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3007701 
Journal Article 
SMAD Signaling in the Airways of Healthy Versus Asthmatic Rhesus Macaques Highlights a Relationship Between Inflammation and BMPs 
Lynn, TM; Molloy, EL; Masterson, JC; Glynn, SF; Costello, RW; Avdalovic, MV; Schelegle, ES; Miller, LA; Hyde, DM; O'Dea, S 
2015 
Yes 
American Journal of Respiratory Cell and Molecular Biology
ISSN: 1044-1549
EISSN: 1535-4989 
54 
4 
562-573 
English 
26414797 
WOS:000373707500012 
Bone Morphogenetic Protein (BMP) signaling is important for correct lung morphogenesis and there is evidence of BMP signaling re-activation in lung diseases. However, little is known about BMP signaling patterns in healthy airway homeostasis, inflammatory airway disease and during epithelial repair. In this study, a rhesus macaque (Macaca mulatta) model of allergic airway disease was used to investigate BMP signaling throughout the airways in health, disease and regeneration. Stereologic quantification of immunofluorescent images was used to determine the expression of BMPRIa and pSMAD 1/5/8 in the airway epithelium. A pSMAD 1/5/8 expression gradient was found along the airways of healthy juvenile rhesus macaques (n=3, p<0.005). Membrane-localized BMPRIa expression was also present in the epithelium of the healthy animals. Following exposure to house dust mite allergen and ozone, significant downregulation of nuclear pSMAD 1/5/8 occurs in the epithelium. When the animals were provided with a recovery period in filtered air, nuclear PCNA, pSMAD 1/5/8 and membrane-localized BMPRIa expression were significantly increased in the epithelium of conducting airways (p<0.005). Furthermore in the asthmatic airways, altered BMPRIa localization was evident. Due to the elevated eosinophil presence in these airways, we investigated the effect of eosinophil-derived proteins on BMPRIa trafficking in epithelial cells. Eosinophil-derived proteins (EDN, EPO and MBP) induced transient nuclear translocation of membrane-bound BMPRIa. This work mapping SMAD signaling in the airways of non-human primates highlights a mechanistic relationship between inflammatory mediators and BMP signaling and provides evidence that basal expression of the BMP signaling pathway is important for maintaining healthy airways. 
BMP; asthma; airways; homeostasis; repair