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Am. J. Respir. Crit. Care Med., Volume 161, Number 6, June 2000, 1999-2004

Angiotensin II Is Mitogenic for Human Lung Fibroblasts via Activation of the Type 1 Receptor

RICHARD P. MARSHALL, ROBIN J. MCANULTY, and GEOFFREY J. LAURENT

Centre for Cardiopulmonary Biochemistry and Respiratory Medicine, Royal Free and University College London Medical School, Rayne Institute, London, United Kingdom

The expression of renin-angiotensin system components and the elevation of angiotensin-converting enzyme (ACE) in a number of fibrotic lung diseases suggests angiotensin II (AII) could play a role in the pathogenesis of pulmonary fibrosis. However, the effect of AII on lung fibroblasts has not previously been assessed and the mechanisms by which AII induces cell proliferation in mesenchymal cells are not fully understood. We have examined the ability of AII to stimulate fetal and adult human lung fibroblast proliferation in vitro. In particular, we have assessed the receptor subtypes involved and the possible autocrine role of transforming growth factor beta  (TGF-beta ) and platelet-derived growth factor (PDGF), two recognized fibroblast mitogens. Angiotensin type 1 (AT1), but not type 2, receptors were identified on fetal and adult human lung fibroblasts by immunocytochemistry. AII (1 µM) increased DNA synthesis (determined by [3H]thymidine incorporation) in fetal and adult cells by 211 ± 18% and 150 ± 14%, respectively (p < 0.01), and was inhibited by a specific AT1 receptor antagonist, Losartan (74 ± 14%). A proliferative response to AII was confirmed by direct cell counts. Subsequently, fibroblasts were incubated with neutralizing antibodies to TGF-beta and PDGF. Anti-TGF-beta antibodies inhibited AII-induced DNA synthesis by 73 ± 13%. However, no effect was seen with anti-PDGF antibodies. In conclusion, we have shown that angiotensin II induces human lung fibroblast proliferation in vitro via activation of the AT1 receptor and involves the autocrine action of TGF-beta .




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