American journal of respiratory and critical care medicine
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Am. J. Respir. Crit. Care Med. · Apr 2020
Follistatin-like 1 Attenuation Causes Spontaneous Smoke-Resistant Pulmonary Emphysema.
Rationale: The role of FSTL-1 (follistatin-like 1) in lung homeostasis is unknown. Objectives: We aimed to define the impact of FSTL-1 attenuation on lung structure and function and to identify FSTL-1-regulated transcriptional pathways in the lung. Further, we aimed to analyze the association of FSTL-1 SNPs with lung disease. ⋯ Conclusions: This work identifies a novel role for FSTL-1 protecting against emphysema development independent of smoke exposure. This FSTL-1-deficient emphysema implicates regulation of immune tolerance in lung macrophages through Nr4a1. Further study of the mechanisms involving FSTL-1 in lung homeostasis, immune regulation, and NF-κB signaling may provide additional insight into the pathophysiology of emphysema and inflammatory lung diseases.
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Am. J. Respir. Crit. Care Med. · Apr 2020
TMEM16A Potentiation: A Novel Therapeutic Approach for the Treatment of Cystic Fibrosis.
Rationale: Enhancing non-CFTR (cystic fibrosis transmembrane conductance regulator)-mediated anion secretion is an attractive therapeutic approach for the treatment of cystic fibrosis (CF) and other mucoobstructive diseases. Objectives: To determine the effects of TMEM16A potentiation on epithelial fluid secretion and mucociliary clearance. Methods: The effects of a novel low-molecular-weight TMEM16A potentiator (ETX001) were evaluated in human cell and animal models of airway epithelial function and mucus transport. ⋯ In ovine models of mucus clearance (tracheal mucus velocity and mucociliary clearance), inhaled ETX001 was able to accelerate clearance both when CFTR function was reduced by administration of a pharmacological blocker and when CFTR was fully functional. Conclusions: Enhancing the activity of TMEM16A increases epithelial fluid secretion and enhances mucus clearance independent of CFTR function. TMEM16A potentiation is a novel approach for the treatment of patients with CF and non-CF mucoobstructive diseases.