Activation of the Ca2+ activated Cl- channel TMEM16A is proposed as a treatment in inflammatory airway disease. It is assumed that activation of TMEM16A will induce electrolyte secretion, and thus reduce airway mucus plugging and improve mucociliary clearance. A benefit of activation of TMEM16A was shown in vitro and in studies in sheep, but others reported an increase in mucus production and airway contraction by activation of TMEM16A. We analyzed expression of TMEM16A in healthy and inflamed human and mouse airways and examined the consequences of activation or inhibition of TMEM16A in asthmatic mice. TMEM16A was found to be upregulated in the lungs of patients with asthma or cystic fibrosis, as well as in the airways of asthmatic mice. Activation or potentiation of TMEM16A by the compounds Eact or brevenal, respectively, induced acute mucus release from airway goblet cells and induced bronchoconstriction in mice in vivo. In contrast, niclosamide, an inhibitor of TMEM16A, blocked mucus production and mucus secretion in vivo and in vitro. Treatment of airway epithelial cells with niclosamide strongly inhibited expression of the essential transcription factor of Th2-dependent inflammation and goblet cell differentiation, SAM pointed domain-containing ETS-like factor (SPDEF). Activation of TMEM16A in people with inflammatory airway diseases is likely to induce mucus secretion along with airway constriction. In contrast, inhibitors of TMEM16A may suppress pulmonary Th2 inflammation, goblet cell metaplasia, mucus production, and bronchoconstriction, partially by inhibiting expression of SPDEF.

• MeSH
• Anoctamin-1 genetics   metabolism   MeSH
• Asthma etiology   metabolism   pathology   MeSH
• Cystic Fibrosis etiology   metabolism   pathology   MeSH
• HEK293 Cells MeSH
• Mucus metabolism   MeSH
• Humans MeSH
• Mice MeSH
• Respiratory Mucosa metabolism   pathology   MeSH
• Constriction, Pathologic complications   MeSH
• Inflammation etiology   metabolism   pathology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

We present a 72 years old male with a left nasal cavity (mammary analogue) secretory carcinoma (SC) which exhibited classical morphological features on light microscopical examination, diffuse strong S100 and mammoglobin positivity on immunohistochemistry, and ETV6-NTRK3 gene fusion on next generation sequencing (NGS) analysis. Unusual features of this tumor are expression of p63 and DOG1 on immunohistochemistry and the atypical junction between Exon 4 of the ETV6 gene and Exon 14 of the NTRK3 gene.

• MeSH
• Anoctamin-1 biosynthesis   MeSH
• Exons genetics   MeSH
• Oncogene Proteins, Fusion genetics   MeSH
• Humans MeSH
• Membrane Proteins biosynthesis   MeSH
• Biomarkers, Tumor analysis   MeSH
• Neoplasm Proteins biosynthesis   MeSH
• Nose Neoplasms genetics   pathology   MeSH
• Nasal Cavity pathology   MeSH
• Mammary Analogue Secretory Carcinoma genetics   pathology   MeSH
• Sequence Analysis, DNA MeSH
• Aged MeSH
• High-Throughput Nucleotide Sequencing MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged MeSH
• Publication type
• Journal Article MeSH
• Case Reports MeSH

• Keywords
• 3-methylglutakonová acidurie, 3-methylglutakonová acidurie,
• MeSH
• Acidosis, Lactic epidemiology   prevention & control   therapy   MeSH
• Anoctamin-1 * genetics   deficiency   MeSH
• Diet Therapy standards   MeSH
• Child MeSH
• Ethnicity MeSH
• Gastrostomy MeSH
• Glutarates metabolism   urine   MeSH
• Bicarbonates therapeutic use   MeSH
• Hypospadias MeSH
• Hernia, Inguinal MeSH
• Pregnancy Complications MeSH
• Craniofacial Abnormalities MeSH
• Humans MeSH
• Mitochondrial Diseases genetics   MeSH
• Oligohydramnios MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Publication type
• Case Reports MeSH
• Research Support, Non-U.S. Gov't MeSH