Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

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 l...

Full description

Bibliographic Details
Main Authors: Galluzzo, Maria, Ciraolo, Elisa, Lucattelli, Monica, Hoxha, Eriola, Ulrich, Martina, Campa, Carlo Cosimo, Lungarella, Giuseppe, Doring, Gerd, Zhou-Suckow, Zhe, Mall, Marcus, Hirsch, Emilio, De Rose, Virginia
Format: Online
Language:English
Published: Hindawi Publishing Corporation 2015
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491401/
id pubmed-4491401
recordtype oai_dc
spelling pubmed-44914012015-07-16 Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease Galluzzo, Maria Ciraolo, Elisa Lucattelli, Monica Hoxha, Eriola Ulrich, Martina Campa, Carlo Cosimo Lungarella, Giuseppe Doring, Gerd Zhou-Suckow, Zhe Mall, Marcus Hirsch, Emilio De Rose, Virginia Research Article 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 (PI3Kγ KO) 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 PI3Kγ KO/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. Hindawi Publishing Corporation 2015 2015-06-21 /pmc/articles/PMC4491401/ /pubmed/26185363 http://dx.doi.org/10.1155/2015/545417 Text en Copyright © 2015 Maria Galluzzo et al. https://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Galluzzo, Maria
Ciraolo, Elisa
Lucattelli, Monica
Hoxha, Eriola
Ulrich, Martina
Campa, Carlo Cosimo
Lungarella, Giuseppe
Doring, Gerd
Zhou-Suckow, Zhe
Mall, Marcus
Hirsch, Emilio
De Rose, Virginia
spellingShingle Galluzzo, Maria
Ciraolo, Elisa
Lucattelli, Monica
Hoxha, Eriola
Ulrich, Martina
Campa, Carlo Cosimo
Lungarella, Giuseppe
Doring, Gerd
Zhou-Suckow, Zhe
Mall, Marcus
Hirsch, Emilio
De Rose, Virginia
Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease
author_facet Galluzzo, Maria
Ciraolo, Elisa
Lucattelli, Monica
Hoxha, Eriola
Ulrich, Martina
Campa, Carlo Cosimo
Lungarella, Giuseppe
Doring, Gerd
Zhou-Suckow, Zhe
Mall, Marcus
Hirsch, Emilio
De Rose, Virginia
author_sort Galluzzo, Maria
title 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_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_sort genetic deletion and pharmacological inhibition of pi3kγ reduces neutrophilic airway inflammation and lung damage in mice with cystic fibrosis-like lung disease
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 (PI3Kγ KO) 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 PI3Kγ KO/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.
publisher Hindawi Publishing Corporation
publishDate 2015
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491401/
_version_ 1613243919646064640

Similar Items