Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease
Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF). Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in le...
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| Format: | Article |
| Language: | English |
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Wiley
2015-01-01
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| Series: | Mediators of Inflammation |
| Online Access: | http://dx.doi.org/10.1155/2015/545417 |
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| author | Maria Galluzzo Elisa Ciraolo Monica Lucattelli Eriola Hoxha Martina Ulrich Carlo Cosimo Campa Giuseppe Lungarella Gerd Doring Zhe Zhou-Suckow Marcus Mall Emilio Hirsch Virginia De Rose |
| author_facet | Maria Galluzzo Elisa Ciraolo Monica Lucattelli Eriola Hoxha Martina Ulrich Carlo Cosimo Campa Giuseppe Lungarella Gerd Doring Zhe Zhou-Suckow Marcus Mall Emilio Hirsch Virginia De Rose |
| author_sort | Maria Galluzzo |
| collection | DOAJ |
| description | Purpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF). Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg) were backcrossed with PI3Kγ-deficient (PI3KγKO) mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF). Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240) on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo. |
| format | Article |
| id | doaj-art-10e9eed7de0345ceb9e15ae2ed246132 |
| institution | Kabale University |
| issn | 0962-9351 1466-1861 |
| language | English |
| publishDate | 2015-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Mediators of Inflammation |
| spelling | doaj-art-10e9eed7de0345ceb9e15ae2ed2461322025-02-03T01:29:08ZengWileyMediators of Inflammation0962-93511466-18612015-01-01201510.1155/2015/545417545417Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung DiseaseMaria Galluzzo0Elisa Ciraolo1Monica Lucattelli2Eriola Hoxha3Martina Ulrich4Carlo Cosimo Campa5Giuseppe Lungarella6Gerd Doring7Zhe Zhou-Suckow8Marcus Mall9Emilio Hirsch10Virginia De Rose11Department of Clinical and Biological Sciences, University of Torino, A.O.U. S.Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043 Turin, ItalyDepartment of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, ItalyDepartment of Physiopathology, Experimental Medicine, and Public Health, University of Siena, 53100 Siena, ItalyDepartment of Neuroscience, University of Torino, 10126 Turin, ItalyInstitute of Medical Microbiology and Hygiene, University of Tübingen, 72074 Tübingen, GermanyDepartment of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, ItalyDepartment of Physiopathology, Experimental Medicine, and Public Health, University of Siena, 53100 Siena, ItalyInstitute of Medical Microbiology and Hygiene, University of Tübingen, 72074 Tübingen, GermanyDepartment of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120 Heidelberg, GermanyDepartment of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, ItalyDepartment of Clinical and Biological Sciences, University of Torino, A.O.U. S.Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043 Turin, ItalyPurpose. Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF). Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg) were backcrossed with PI3Kγ-deficient (PI3KγKO) mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF). Furthermore, we assessed the effect of a specific PI3Kγ inhibitor (AS-605240) on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3KγKO/βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme. Conclusions. These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.http://dx.doi.org/10.1155/2015/545417 |
| spellingShingle | Maria Galluzzo Elisa Ciraolo Monica Lucattelli Eriola Hoxha Martina Ulrich Carlo Cosimo Campa Giuseppe Lungarella Gerd Doring Zhe Zhou-Suckow Marcus Mall Emilio Hirsch Virginia De Rose Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease Mediators of Inflammation |
| title | Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease |
| title_full | Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease |
| title_fullStr | Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease |
| title_full_unstemmed | Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease |
| title_short | Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease |
| title_sort | genetic deletion and pharmacological inhibition of pi3kγ reduces neutrophilic airway inflammation and lung damage in mice with cystic fibrosis like lung disease |
| url | http://dx.doi.org/10.1155/2015/545417 |
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