title: The activin A antagonist follistatin inhibits cystic fibrosis-like lung inflammation and pathology.
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.
authors.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.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Hardy
authors.affiliation: Department of Allergy, Immunology & Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: King
authors.affiliation: 1] Department of Allergy, Immunology & Respiratory Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia [2] Department of Allergy, Immunology & Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Mifsud
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Hedger
authors.affiliation: MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Phillips
authors.affiliation: Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Mackay
authors.affiliation: 1] MIMR-PHI Institute of Medical Research, Clayton, Victoria, Australia [2] Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: de Kretser
authors.affiliation: 1] Department of Allergy, Immunology & Respiratory Medicine, Central Clinical School, Monash University, Melbourne, Victoria, Australia [2] Department of Allergy, Immunology & Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: John W
authors.initials: JW
authors.lastname: Wilson
authors.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.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Rolland
authors.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 [3] Department of Allergy, Immunology & Respiratory Medicine, The Alfred Hospital, Melbourne, Victoria, Australia.
authors.forename: Robyn E
authors.initials: RE
authors.lastname: O'Hehir
mesh_terms: D028341:Activins / Q000037:antagonists & inhibitors* / Q000097:blood; D000328:Adult; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003550:Cystic Fibrosis / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D038681:Follistatin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009093:Mucus / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000473:pathology; D011014:Pneumonia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D012129:Respiratory Function Tests; D020545:Respiratory Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055815:Young Adult
chemical_list: D038681:Follistatin; D018836:Inflammation Mediators; C422405:activin A; D028341:Activins