Activation of bone morphogenetic protein/Smad signaling in bronchial epithelial cells during airway inflammation.
Bone morphogenetic proteins (BMPs) are pleiotropic secreted proteins, structurally related to transforming growth factor (TGF)-beta 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.
Rosendahl
Alexander
A
Astrazeneca R&D Lund, Department of Molecular & Biosciences, Lund, Sweden. alexander.rosendahl@astrazeneca.com
Pardali
Evangelia
E
Speletas
Matthaios
M
Ten Dijke
Peter
P
Heldin
Carl-Henrik
CH
Sideras
Paschalis
P
D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D011014:Pneumonia / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017978:Receptors, Growth Factor / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins; D051898:Smad1 Protein; D015534:Trans-Activators / Q000378:metabolism*
D019485:Bone Morphogenetic Proteins; D004268:DNA-Binding Proteins; D008024:Ligands; D017978:Receptors, Growth Factor; C497399:SMAD1 protein, human; D051785:Smad Proteins; D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D015534:Trans-Activators; D017346:Protein Serine-Threonine Kinases; C498214:BMPR1B protein, human; C498212:Bmpr1a protein, mouse; C498215:Bmpr1b protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I