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Basal Expression of Bone Morphogenetic Protein Receptor Is Reduced in Mild Asthma

¹ Allergy and Clinical Immunology Section, ² Leukocyte Biology Section, and ³ MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, United Kingdom; and ⁴ Biomedical Research Foundation of the Academy of Athens, Athens, Greece

Correspondence and requests for reprints should be addressed to Dr. A. B. Kay, M.D., Ph.D., Emeritus Professor of Allergy and Clinical Immunology, Sir Alexander Fleming Building, Leukocyte Biology Section, Imperial College, South Kensington Campus, London, SW7 2AZ UK. E-mail: a.b.kay{at}imperial.ac.uk

Rationale: Despite increasing recognition of bone morphogenetic protein (BMP) signaling in tissue remodeling, the expression pattern of ligands and signaling pathways remain undefined in the asthmatic airway.

Objectives: To determine expression of BMP ligands (BMP-2, BMP-4, and BMP-7) and type I and type II receptors (ALK-2, ALK-3, ALK-6, and BMPRII) as well as evidence for activation of BMP signaling via detection of phosphorylated Smad1/5 (pSmad1/5) expression in asthmatic airways at baseline (compared with nonasthmatic controls), and after allergen challenge.

Methods: Bronchial biopsies were obtained from 6 nonasthmatic control volunteers, and 15 atopic patients with asthma (median age, 25 yr; median FEV₁% predicted, 97%) at baseline, then at 24 hours and 7 days after allergen challenge. Expression of BMP ligands, receptors, and signaling was analyzed using immunohistochemistry.

Measurements and Main Results: BMP ligand expression did not differ between asthmatic and control airways at baseline. Compared with the normal airway, there was significant down-regulation of ALK-2 (P = 0.001), ALK-6 (P = 0.0009), and BMPRII (P = 0.009) expression in asthma. Allergen challenge was associated with marked and sustained up-regulation of BMP-7 in airway epithelium (P = 0.017) and infiltrating inflammatory cells (P = 0.071) (predominantly in eosinophils, but also CD4⁺ T cells, mast cells, and macrophages). Up-regulation of pSmad1/5 expression (P = 0.031), ALK-2 (P = 0.002), and ALK-6 (P < 0.001) was observed indicating active signaling.

Conclusions: BMP receptor expression is down-regulated in the asthmatic airway, which may impede repair responses. Allergen provocation increases expression of the regulatory ligand BMP-7, activates BMP signaling, and increases receptor expression, all of which may contribute to repair and control of inflammation.

Key Words: bone morphogenetic protein • BMP ligands • BMP receptors • asthma • signaling

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Bone morphogenetic proteins (BMPs) have an essential role in organogenesis and tissue repair, suggesting an important role in airway remodeling. The expression of BMP ligands and signaling pathways are undefined in the normal airway and asthma. What This Study Adds to the Field BMP receptor expression is markedly different in the asthmatic airway compared with that of normal airways. Furthermore, BMP signaling is rapidly modulated in response to allergen challenge, suggesting a role in the disease process.