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Inflammatory Cell Infiltrate and Pulmonary Fibrosis in Mice Overexpressing Endothelin-1*

Karen A. Fagan, MD; B. Hocher; C. Schwarz; K. Thone-Reineke; K. El-Hag; S. Elitok; C. Bauer; H. Neumayer; D. M. Rodman, MD; F. Theuring
Author and Funding Information

*From the Universitatsklinikum Charite der Humboldt Universitat zu Berlin, Free University of Berlin, Berlin, Germany; and University of Colorado Health Sciences Center, Denver, CO.

Correspondence to: Karen A. Fagan, MD, Assistant Professor of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 E Ninth Ave, Denver, CO 80262



Chest. 2001;120(1_suppl):S9-S10. doi:10.1378/chest.120.1_suppl.S9
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Endothelin-1 (ET-1) has been associated with several chronic lung diseases, including pulmonary hypertension, asthma, bronchiolitis obliterans, and pulmonary fibrosis. However, the role of ET-1 in the pathogenesis of these diseases is uncertain. Transgenic mice overexpressing human ET-1 have highest levels of transgene expression in lung, kidney, and brain, and develop renal interstitial fibrosis and glomerulosclerosis. Using these mice, we hypothesized that increased lung ET-1 would lead to pulmonary fibrosis. Overexpression of human ET-1 resulted in a 30 to 50% increase in whole-lung ET-1 peptide level, and expression was localized throughout the lung (blood vessels, airways, alveoli, interstitium) but most markedly in the bronchial smooth muscle. There was no difference in vessel wall thickness or right ventricular hypertrophy and pressure compared to littermates with negative findings, suggesting that increased ET-1 did not lead to pulmonary hypertension. However, there was an increase in extracellular matrix deposition especially in the perivascular space. Increased cell proliferation of peribronchial cells was found, but there was no increase in bronchial thickness. There was no increase in apoptosis in the lungs of transgene-positive mice. The alveoli appeared normal. Perivascular accumulation of mononuclear cells (CD4+) was also seen in the transgenic animals. In conclusion, overexpression of ET-1 in the lung leads to a chronic lymphocytic inflammation and perivascular fibrosis but not bronchial hypertrophy or pulmonary hypertension. This finding is consistent with a central role of ET-1 in inflammatory and fibrotic lung disease. We speculate that targeting ET-1 transgene expression to the alveoli may further define the role of ET-1 in pulmonary fibrosis.

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