activation of pMLC, which was detectable at 5-60 min. No MLCK content modification was observed. The different manifestations of the BK-induced fibroblast activation were downregulated at different levels (25-100%) by HOE140, a specific BK B2 receptor (B2R) antagonist and by the Ca 2+ chelator, EGTA.Thus, BK-induced fibroblast contraction, associated with differentiation into a-SMA + myofibroblasts, is mediated through the activation of the B2R and involves the Ca 2+ /calmodulin pMLCdependent pathway.

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Modulation of human lung fibroblast functions by ciclesonide: Evidence for its conversion into the active metabolite desisobutyryl-ciclesonide

Cited by 19 publications

References 28 publications

Rhinovirus‐induced basic fibroblast growth factor release mediates airway remodeling features

Rhinovirus‐induced basic fibroblast growth factor release mediates airway remodeling features

Ciclesonide modulates in vitro allergen-driven activation of blood mononuclear cells and allergen-specific T-cell blasts

Mechanisms of bradykinin-induced contraction in human fetal lung fibroblasts

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