Published ahead of print on February 10, 2006, doi:10.1165/rcmb.2005-0387OC Am. J. Respir. Cell Mol. Biol., Volume 35, Number 1, July 2006, 40-47 A more recent version of this article appeared on July 1, 2006
Submitted on October 14, 2005 Tissue-Specific Renin-Angiotensin System in Pulmonary Lymphangioleiomyomatosis (LAM)Julio C Valencia1,1 Pulmonary-Critical Care Medicine Branch, National Institutes of Health, Bethesda, MD, USA; Pathology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA, 2 Pulmonary-Critical Care Medicine Branch, National Institutes of Health, Bethesda, MD, USA, 3 Biophysics Department, Universidade Federal de Sao Paulo, Sao Paulo, Brazil, 4 Laboratoire d'Anatomie Pathologique, Hopital Europeen G Pompidou, Paris, France, 5 Pathology Core, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA * To whom correspondence should be addressed. E-mail: mossj{at}nhlbi.nih.gov.
Lymphangioleiomyomatosis (LAM), a multisystem disease found in middle-aged age women, is characterized by cystic lung destruction and abdominal tumors (e.g., angiomyolipomas [AML], lymphangioleimyomas), resulting from proliferation of abnormal-appearing, smooth muscle-like cells (LAM cells). The LAM cells, in combination with other cells, form nodular structures within the lung interstitium and in the walls of the cysts. LAM cells contain mutations in the tuberous sclerosis complex TSC1 and/or TSC2 genes, which lead to dysregulation of the mammalian target of rapamycin (mTOR), affecting cell growth and proliferation. Proliferation and migration of vascular smooth muscle cells, and production of angiogenic factors are regulated, in part, by angiotensin II. To determine whether a LAM-specific renin-angiotensin system might play role in the pathogenesis of LAM, we investigated the expression of genes and gene products of this system in LAM nodules. mRNA for angiotensinogen was present in RNA isolated by laser captured-microdissection from LAM nodules. Angiotensin I-converting enzyme (ACE) and chymase-producing mast cells were present within the LAM nodules. We detected renin in LAM cells, as determined by the presence of mRNA and immunohistochemistry. Angiotensin II-type 1 and type II receptors were identified in LAM cells by immunohistochemistry and immunoblotting of microdissected LAM nodules. Angiotensin II is localized in cells containing alpha-smooth muscle actin (LAM cells). A LAM-specific renin-angiotensin system appears to function within the LAM nodule as an autocrine system that could promote LAM cell proliferation and migration, and could represent a pharmacological target.
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