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Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

¹ Department of Anesthesiology and Critical Care Medicine, ² Division of Pulmonary and Critical Care Medicine, Department of Medicine, ³ Division of Thoracic Surgery, Department of Surgery, ⁴ Division of Cardiology, Department of Medicine, and ⁵ Division of Cardiopulmonary Pathology, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Roger A. Johns, M.D., M.H.S., Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, 720 Rutland Avenue, Ross 361, Baltimore, MD 21205. E-mail: rajohns{at}jhmi.edu

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-β, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-β is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-β induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-β may be involved in the development of scleroderma-associated pulmonary hypertension.

Key Words: pulmonary hypertension • scleroderma • resistin-like molecule β • hypoxia-induced mitogenic factor • T helper type 2

CLINICAL RELEVANCE We have demonstrated that resistin-like molecule (RELM)-β is up-regulated in the lungs of patients diagnosed with scleroderma-associated pulmonary hypertension. We also have shown that the addition of recombinant RELM-β induces proliferation of cultured pulmonary vascular smooth muscle cells and endothelial cells. Understanding the role of RELM-β in the development of pulmonary hypertension will provide insights for the future development of much-needed therapies for this disease.

 

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