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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 160-169, 2002
© 2002 American Thoracic Society

Activation of Bone Morphogenetic Protein/Smad Signaling in Bronchial Epithelial Cells during Airway Inflammation

Alexander Rosendahl, Evangelia Pardali, Matthaios Speletas, Peter ten Dijke, Carl-Henrik Heldin and Paschalis Sideras

Astrazeneca R&D Lund, Department of Molecular & Biosciences, Lund, Sweden; Department of Immunology, BioMedical Center, Lund University, Lund, Sweden; Division of Cellular Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands; and Ludwig Institute for Cancer Research, Uppsala, Sweden

Address correspondence to: Alexander Rosendahl, Ph.D., AstraZeneca R&D Lund, Department of Biosciences, Scheelev 2, S-221 87 Lund, Sweden. E-mail: alexander.rosendahl{at}astrazeneca.com

Bone morphogenetic proteins (BMPs) are pleiotropic secreted proteins, structurally related to transforming growth factor (TGF)-ß and activins. BMPs play pivotal roles in the regulation of embryonic lung development and branching of airways and have recently been considered to influence inflammatory processes in adults due to their chemotactic activity on fibroblasts, myocytes, and inflammatory cells. In this study, we have investigated the possible involvement of BMPs in a model of experimental allergic–airway inflammation in situ using antibodies that detect activated Smad proteins, and have monitored the modulation of BMP ligands during the inflammatory response. Inflamed bronchial epithelial cells and a few scattered alveolar cells expressed levels of phosphorylated Smad1 (pSmad1/5), indicative of active BMP/Smad signaling. This was in contrast to healthy epithelium, which was devoid of immunoreactivity. A mechanistic explanation for increased pSmad1/5 staining during inflammation was provided by the upregulated expression of all the BMP type I receptors, i.e., activin receptor–like kinase (ALK)2, ALK3, and ALK6, in the inflamed bronchial epithelial cells. Furthermore, the mRNA and protein profiles for BMP ligands were significantly altered during airway inflammation with induction of BMP2, BMP4, and BMP6, and downregulation of BMP5 and BMP7. Collectively, our data demonstrate for the first time active BMP/Smad signaling during airway inflammation in bronchial epithelial cells and thus raise the possibility that BMPs could play a determining role in respiratory pathophysiology.

Abbreviations: activin receptor–like kinase, ALK • bone morphogenetic proteins, BMP • BMP type II receptor, BMPR-II • diaminobenzidine, DAB • extracellular matrix, ECM • epidermal growth factor, EGF • immunoglobulin, Ig • interleukin, IL • ovalbumin, OVA • phosphate-buffered saline, PBS • phosphorylated Smad1 protein, pSmad1/5 • transforming growth factor-ß, TGF-ß




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