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Original Research: Cardiovascular Disease |

Cardiac AsthmaTransforming Growth Factor-03B2 and Cardiac Asthma: Transforming Growth Factor-β From the Failing Heart Leads to Squamous Metaplasia in Human Airway Cells and in the Murine Lung

Tsuyoshi Tanabe, MD, PhD; Soichiro Kanoh, MD, PhD; William B. Moskowitz, MD; Bruce K. Rubin, MD, MEngr, MBA, FCCP
Author and Funding Information

From the Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA.

Correspondence to: Bruce K. Rubin, MD, MEngr, MBA, FCCP, Department of Pediatrics, Virginia Commonwealth University School of Medicine, 1001 E Marchall St, PO Box 980646, Richmond, VA; e-mail: brubin@vcu.edu


Funding/Support: This research was funded by a grant from the Lung Disease Research Center of Virginia Commonwealth University and through a stipend from Shinshu University in Japan in support of Dr Tanabe.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2012;142(5):1274-1283. doi:10.1378/chest.11-1710
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Background:  Cardiac asthma describes symptoms of airflow obstruction due to heart failure. Chronic heart failure is associated with decreased FEV1, and FEV1 improves after heart transplantation. Fibrotic remodeling of the heart and airways is mediated, in part, through transforming growth factor (TGF)-β. Blood TGF-β1 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-β1 was increased in coculture conditioned medium (P < .001). After 14 days of exposure to recombinant TGF-β1, 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-β1 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-β 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.

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