(1986) U. of Michigan, Ann Arbor, MI
(1990) U. of Michigan, Ann Arbor, MI
1990-93) Dartmouth, Hanover, NH
(1993-98) UNC, Chapel Hill, NC
Associate Professor of Medicine
Office: 6007-A Thurston-Bowles
The lung is protected against inhaled organisms and particles by mucociliary clearance. Inhaled particles bind to a secreted mucus layer, which rests on top of a thin film of fluid. The volume/height of this thin fluid layer is tightly regulated so that coordinated ciliary beating efficiently propels this mucus blanket toward the proximal airways. A key determinant of airway surface liquid volume is the rate of sodium absorption through the epithelial sodium channel (ENaC). In cystic fibrosis (CF) sodium absorption is excessive, leading to a depleted airway surface liquid layer, poor mucociliary clearance, and subsequent chronic infection. Research in this lab is directed at understanding the processes that regulate ion transport and mucociliary clearance, in an attempt to develop therapies aimed at correcting the underlying defects in CF lung disease.
One focus of this lab is the regulation of the ENaC, which forms the rate-limiting step in fluid absorption from the lung. Using the xenopus oocyte expression system, the impact of genes encoding candidate proteins on whole cell ENaC currents and single channel kinetics are tested. These results are then used to guide experiments using various epithelial cell models. Ultimately, the goal of this research is to modify ion transport in vivo in a way that improves mucociliary clearance.
A second avenue being explored as a means to alter ion transport in vivo, and thereby enhance mucociliary clearance, is the use of nucleotide receptor agonists. Activation of the dominant airway nucleotide receptor, P2Y2, leads to secretion of chloride/water via non-CFTR chloride channels, mucin secretion via goblet cells, and more rapid ciliary beating. This triad of effects combines to increase mucociliary clearance in normal subjects, as well as in patients with CF. A potential shortcoming of this therapy is the presence of enzymes that hydrolyze typical P2Y2 agonists (e.g. ATP, UTP), thus dramatically decreasing their half-life. Our lab, therefore, is characterizing cell surface and secreted enzymes that may impact the profile of endogenous/exogenous nucleotides in airways, so that therapeutic rational approaches aimed at targeting these receptors may be devised.
- Dellon EP, Donaldson SH, Johnson R, Davis SD. Safety and Tolerability of Inhaled Hypertonic Saline in Young Children with Cystic Fibrosis. Ped Pulm. 2008, accepted.
- Donaldson SH. Mucociliary Clearance: A Target for Treatment in CF and COPD. Respir Drug Deliv. 2008: 29-36.
- Rollins BM, Burns M, Coakley RD, Chambers LA, Hirsh AJ, Clunes MT, Lethem MI, Donaldson SH, Tarran R. A2B Adenosine Receptors Regulate the Mucus Clearance Component of the Lungs Innate Defense System. Am J Respir Cell Mol Biol. 2008, Mar 26 [Epub ahead of print].
- Donaldson SH. Hydrator Therapies for Cystic Fibrosis Lung Disease. Ped Pulm. 2008, accepted.
- Esther CR, Alexis NE, Clas ML, Lazarowski ER, Donaldson SH, Pedrosa Ribiero CM, Moore CG, Davis SD, and Boucher RC. Extracellular Purines are Biomarkers of Neutrophilic Airway Inflammation. Eur Respir J 2008, Feb 6 [Epub ahead of print].
- Donaldson SH, and Boucher RC. Sodium Channels in Cystic Fibrosis. Chest. 2007, 132(5):1631-6.
- Donaldson SH, Corcoran TE, Laube BL, and Bennett WD. Mucociliary clearance as an outcome measure for cystic fibrosis clinical research. Proc. ATS 2007, 4(4):399-405.
- Tarran R, Donaldson S, and Boucher RC. Rationale for hypertonic saline for cystic fibrosis lung disease. Seminary in Respiratory and Critical Care Medicine 2007, 28(3):295-302.
- Kennedy MP, Coakley RD, Donaldson SH et al. Burkholderia gladioli: Five year experience in a cystic fibrosis and lung transplantation center. J Cyst Fibros 2007;6(4):267-73.
- Donaldson SH, and Boucher RC. Pathophysiology of Cystic Fibrosis. Ann Nestle’ [Engl] 2006;64:101-108.
- Tarran R, Trout L, Donaldson SH, and Boucher RC. Soluble mediators, not cilia, determine airway surface liquid volume in normal and cystic fibrosis superficial airway epithelia. J Gen Physiol 2006; 127(5):591-604.
- I. Aziz, J. A. Kastelik, S. Zarogiannis, C. Hatzoglou, K. Gourgoulianis, R. Kuver, S. P. Lee, P. T.P. Bye, M. R. Elkins, S. H. Donaldson, R. Tarran, R. C. Boucher, and F. Ratjen. N. Engl. J. Med. 2006; 354(17): 1848 - 1851.
- Donaldson SH, Bennett W, Zeman K, Knowles MR, Tarran R, and Boucher RC. Mucus Clearance and Lung Function in Cystic Fibrosis with Hypertonic Saline. N. Engl. J. Med. 2006; 354(3):241-250.
- Donaldson SH and Boucher RC. Update on the Pathogenesis of Cystic Fibrosis Lung Disease. Curr Opp Pulm Med 2003; Nov;9(6):486-91.
- Donaldson SH, Poligone, E, Stutts MJ. CFTR Regulation of ENaC. Methods Mol Med 2002; 70:343-364.
- Donaldson SH, Picher P, Boucher RC. Cell surface and secreted adenylate kinase and nucleoside diphosphokinase contribute to extracellular nucleotide metabolism in airways. Am J Respir Cell Mol Biol. 2002 Feb;26(2):209-15.
- Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, Gabriel SE. Regulation of the Epithelial Sodium Channel by Serine Proteases in Human Airways. J Biol Chem 2002;277(10):8338-45.
- Donaldson SH, Lazarowski ER, Picher M, Knowles MR, Stutts MJ, and Boucher, RC. Basal Nucleotide Levels, Release, and Metabolism in Normal and Cystic Fibrosis Airways. Molecular Medicine. 2000; 6(11):969-982.
- Donaldson S, Novotny D, Paradowski L, Aris R: Acute and chronic lung allograft rejection during pregnancy. Chest. 1996;110:293-296.
- Pinto-Powell R, Olivier KN, Marsh BJ, Donaldson S, Parker W, Boyle W, Knowles M, Magnusson M, von Reyn CF. Skin testing with Mycobacterium avium sensitin to identify infection with M. avium complex in cystic fibrosis. Clin. Inf. Dis. 1996;22:560-562.
- Bennett WD, Zeman KL, Mattingly D, and Donaldson S. Standardization of Mucociliary and Cough Clearance Methodology. Ped. Pulm. Supp 30. 2007. A80.
- Gaillard EA, Donaldson S, Caballero A, Stutts J, and Tarran R. The Soluble Protein PLUNC Regulates ENaC in Human Bronchial Epithelial Cell Cultures. Ped. Pulm. Supp 30. 2007. A98.
- Dellon EP, Donaldson S, Johnson R, and Davis SD. Safety of Inhaled Hypertonic Saline in Infants and Young Children with Cystic Fibrosis. Ped. Pulm. Supp 30. 2007. A272.
- Bennett WD, Donaldson SH, Zeman KL, Henderson AG, Boucher RC. Efficacy of new therapies for improving clearance in patients. ISAM 2007
- Trout L, Boucher RC, O’Neal WK and Donaldson SH. Comparison of the Quantitation of mRNA Encoding Serine Proteases and Kunitz-type Inhibitors Between Human Airways and Primary Cell Culture. Ped. Pulm Supp 29. 2006. A127.
- Esther CR, Alexis, NE, Clas ML, Donaldson SH, and Boucher RC. Extracellular Purines are Biomarkers of Airway Inflammation in Cystic Fibrosis. Ped. Pulm Supp 29. 2006. A130.
- Dellon EP, Donaldson SH, Johnson R, and Davis SD. Safety and Tolerability of Hypertonic Saline in Young Children with Cystic Fibrosis. Ped. Pulm Supp 29. 2006. A283.
- Stephenson DH, Donaldson S, Yankaskas J, Lee N, Hohneker K, McGibbon L, Barker P, and Leigh M. Three-year Experience of Our Continuous Quality Improvement Team: Adult and Pediatric CF Programs at UNC. Ped. Pulm Supp 29. 2006. A457.
- Donaldson S, Smith R, Doran J, DiMassimo B, Zeman K, Bennett B, Hurd H, and Hopkins S. Safety, Pharmacokinetics and Effects on Mucus Clearance Following Administration of 552-02 to Normal Healthy Volunteers. Ped. Pulm. Supp 28. 2005. A218.
- >Tarran R, Donaldson S, van Boul J, Button B, Rollins B and Burridge K. Shear Stress-Induced Airway Surface Liquid (ASL) Homeostasis Requres Cytoskeletal Reorganization. Ped. Pulm. Supp 28. 2005. A112.
- Bennett WD, Donaldson SH, Zeman KL, Knowles MR and Boucher RC. Sustained Correction of Abnormal Mucociliary Clearance and Lung Function in Cystic Fibrosis with Aerosolized Hypertonic Saline. J. Aerosol. Med. 2005. in press.
- Donaldson SH, Bennett WD, Zeman KL, Kairalla AA, Knowles MR and Boucher RC. A Pilot Study of Amiloride and Hypertonic Saline in Cystic Fibrosis. Ped. Pulm. Supp 26. 2004. A325.
- Trout L, Boucher RC, Jones L, O’Neal WK and Donaldson SH. Quantitation of mRNA Encoding Serine Proteases and Kunitz-type Inhibitors in Human Airways – Implications for ENaC Regulation. Ped. Pulm. Supp 26. 2004. A55.
- Callahan TL; Retsch-Bogart GZ, Knowles MR, Minnix SL, Donaldson SH, and Leigh MW. Challenges Faced by CF Clinical Researchers: Tight Study Timelines and Patient Recruitment. Ped Pulm. Supp 26. 2004. A500.
- Bennett WD, Zeman KL, Donaldson SH, Donohue JF, Knowles MR, and Boucher RC. Cough Clearance is Less Effective in Cystic Fibrosis than Chronic Bronchitis. Am. J. Resp. Crit. Care Med. 2004;169(7):A386.
- Donaldson, SH, Bennett, W, Zeman, K, Knowles, MR, Boucher, RC. Efficacy of Amiloride and Hypertonic Saline in Cystic Fibrosis. Ped. Pulm. Supp 25. 2003: A194.
- Lazarowski ER, Grubb B, Donaldson S, van Heusden CA, Boucher RC. Extracellular Adenyl Purines Provide a Mechanism of Control for A2B Receptor-Mediated Epithelial Cell Responses. Ped. Pulm. Supp 24. 2002: A163.
- Donaldson SH, Gilmore ES, Milgram SL, Stutts MJ. Regulation of the epithelial sodium channel by Src-family kinases. Ped. Pulm. Supp 20. 2000: A112.
- Mohler PJ, Donaldson SH, Kreda SK, Boucher RC, Stutts MJ, Milgram SL. Yes-associated protein 65 localizes P62C-Yes to the apical compartment of airway epithelia by association with EBP50. Ped. Pulm. Supp 19. 1999:A293.
- Donaldson SH, Holloway G, Li DC, Chao J, Boucher RC, Gabriel SE: Serine protease regulation of the epithelial sodium channel (ENaC). Ped. Pulm. Supp 17. 1998
- Milgram SL, Kreda S, Donaldson S, Short B, Kultgen P, Winders A, Boucher RC, Stutts MJ: The COOH-terminus of CFTR associates with the apical cytoskeleton via a PDZ domain in EBP50. Ped. Pulm. Supp 17. 1998
- Donaldson SH, Stutts MJ, Boucher RC, Knowles MR: In vivo regulation of ATP levels in human nasal epithelia. Ped. Pulm. Supp 13. 1996. A289.
- Donaldson SH, Stutts MJ, Boucher RC, Knowles MR: Adenosine triphosphate levels in nasal surface liquid. Am. J. Resp. Crit. Care Med. 1996;153(4):A854.
- Pinto-Powell R, Donaldson S, Olivier K, Parker, HW, Boyle W, Hohneker K, Knowles MR, von Reyn CF: Dual skin testing and sputum cultures to identify infection with Mycobacterium avium complex in patients with cystic fibrosis. Ped. Pulm. Supp 10. 1994. A257.
- Donaldson SH and Boucher SH: Microbiology and Infection in Cystic Fibrosis, in Fishman’s Pulmonary Diseases and Disorders, 4th Edition. McGraw Hill Publishers; in press.
- Donaldson SH and Boucher RC: Cystic Fibrosis, in Runge M and Patterson C (eds): Principles of Molecular Medicine, 2nd Edition. Totowa, NJ, Humana Press; 2006:251-258.
- Donaldson SH, Yankaskas J: Cystic Fibrosis, in Hess D, MacIntyre N, Mishoe SC, Galvin WF, Saposnick AB, Adams A (eds): Respiratory Care: Principles and Practice. Orlando, FL, W.B. Saunders Company; 2002:1003-1021.
- Donaldson SH, Boucher RC: Therapeutic Applications for Nucleotides in Lung Disease, in Turner J, Weisman G, and Fedan J (eds): The P2 Nucleotide Receptors. Totowa, NJ, The Humana Press Inc.; 1998:413-424.
- Erickson RP, Bevilacqua A, Ross C, Donaldson S, Stalvey JRD: Do BKM sequences play a role in human sex determination? In Haseltine FP, McClure ME, and Goldberg EH (eds): Genetic Markers of Sex Differentiation. New York, NY, Plenum Publishing Corporation; 1987:149-159.