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The activin A antagonist follistatin inhibits cystic fibrosis-like lung inflammation and pathology.

Hardy CL, King SJ, Mifsud NA, Hedger MP, Phillips DJ, Mackay F, de Kretser DM, Wilson JW, Rolland JM, O'Hehir RE - Immunol. Cell Biol. (2015)

Bottom Line: Current management targets airway infection and mucus clearance, but despite recent advances in care, life expectancy is still only 40 years.We measured serum activin A levels, lung function and nutritional status in CF patients.Activin A levels were elevated in the serum of adult CF patients, and correlated inversely with lung function and body mass index.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Allergy, Immunology & Respiratory Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia [2] Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

ABSTRACT
Cystic fibrosis (CF) is the most common life-limiting genetically acquired respiratory disorder. Patients with CF have thick mucus obstructing the airways leading to recurrent infections, bronchiectasis and neutrophilic airway inflammation culminating in deteriorating lung function. Current management targets airway infection and mucus clearance, but despite recent advances in care, life expectancy is still only 40 years. We investigated whether activin A is elevated in CF lung disease and whether inhibiting activin A with its natural antagonist follistatin retards lung disease progression. We measured serum activin A levels, lung function and nutritional status in CF patients. We studied the effect of activin A on CF lung pathogenesis by treating newborn CF transgenic mice (β-ENaC) intranasally with the natural activin A antagonist follistatin. Activin A levels were elevated in the serum of adult CF patients, and correlated inversely with lung function and body mass index. Follistatin treatment of newborn β-ENaC mice, noted for respiratory pathology mimicking human CF, decreased the airway activin A levels and key features of CF lung disease including mucus hypersecretion, airway neutrophilia and levels of mediators that regulate inflammation and chemotaxis. Follistatin treatment also increased body weight and survival of β-ENaC mice, with no evidence of local or systemic toxicity. Our findings demonstrate that activin A levels are elevated in CF and provide proof-of-concept for the use of the activin A antagonist, follistatin, as a therapeutic in the long-term management of lung disease in CF patients.

No MeSH data available.


Related in: MedlinePlus

FS288 instillation inhibits BAL fluid cytokine and chemokine levels in β-ENaC mice. WT or β-ENaC mice were treated with saline or FS288 intranasally as per Figure 2. (a–i) BAL fluid levels of IL-1α, IL-6, IL-10, IL-12p40, IL-13, granulocyte-colony stimulating factor, monocyte chemotactic protein-1, MIP-1α and MIP-1β. Mean±s.e.m., n=15–27 mice per group.
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fig4: FS288 instillation inhibits BAL fluid cytokine and chemokine levels in β-ENaC mice. WT or β-ENaC mice were treated with saline or FS288 intranasally as per Figure 2. (a–i) BAL fluid levels of IL-1α, IL-6, IL-10, IL-12p40, IL-13, granulocyte-colony stimulating factor, monocyte chemotactic protein-1, MIP-1α and MIP-1β. Mean±s.e.m., n=15–27 mice per group.

Mentions: To further analyse the effects of follistatin treatment on lung inflammation, we measured the levels of BAL fluid inflammatory mediators. Multiplex analysis showed that, compared with WT mice, β-ENaC mice had increased levels of cytokines and chemokines important in (i) regulation of inflammatory responses (IL-1α, IL-6, IL-10, IL-12p40; Figures 4a–d), (ii) induction of mucus production (IL-13; Figure 4e) and (iii) maturation and/or recruitment of dendritic cells, monocyte/macrophages and neutrophils (granulocyte-colony stimulating factor [G-CSF], monocyte chemotactic protein-1 [MCP-1], monocyte inhibitory protein (MIP-1α and MIP-1β Figures 4f–i). Notably, FS288 treatment caused a two- to threefold reduction in the levels of these inflammatory mediators in the BAL fluid of β-ENaC mice such that for the majority, levels approximated those seen in saline-treated WT mice, providing a rationale for the anti-inflammatory action of FS288 in CF. No significant changes in BAL IL-17 levels were observed between WT mice and β-ENaC mice (data not shown).


The activin A antagonist follistatin inhibits cystic fibrosis-like lung inflammation and pathology.

Hardy CL, King SJ, Mifsud NA, Hedger MP, Phillips DJ, Mackay F, de Kretser DM, Wilson JW, Rolland JM, O'Hehir RE - Immunol. Cell Biol. (2015)

FS288 instillation inhibits BAL fluid cytokine and chemokine levels in β-ENaC mice. WT or β-ENaC mice were treated with saline or FS288 intranasally as per Figure 2. (a–i) BAL fluid levels of IL-1α, IL-6, IL-10, IL-12p40, IL-13, granulocyte-colony stimulating factor, monocyte chemotactic protein-1, MIP-1α and MIP-1β. Mean±s.e.m., n=15–27 mice per group.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4495664&req=5

fig4: FS288 instillation inhibits BAL fluid cytokine and chemokine levels in β-ENaC mice. WT or β-ENaC mice were treated with saline or FS288 intranasally as per Figure 2. (a–i) BAL fluid levels of IL-1α, IL-6, IL-10, IL-12p40, IL-13, granulocyte-colony stimulating factor, monocyte chemotactic protein-1, MIP-1α and MIP-1β. Mean±s.e.m., n=15–27 mice per group.
Mentions: To further analyse the effects of follistatin treatment on lung inflammation, we measured the levels of BAL fluid inflammatory mediators. Multiplex analysis showed that, compared with WT mice, β-ENaC mice had increased levels of cytokines and chemokines important in (i) regulation of inflammatory responses (IL-1α, IL-6, IL-10, IL-12p40; Figures 4a–d), (ii) induction of mucus production (IL-13; Figure 4e) and (iii) maturation and/or recruitment of dendritic cells, monocyte/macrophages and neutrophils (granulocyte-colony stimulating factor [G-CSF], monocyte chemotactic protein-1 [MCP-1], monocyte inhibitory protein (MIP-1α and MIP-1β Figures 4f–i). Notably, FS288 treatment caused a two- to threefold reduction in the levels of these inflammatory mediators in the BAL fluid of β-ENaC mice such that for the majority, levels approximated those seen in saline-treated WT mice, providing a rationale for the anti-inflammatory action of FS288 in CF. No significant changes in BAL IL-17 levels were observed between WT mice and β-ENaC mice (data not shown).

Bottom Line: Current management targets airway infection and mucus clearance, but despite recent advances in care, life expectancy is still only 40 years.We measured serum activin A levels, lung function and nutritional status in CF patients.Activin A levels were elevated in the serum of adult CF patients, and correlated inversely with lung function and body mass index.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Allergy, Immunology & Respiratory Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia [2] Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.

ABSTRACT
Cystic fibrosis (CF) is the most common life-limiting genetically acquired respiratory disorder. Patients with CF have thick mucus obstructing the airways leading to recurrent infections, bronchiectasis and neutrophilic airway inflammation culminating in deteriorating lung function. Current management targets airway infection and mucus clearance, but despite recent advances in care, life expectancy is still only 40 years. We investigated whether activin A is elevated in CF lung disease and whether inhibiting activin A with its natural antagonist follistatin retards lung disease progression. We measured serum activin A levels, lung function and nutritional status in CF patients. We studied the effect of activin A on CF lung pathogenesis by treating newborn CF transgenic mice (β-ENaC) intranasally with the natural activin A antagonist follistatin. Activin A levels were elevated in the serum of adult CF patients, and correlated inversely with lung function and body mass index. Follistatin treatment of newborn β-ENaC mice, noted for respiratory pathology mimicking human CF, decreased the airway activin A levels and key features of CF lung disease including mucus hypersecretion, airway neutrophilia and levels of mediators that regulate inflammation and chemotaxis. Follistatin treatment also increased body weight and survival of β-ENaC mice, with no evidence of local or systemic toxicity. Our findings demonstrate that activin A levels are elevated in CF and provide proof-of-concept for the use of the activin A antagonist, follistatin, as a therapeutic in the long-term management of lung disease in CF patients.

No MeSH data available.


Related in: MedlinePlus