Abstract
Rationale Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. Study design/methods F508del homozygous mice (Cftr F508del) and transgenic mice overexpressing the ENaC channel β-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 μg/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARγ) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Results Nebulized HA reduced TNFα expression (P <0.005); TNFα, MIP-2, and MPO protein levels (P <0.05); MPO activity (P <0.05); and CD68+ cells counts (P <0.005) in lung tissues of CftrF508del and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARγ protein in both IB3-1 and CFBE41o cells (P <0.05). Conclusions Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy.
| Original language | English |
|---|---|
| Pages (from-to) | 761-771 |
| Number of pages | 11 |
| Journal | Pediatric Pulmonology |
| Volume | 48 |
| Issue number | 8 |
| DOIs | |
| Publication status | Published - 2013 |
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Keywords
- cystic fibrosis
- Hyaluronan
- inflammation
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Pulmonary and Respiratory Medicine
Cite this
Nebulized Hyaluronan Ameliorates lung inflammation in cystic fibrosis mice. / Gavina, Manuela; Luciani, Alessandro; Villella, Valeria R.; Esposito, Speranza; Ferrari, Eleonora; Bressani, Ilaria; Casale, Alida; Bruscia, Emanuela M.; Maiuri, Luigi; Raia, Valeria.
In: Pediatric Pulmonology, Vol. 48, No. 8, 2013, p. 761-771.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Nebulized Hyaluronan Ameliorates lung inflammation in cystic fibrosis mice
AU - Gavina, Manuela
AU - Luciani, Alessandro
AU - Villella, Valeria R.
AU - Esposito, Speranza
AU - Ferrari, Eleonora
AU - Bressani, Ilaria
AU - Casale, Alida
AU - Bruscia, Emanuela M.
AU - Maiuri, Luigi
AU - Raia, Valeria
PY - 2013
Y1 - 2013
N2 - Rationale Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. Study design/methods F508del homozygous mice (Cftr F508del) and transgenic mice overexpressing the ENaC channel β-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 μg/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARγ) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Results Nebulized HA reduced TNFα expression (P <0.005); TNFα, MIP-2, and MPO protein levels (P <0.05); MPO activity (P <0.05); and CD68+ cells counts (P <0.005) in lung tissues of CftrF508del and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARγ protein in both IB3-1 and CFBE41o cells (P <0.05). Conclusions Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy.
AB - Rationale Chronic lung inflammation with increased susceptibility to bacterial infections cause much of the morbidity and mortality in patients with cystic fibrosis (CF), the most common severe, autosomal recessively inherited disease in the Caucasian population. Exogenous inhaled hyaluronan (HA) can exert a protective effect against injury and beneficial effects of HA have been shown in experimental models of chronic respiratory diseases. Our objective was to examine whether exogenous administration of nebulized HA might interfere with lung inflammation in CF. Study design/methods F508del homozygous mice (Cftr F508del) and transgenic mice overexpressing the ENaC channel β-subunit (Scnn1b-Tg) were treated with nebulized HA (0.5 mg/mouse/day for 7 days). Tumor necrosis factor-alpha (TNFα), macrophage inflammatory protein-2 (MIP-2), myeloperoxidase (MPO) levels, and macrophage infiltration were assessed on lung tissues. IB3-1 and CFBE41o-epithelial cell lines were cultured with HA (24 hr, 100 μg/ml) and Reactive Oxygen Species (ROS), Tissue Transglutaminase (TG2) SUMOylation and Peroxisome Proliferator Activated Receptor gamma (PPARγ) and phospho-p42/p44 levels were measured by dichlorodihydrofluorescein assay, or fluorescence resonance energy transfer (FRET) microscopy or immunoblots. Results Nebulized HA reduced TNFα expression (P <0.005); TNFα, MIP-2, and MPO protein levels (P <0.05); MPO activity (P <0.05); and CD68+ cells counts (P <0.005) in lung tissues of CftrF508del and Scnn1b-Tg mice, compared with saline-treated mice. HA reduced ROS, TG2 SUMOylation, TG2 activity, phospho-p42-44, and increased PPARγ protein in both IB3-1 and CFBE41o cells (P <0.05). Conclusions Nebulized HA is effective in controlling inflammation in vivo in mice CF airways and in vitro in human airway epithelial cells. We provide the proof of concept for the use of inhaled HA as a potential anti-inflammatory drug in CF therapy.
KW - cystic fibrosis
KW - Hyaluronan
KW - inflammation
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U2 - 10.1002/ppul.22637
DO - 10.1002/ppul.22637
M3 - Article
C2 - 22825912
AN - SCOPUS:84881385110
VL - 48
SP - 761
EP - 771
JO - Pediatric Pulmonology
JF - Pediatric Pulmonology
SN - 8755-6863
IS - 8
ER -