CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice
Inhibitors of phosphodiesterase 4 (PDE4) are potent anti-inflammatory agents, inhibiting the production of inflammatory mediators through the elevation of intracellular cAMP concentrations. We studied the activity of a novel PDE4 inhibitor, CHF6001, both in vitro in human cells and in vivo, using bi...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.01337/full |
| _version_ | 1828338087960248320 |
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| author | Fabio F. Stellari Angelo Sala Angelo Sala Francesca Ruscitti Carola Buccellati Andrew Allen Patrizia Risé Maurizio Civelli Gino Villetti |
| author_facet | Fabio F. Stellari Angelo Sala Angelo Sala Francesca Ruscitti Carola Buccellati Andrew Allen Patrizia Risé Maurizio Civelli Gino Villetti |
| author_sort | Fabio F. Stellari |
| collection | DOAJ |
| description | Inhibitors of phosphodiesterase 4 (PDE4) are potent anti-inflammatory agents, inhibiting the production of inflammatory mediators through the elevation of intracellular cAMP concentrations. We studied the activity of a novel PDE4 inhibitor, CHF6001, both in vitro in human cells and in vivo, using bioluminescence imaging (BLI) in mice lung inflammation. Mice transiently transfected with the luciferase gene under the control of an NF-κB responsive element (NF-κB-luc) have been used to assess the in vivo anti-inflammatory activity of CHF6001 in lipopolysaccharide (LPS)-induced lung inflammation. BLI as well as inflammatory cells and the concentrations of pro-inflammatory cytokines were monitored in bronchoalveolar lavage fluids (BALF) while testing in vitro its ability to affect the production of leukotriene B4 (LTB4), measured by LC/MS/MS, by LPS/LPS/N-formyl--methionyl--leucyl-phenylalanine (fMLP)-activated human blood. CHF6001 inhibited the production of LTB4 in LPS/fMLP-activated human blood at sub-nanomolar concentrations. LPS-induced an increase of BLI signal in NF-κB-luc mice, and CHF6001 administered by dry powder inhalation decreased in parallel luciferase signal, cell airway infiltration, and pro-inflammatory cytokine concentrations in BALF. The results obtained provide in vitro and in vivo evidence of the anti-inflammatory activity of the potent PDE4 inhibitor CHF6001, showing that with a topical administration that closely mimics inhalation in humans, it efficiently disrupts the NF-κB activation associated with LPS challenge, an effect that may be relevant for the prevention of exacerbation episodes in chronic obstructive pulmonary disease subjects. |
| first_indexed | 2024-04-13T22:23:34Z |
| format | Article |
| id | doaj.art-25ab30e8b2214074b4c43bb467987421 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-13T22:23:34Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-25ab30e8b2214074b4c43bb4679874212022-12-22T02:27:08ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-11-011010.3389/fphar.2019.01337493317CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in MiceFabio F. Stellari0Angelo Sala1Angelo Sala2Francesca Ruscitti3Carola Buccellati4Andrew Allen5Patrizia Risé6Maurizio Civelli7Gino Villetti8Pharmacology and Toxicology Department Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A, Parma, ItalyDepartment of Pharmaceutical Sciences, School of Drug Sciences, University of Milan, Milan, ItalyIBIM, Consiglio Nazionale delle Ricerche, Palermo, ItalyPharmacology and Toxicology Department Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A, Parma, ItalyDepartment of Pharmaceutical Sciences, School of Drug Sciences, University of Milan, Milan, ItalyPharmacology and Toxicology Department Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A, Parma, ItalyDepartment of Pharmaceutical Sciences, School of Drug Sciences, University of Milan, Milan, ItalyPharmacology and Toxicology Department Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A, Parma, ItalyPharmacology and Toxicology Department Corporate Pre-Clinical R&D, Chiesi Farmaceutici S.p.A, Parma, ItalyInhibitors of phosphodiesterase 4 (PDE4) are potent anti-inflammatory agents, inhibiting the production of inflammatory mediators through the elevation of intracellular cAMP concentrations. We studied the activity of a novel PDE4 inhibitor, CHF6001, both in vitro in human cells and in vivo, using bioluminescence imaging (BLI) in mice lung inflammation. Mice transiently transfected with the luciferase gene under the control of an NF-κB responsive element (NF-κB-luc) have been used to assess the in vivo anti-inflammatory activity of CHF6001 in lipopolysaccharide (LPS)-induced lung inflammation. BLI as well as inflammatory cells and the concentrations of pro-inflammatory cytokines were monitored in bronchoalveolar lavage fluids (BALF) while testing in vitro its ability to affect the production of leukotriene B4 (LTB4), measured by LC/MS/MS, by LPS/LPS/N-formyl--methionyl--leucyl-phenylalanine (fMLP)-activated human blood. CHF6001 inhibited the production of LTB4 in LPS/fMLP-activated human blood at sub-nanomolar concentrations. LPS-induced an increase of BLI signal in NF-κB-luc mice, and CHF6001 administered by dry powder inhalation decreased in parallel luciferase signal, cell airway infiltration, and pro-inflammatory cytokine concentrations in BALF. The results obtained provide in vitro and in vivo evidence of the anti-inflammatory activity of the potent PDE4 inhibitor CHF6001, showing that with a topical administration that closely mimics inhalation in humans, it efficiently disrupts the NF-κB activation associated with LPS challenge, an effect that may be relevant for the prevention of exacerbation episodes in chronic obstructive pulmonary disease subjects.https://www.frontiersin.org/article/10.3389/fphar.2019.01337/fullLPSinhalation towersNF-kBin vivo bioluminescence imaginglung inflammationmouse model |
| spellingShingle | Fabio F. Stellari Angelo Sala Angelo Sala Francesca Ruscitti Carola Buccellati Andrew Allen Patrizia Risé Maurizio Civelli Gino Villetti CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice Frontiers in Pharmacology LPS inhalation towers NF-kB in vivo bioluminescence imaging lung inflammation mouse model |
| title | CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice |
| title_full | CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice |
| title_fullStr | CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice |
| title_full_unstemmed | CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice |
| title_short | CHF6001 Inhibits NF-κB Activation and Neutrophilic Recruitment in LPS-Induced Lung Inflammation in Mice |
| title_sort | chf6001 inhibits nf κb activation and neutrophilic recruitment in lps induced lung inflammation in mice |
| topic | LPS inhalation towers NF-kB in vivo bioluminescence imaging lung inflammation mouse model |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.01337/full |
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