title: Cardiac asthma: transforming growth factor-β from the failing heart leads to squamous metaplasia in human airway cells and in the murine lung.
abstract: BACKGROUND
  Cardiac asthma describes symptoms of airflow obstruction due to heart failure. Chronic heart failure is associated with decreased FEV 1 , and FEV 1 improves after heart transplantation. Fibrotic remodeling of the heart and airways is mediated, in part, through transforming growth factor (TGF)- β . Blood TGF- b 1 concentration correlates with ventricular remodeling in cardiac disease, and TGF- β decreases after repair.
  
  
  METHODS
  We established a coculture of normal human bronchial epithelial (NHBE) cells differentiated at air-liquid interface with submerged basal cardiomyoblasts. Airway cells were immunostained with cytokeratin, actin, and involucrin. TGF- β synthesis was assayed using enzyme-linked immunosorbent assay. Phosphorylation of Smad in NHBE cells was determined by Western blotting.Mice given doxorubicin developed cardiac failure, and their airways were histologically examined.
  
  
  RESULTS
  Coculture induced involucrin-positive squamous metaplasia of NHBE cells, and this was attenuated by TGF- β antibody. Total TGF- β 1 was increased in coculture conditioned medium( P < .001). After 14 days of exposure to recombinant TGF- β 1 , there was squamous transformation of NHBE cells. One week after removing cardiomyoblasts from culture, squamous metaplasia resolved into normal ciliated epithelia. Smad was phosphorylated in NHBE cells with cardiomyoblasts or with recombinant TGF- β 1 exposure. The airways of mice with heart failure also demonstrated involucrin-positive squamous transformation.
  
  
  CONCLUSIONS
  TGF- β from cardiomyoblasts or from the failing heart can cause airway squamous metaplasia via Smad signaling, and this is blocked by anti-TGF- b antibody and reversed when cardiac cells are removed from culture. This appears to be an important mechanism for airflow obstruction with heart failure, sometimes described as cardiac asthma.
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Tanabe
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kanoh
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA.
authors.forename: William B
authors.initials: WB
authors.lastname: Moskowitz
authors.affiliation: Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA. Electronic address: brubin@vcu.edu.
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Rubin
mesh_terms: D000402:Airway Obstruction / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001980:Bronchi / Q000166:cytology; D018920:Coculture Techniques; D017931:DNA Primers; D004317:Doxorubicin; D004797:Enzyme-Linked Immunosorbent Assay; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+) / Q000378:metabolism; D006333:Heart Failure / Q000150:complications / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D032383:Myocytes, Cardiac / Q000378:metabolism; D010766:Phosphorylation; D011498:Protein Precursors / Q000378:metabolism; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D017931:DNA Primers; D011498:Protein Precursors; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; C032253:involucrin; D004317:Doxorubicin; D024601:Glyceraldehyde 3-Phosphate Dehydrogenase (NADP+)