Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosis
Wendy K. Steagall, Mario Stylianou, Gustavo Pacheco-Rodriguez, Joel Moss
Wendy K. Steagall, Mario Stylianou, Gustavo Pacheco-Rodriguez, Joel Moss
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Clinical Research and Public Health Pulmonology Therapeutics

Angiotensin-converting enzyme inhibitors may affect pulmonary function in lymphangioleiomyomatosis

Abstract

INTRODUCTION. A local renin-angiotensin system exists in the pulmonary nodules of lymphangioleiomyomatosis patients. Sirolimus, the standard treatment for lymphangioleiomyomatosis, stabilizes lung function, but all patients do not respond to or tolerate sirolimus. As renin-angiotensin systems may affect tumor growth and metastasis, we questioned if angiotensin-converting enzyme inhibitors affected lymphangioleiomyomatosis disease progression. METHODS. Retrospective study of 426 patients was performed, examining angiotensin-converting enzyme levels, pulmonary function data, and angiotensin-converting enzyme inhibitor treatment. RESULTS. Serum angiotensin-converting enzyme levels were elevated in approximately 33% of patients, increased with duration of disease, and were inversely correlated with pulmonary function. Levels decreased significantly over time with sirolimus treatment. Treatment with angiotensin-converting enzyme inhibitors was reported by approximately 15% of patients and was significantly associated with a slower rate of decline in percentage predicted forced expiratory volume (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) in patients not treated with sirolimus. No significant differences in rates of decline of FEV1 or DLCO were seen in patients treated with both inhibitors and sirolimus versus sirolimus alone. CONCLUSIONS. Angiotensin-converting enzyme inhibitors may slow decline of pulmonary function in patients with lymphangioleiomyomatosis not treated with sirolimus. These inhibitors may be an option or adjunct in the treatment of lymphangioleiomyomatosis. A clinical trial may be warranted to examine this possibility. FUNDING. NIH.

Authors

Wendy K. Steagall, Mario Stylianou, Gustavo Pacheco-Rodriguez, Joel Moss

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Figure 5

Pathways impacted by RAS that may play a role in LAM disease.

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Pathways impacted by RAS that may play a role in LAM disease. The compon...
The components of RAS found in LAM lung nodules include AGT, renin, ACE, AngII, AT1R, and AT2R, while chymase, which can also cleave AngI to generate AngII, is detected in mast cells present in the nodules as well (components of LAM RAS in red). Stimulation of AT1R by AngII can promote fibrogenesis and tissue remodeling (through TGF-β), cell proliferation and/or motility (through TGF-β, Stat3, PKC, tyrosine kinases [TyrK], serine/threonine kinases [Ser/Thr-K], and ERK and Akt inhibition of TSC2 resulting in mTOR activation), angiogenesis/lymphangiogenesis (through VEGF), and metastasis (due to VEGF-stimulated lymphangiogenesis and IL-6–, IL-8–, IL-1α–, IL-1β–, Cox2-, and MCP1-stimulated inflammation and creation of a protumorigenic environment). MMPs also affect tissue remodeling and are present in LAM lung nodules, with a sirolimus-insensitive increase in MMP2 expression in TSC2-deficient cells. Sirolimus inhibits mTOR activity and is the treatment of choice for LAM patients. ARBs block the activation of AT1Rs, while ACEIs inhibit ACE activity and the cleavage of AngI to AngII. ACEIs can directly bind to MMPs and inhibit their activity; thus, ACEIs may impact an extra aspect of tissue remodeling not affected by ARBs.