Protein expression of urotensin II, urotensin-related peptide and their receptor in the lungs of patients with lymphangioleiomyomatosis
Introduction
Urotensin II (UII) is a small ancient peptide (11–14 amino acids) that was originally isolated from the urophysis, a neurosecretory organ, of the goby fish [3], [37]. The peptide is conserved from invertebrates to humans, shares similar structure to somatostatin, and is expressed in the nervous system and cardiopulmonary system of various species [1]. UII has a wide range of physiologic actions mediated through binding to the G-protein coupled receptor-14 named UT [1], [28], [34], [36]. Pharmacologic studies have shown UII to be the most potent vasconstricor peptide identified to date, though its vasoactive properties vary depending on the species and type of vessels investigated [10].
The bioactivity of UII is highly variable, and has been attributed in part to the levels of UT in any given tissue [11]. For example, UII constricted human coronary, radial and pulmonary arteries, which are tissues that exhibit abundant expression of UT [1], [12], [13], [30]. On the other hand, UII can also exert endothelium-dependant vasorelaxation through release of nitric oxide and prostaglandin I2 in the aorta, as well as coronary and mesenteric arteries [4], [17], [18], [26], [27], [44]. Others reported no significant effect for UII on pulmonary arteries of humans and animals [44]. Apart from its vascular effects, UII contracted airway smooth muscle cells of human, cat and rat bronchi [2], [19]. UII also stimulates proliferation of the smooth muscle cells of pulmonary and systemic arteries [9], [40], [49], epithelial cells [33], cardiac [20] and adventitial fibroblast [8], as well as umbilical endothelial cells [42], [43].
UII is expressed mainly in the aorta, heart, kidneys, central nervous system and spinal cord [1]. The UII receptor, UT, is expressed in the heart, brain, lungs, brain, skeletal muscles, bladder and pancreas [1], [23], [28], [34], [36]. UT is also expressed in vascular and airway smooth muscle cells, as well as pulmonary vasculature [31], [32]. Recent studies have demonstrated the presence of another ligand for UT named urotensin-related peptide URP [7], [45]; the detailed expression of URP in the human lungs remains to be elucidated. The proliferative effects of UII, a neuropeptide, suggested a potential role in neoplastic diseases of neuroendocrine origin. In agreement, increased UT expression, as well as proliferation in response to UII, was demonstrated in adrenal tumors [47], [50]. We hypothesized that UII and its receptor might play a role in lymphangioleiomyomatosis (LAM), a pulmonary and lymphatic disease caused by abnormal smooth muscle-like cells that also express neural crest markers.
Lymphangioleiomyomatosis (LAM) is a rare disease of young women characterized by abnormal proliferation of smooth muscle-like cells (LAM cells) in the pulmonary interstitium. The nodular proliferation of LAM cells leads to cystic destruction of the lungs and respiratory failure. Recent evidence describing the recurrence of LAM after lung transplantation and the presence of LAM cells with the same mutation in the lung, lymph nodes and kidney suggests that LAM cells are clonal, and can metastasize [24]. Although the origin of LAM cells is unknown, they express markers of smooth muscle differentiation (e.g., α-actin), as well as proteins associated with neural crest lineage (e.g., GP100). Recognition of GP100, by the HMB45 antibody is diagnostic of LAM. Given that urotensin signaling might play an important role in the pathophysiology of neoplastic processes of neural lineage, we sought to determine the expression of UII, URP and UT in the lungs of patients with LAM and compare that to those of normal individuals.
Section snippets
Tissues
Lung tissues from 7 patients with LAM (age 45 ± 2 years) and 6 normal control subjects (age 42 ± 5 years) collected either at transplantation or at autopsy were either snap frozen in liquid nitrogen or fixed in 10% formalin. Anonymized frozen or formalin-fixed lung specimens from patients with LAM were obtained from the National Disease Research Interchange or the NHLBI LAM Tissue registry with approval from the McGill University research ethics board, and in accordance with the NIH policy on
Immunohistochemistry
In the normal human lung, immunoreactivity for UII was seen in the airway epithelium and glands, and in the endothelial cells of mainly large pulmonary arteries (Fig. 1A–C). URP and UT immunoreactivity was also seen in similar distribution, although the presence of UT immunostaining was less apparent in endothelial cells compared to UII and URP (Fig. 1D). There was little to no immunostaining for the three molecules over small-medium sized pulmonary arteries. In comparison, there was abundant
Discussion
The present report details the cellular localization of UII and URP, and their receptor UT in the lungs of normal subjects or patients with LAM. Indeed, protein expression of the three molecules was localized to the airway epithelium and glands, and to the endothelium of pulmonary arteries. UT immunoreactivity was also seen over smooth muscle cells of the large size pulmonary arteries. In the lungs of patients with LAM, these three molecules were also expressed in LAM nodules. Interestingly,
Acknowledgments
Dr. Adel Giaid is supported by the Canadian Institute of Health Research and the Heart and Stroke Foundation of Quebec. Dr. Arnold Kristof is supported by NIH R0-CA125436. We acknowledge use of tissues procured by the National Disease Research Interchange (NDRI) with support from NIH grant no. 2U42RR006042-19.
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