Limits...
Proliferative activity of liver growth factor is associated with an improvement of cigarette smoke-induced emphysema in mice.

Girón-Martínez Á, Pérez-Rial S, Terrón-Expósito R, Díaz-Gil JJ, González-Mangado N, Peces-Barba G - PLoS ONE (2014)

Bottom Line: COPD treatment is based on the administration of bronchodilators and corticosteroids to control symptoms and exacerbations, however, to date, there are no effective therapies to reverse disease progression.Liver growth factor (LGF) is an albumin-bilirubin complex with mitogenic properties, whose therapeutic effects have previously been reported in a model of emphysema and several rodent models of human disease.Taken together, this study suggests that LGF administration ameliorates CS-induced emphysema, highlights the ability of LGF to promote alveolar cell proliferation and may be a promising strategy to revert COPD progression.

View Article: PubMed Central - PubMed

Affiliation: Respiratory Research Group, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz - CIBERES, Universidad Autónoma de Madrid (IIS-FJD-CIBERES-UAM), Madrid, Spain.

ABSTRACT
Cigarette smoke (CS)-induced emphysema is a major component of chronic obstructive pulmonary disease (COPD). COPD treatment is based on the administration of bronchodilators and corticosteroids to control symptoms and exacerbations, however, to date, there are no effective therapies to reverse disease progression. Liver growth factor (LGF) is an albumin-bilirubin complex with mitogenic properties, whose therapeutic effects have previously been reported in a model of emphysema and several rodent models of human disease. To approach the therapeutic effect of LGF in a model of previously established emphysema, morphometric and lung function parameters, matrix metalloproteinase (MMP) activity and the expression of several markers, such as VEGF, PCNA, 3NT and Nrf2, were assessed in air-exposed and CS-exposed C57BL/6J male mice with and without intraperitoneal (i.p.) injection of LGF. CS-exposed mice presented a significant enlargement of alveolar spaces, higher alveolar internal area and loss of lung function that correlated with higher MMP activity, higher expression of 3NT and lower expression of VEGF. CS-exposed mice injected with LGF, showed an amelioration of emphysema and improved lung function, which correlated with lower MMP activity and 3NT expression and higher levels of VEGF, PCNA and Nrf2. Taken together, this study suggests that LGF administration ameliorates CS-induced emphysema, highlights the ability of LGF to promote alveolar cell proliferation and may be a promising strategy to revert COPD progression.

Show MeSH

Related in: MedlinePlus

Alveolar space enlargement and lung function.(A) Histological sections from the lungs stained with H&E (n = 5 per group). Scale bars = 50 µm. Mean chord length (Lm) (B) and the mean of the alveolar internal area (C) of alveoli in the lungs of air-exposed mice untreated (C) and treated with LGF (C+LGF) and CS-exposed mice untreated (CSE) and treated with LGF (CSE+LGF). (D) Distribution analysis of random intercepts obtained from measurements on randomly sampled images on linear scale (n = 5 per group). (E) Vmax was used to evaluate lung function of air-exposed mice (C), CS-exposed mice (CSE) and CS-exposed mice post-treated with LGF (CSE+LGF) (n = 5 per group). * P<0.05 and ** P<0.01 vs. air-exposed mice; ¥ P<0.05 and ¥¥ P<0.01 vs. CS-exposed mice. Data are presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4234533&req=5

pone-0112995-g002: Alveolar space enlargement and lung function.(A) Histological sections from the lungs stained with H&E (n = 5 per group). Scale bars = 50 µm. Mean chord length (Lm) (B) and the mean of the alveolar internal area (C) of alveoli in the lungs of air-exposed mice untreated (C) and treated with LGF (C+LGF) and CS-exposed mice untreated (CSE) and treated with LGF (CSE+LGF). (D) Distribution analysis of random intercepts obtained from measurements on randomly sampled images on linear scale (n = 5 per group). (E) Vmax was used to evaluate lung function of air-exposed mice (C), CS-exposed mice (CSE) and CS-exposed mice post-treated with LGF (CSE+LGF) (n = 5 per group). * P<0.05 and ** P<0.01 vs. air-exposed mice; ¥ P<0.05 and ¥¥ P<0.01 vs. CS-exposed mice. Data are presented as mean ± SEM.

Mentions: Lm, AIA and Vmax parameters were used to assess the degree of lung damage and development of emphysema caused by CS inhalation. When comparing representative images of each group, it was evident that the lungs from mice exposed to CS showed alveolar space enlargement. However, the morphology of alveolar spaces in lungs from mice exposed to CS and then treated with LGF was similar to that observed in normal lungs (Fig. 2A). As measured by mean chord length (Lm) and alveolar internal area (AIA), air-exposed mice presented normal alveolar architecture (Lm = 32.46±0.46 µm; AIA = 794.5±23.39 µm2). In contrast, CS-exposed mice presented enlargement of alveolar spaces (Lm = 41.88±0.64 µm; AIA = 1587.19±59.54 µm2) (Fig. 2B–C). Lung changes observed in CS-exposed mice were substantially reversed in mice treated with LGF for two weeks after CS exposure (Lm = 32.04±0.35 µm; AIA = 517.18±13.13 µm2) (Fig. 2B–C). Additionally, analysis of intercepts lengths distribution in each group showed that in normal lungs, the density curve of the raw data had a slimmer and higher peak, whereas in lungs from mice with emphysema-like pathology (CS-exposed mice), the density curve had a wider but lower peak due to the disruption of alveolar septa (Fig. 2D). The shape of the density curve corresponding to the distribution of the intercept lengths in lungs from mice exposed to CS and then treated with LGF was more similar to that observed in normal lungs, suggesting that LGF was promoting tissue repair.


Proliferative activity of liver growth factor is associated with an improvement of cigarette smoke-induced emphysema in mice.

Girón-Martínez Á, Pérez-Rial S, Terrón-Expósito R, Díaz-Gil JJ, González-Mangado N, Peces-Barba G - PLoS ONE (2014)

Alveolar space enlargement and lung function.(A) Histological sections from the lungs stained with H&E (n = 5 per group). Scale bars = 50 µm. Mean chord length (Lm) (B) and the mean of the alveolar internal area (C) of alveoli in the lungs of air-exposed mice untreated (C) and treated with LGF (C+LGF) and CS-exposed mice untreated (CSE) and treated with LGF (CSE+LGF). (D) Distribution analysis of random intercepts obtained from measurements on randomly sampled images on linear scale (n = 5 per group). (E) Vmax was used to evaluate lung function of air-exposed mice (C), CS-exposed mice (CSE) and CS-exposed mice post-treated with LGF (CSE+LGF) (n = 5 per group). * P<0.05 and ** P<0.01 vs. air-exposed mice; ¥ P<0.05 and ¥¥ P<0.01 vs. CS-exposed mice. Data are presented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4234533&req=5

pone-0112995-g002: Alveolar space enlargement and lung function.(A) Histological sections from the lungs stained with H&E (n = 5 per group). Scale bars = 50 µm. Mean chord length (Lm) (B) and the mean of the alveolar internal area (C) of alveoli in the lungs of air-exposed mice untreated (C) and treated with LGF (C+LGF) and CS-exposed mice untreated (CSE) and treated with LGF (CSE+LGF). (D) Distribution analysis of random intercepts obtained from measurements on randomly sampled images on linear scale (n = 5 per group). (E) Vmax was used to evaluate lung function of air-exposed mice (C), CS-exposed mice (CSE) and CS-exposed mice post-treated with LGF (CSE+LGF) (n = 5 per group). * P<0.05 and ** P<0.01 vs. air-exposed mice; ¥ P<0.05 and ¥¥ P<0.01 vs. CS-exposed mice. Data are presented as mean ± SEM.
Mentions: Lm, AIA and Vmax parameters were used to assess the degree of lung damage and development of emphysema caused by CS inhalation. When comparing representative images of each group, it was evident that the lungs from mice exposed to CS showed alveolar space enlargement. However, the morphology of alveolar spaces in lungs from mice exposed to CS and then treated with LGF was similar to that observed in normal lungs (Fig. 2A). As measured by mean chord length (Lm) and alveolar internal area (AIA), air-exposed mice presented normal alveolar architecture (Lm = 32.46±0.46 µm; AIA = 794.5±23.39 µm2). In contrast, CS-exposed mice presented enlargement of alveolar spaces (Lm = 41.88±0.64 µm; AIA = 1587.19±59.54 µm2) (Fig. 2B–C). Lung changes observed in CS-exposed mice were substantially reversed in mice treated with LGF for two weeks after CS exposure (Lm = 32.04±0.35 µm; AIA = 517.18±13.13 µm2) (Fig. 2B–C). Additionally, analysis of intercepts lengths distribution in each group showed that in normal lungs, the density curve of the raw data had a slimmer and higher peak, whereas in lungs from mice with emphysema-like pathology (CS-exposed mice), the density curve had a wider but lower peak due to the disruption of alveolar septa (Fig. 2D). The shape of the density curve corresponding to the distribution of the intercept lengths in lungs from mice exposed to CS and then treated with LGF was more similar to that observed in normal lungs, suggesting that LGF was promoting tissue repair.

Bottom Line: COPD treatment is based on the administration of bronchodilators and corticosteroids to control symptoms and exacerbations, however, to date, there are no effective therapies to reverse disease progression.Liver growth factor (LGF) is an albumin-bilirubin complex with mitogenic properties, whose therapeutic effects have previously been reported in a model of emphysema and several rodent models of human disease.Taken together, this study suggests that LGF administration ameliorates CS-induced emphysema, highlights the ability of LGF to promote alveolar cell proliferation and may be a promising strategy to revert COPD progression.

View Article: PubMed Central - PubMed

Affiliation: Respiratory Research Group, Instituto de Investigación Sanitaria - Fundación Jiménez Díaz - CIBERES, Universidad Autónoma de Madrid (IIS-FJD-CIBERES-UAM), Madrid, Spain.

ABSTRACT
Cigarette smoke (CS)-induced emphysema is a major component of chronic obstructive pulmonary disease (COPD). COPD treatment is based on the administration of bronchodilators and corticosteroids to control symptoms and exacerbations, however, to date, there are no effective therapies to reverse disease progression. Liver growth factor (LGF) is an albumin-bilirubin complex with mitogenic properties, whose therapeutic effects have previously been reported in a model of emphysema and several rodent models of human disease. To approach the therapeutic effect of LGF in a model of previously established emphysema, morphometric and lung function parameters, matrix metalloproteinase (MMP) activity and the expression of several markers, such as VEGF, PCNA, 3NT and Nrf2, were assessed in air-exposed and CS-exposed C57BL/6J male mice with and without intraperitoneal (i.p.) injection of LGF. CS-exposed mice presented a significant enlargement of alveolar spaces, higher alveolar internal area and loss of lung function that correlated with higher MMP activity, higher expression of 3NT and lower expression of VEGF. CS-exposed mice injected with LGF, showed an amelioration of emphysema and improved lung function, which correlated with lower MMP activity and 3NT expression and higher levels of VEGF, PCNA and Nrf2. Taken together, this study suggests that LGF administration ameliorates CS-induced emphysema, highlights the ability of LGF to promote alveolar cell proliferation and may be a promising strategy to revert COPD progression.

Show MeSH
Related in: MedlinePlus