Scott H. Randell, PhD
Associate Professor
Joint Appointment in Medicine

Education:

BS, State University of NY College at New Paltz 1979
PhD, Johns Hopkins University 1985

Airway Epithelial Cell Biology - Stem Cells, Host Defense & Response to Injury

Epithelial cells lining the airways are a crucial interface between the organism and environment.  Their normal physiologic function serves to protect the host from a battery of potential insults such as inhaled particulates, pollutants, carcinogens and infectious agents.  Abnormalities in airway epithelial cells frequently contribute to the descending spiral of physiologic impairment inherent to chronic lung disease.  Despite a pivotal role for the airway epithelium, several basic biologic properties remain poorly understood.  Research in my lab is focused on three areas where a greater knowledge of basic cell biology can be applied towards overcoming current clinical airway disease problems.

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Identification of airway epithelial stem cells. The airway epithelium occupies a critical interface between organism and environment and its normal physiologic function is essential for host well-being. It is central to the pathogenesis of asthma, chronic bronchitis, cystic fibrosis, well known and emerging infectious diseases, lung cancer, post transplant lung allograft rejection, and is a prime target for gene therapy. Understanding basic cellular processes such as progenitor-progeny relationships and regulation of proliferation and differentiation is of fundamental importance. Stem cell biology is the basis for the emerging fields of cellular therapy and regenerative medicine. However, stem cells of the airway epithelium and patterns of cell renewal and migration, at steady state, after injury, or in disease, have not yet been identified with certainty. Our goals are to identify and isolate airway epithelial stem cells and to understand molecular mechanisms regulating airway epithelial cell proliferation and fate decisions.

Innate immunity in the airway. The airway epithelium is poised to detect and respond to noxious stimuli. It can act either as a “sensor” or “insulator”, thereby determining the intensity of the inflammatory response. While vital for eliminating pathogens penetrating initial physical barriers, airway inflammation is a two-edged sword that must be precisely regulated. Thus, for every pro-inflammatory event, anti-inflammatory mechanisms are induced to return the host to homeostasis. Adaptation to the continuous presence of pathogens must be very important in chronic infectious airway diseases such as cystic fibrosis and chronic bronchitis, but remains understudied and poorly understood. We have found that airway epithelial cells become tolerant to the respiratory tract pathogen Pseudomonas aeruginosa as manifested by decreased cytokine production and hyporesponsiveness to secondary stimulation. In contrast, chronic exposure to Staphylococcus aureus results in mounting production of pro-inflammatory cytokines and hypersensitivity to secondary stimuli. Our goals are to better understand molecular mechanisms regulating these extremes of airway epithelial adaptation and to understand the relationship of adaptation to the pathogenesis of chronic infectious airway diseases.

Post-lung transplant ischemia reperfusion injury and bronchiolitis obliterans syndrome. Lung transplantation is a final option for many patients with end stage lung disease. However due to a limited supply of transplantable lungs, many individuals die on the waiting list. The extensive surgery entails an approximately 15% one-year mortality rate and lung transplants fare the worst of all solid organs, with only 50% 5 year survival. I feel a strong obligation towards improving the outcome of lung transplantation. Studies of lung ischemia reperfusion injury may help to develop strategies to enhance the supply of transplantable lungs and to lengthen storage time to allow for histocompatibility matching. We are also examining basic mechanisms of airway epithelial injury in the allogenic environment to better understand bronchiolitis obliterans syndrome, the leading cause of lung allograft failure.

I direct the UNC CF Center Tissue Procurement and Cell Culture Core that provides primary and passaged human airway epithelial cells, media and expertise to Cystic Fibrosis Center and Gene Therapy Center investigators and collaborators.  We are actively pursuing novel strategies to create superior cell lines as better tools for cystic fibrosis basic research and testing of therapeutics.

Recent Publications

Book Chapters and Review Articles

Livraghi A, Randell SH. Cystic Fibrosis and Other Respiratory Diseases of Impaired Mucus Clearance. Toxicologic Pathology. 2006, In Press.

Randell SH. Airway Epithelial Stem Cells and the Pathophysiology of Chronic Obstructive Pulmonary Disease. Proc Am Thoracic Soc. 2006. In Press.

Randell SH, Boucher RC. Effective Mucus Clearance is Essential for Respiratory Health. Am J Respir Cell Mol Biol. 2006 Jul; 35(1):20-8. Epub 2006 Mar 9.

Neuringer IP, Randell SH. Lung stem cell update: promise and controversy.
Monaldi Arch Chest Dis. 2006 Mar;65(1):47-51.

Randell SH, Broers JV, Ramaekers FCS. Keratin. In Encyclopedia of Respiratory Medicine. GJ Laurent and SJ Shapiro Eds, Elsevier Press, 2005.

Fulcher L, Gabriel SE, Burns KA, Yankaskas JR, and SH Randell. Well-Differentiated Human Airway Epithelial Cell Cultures. Methods in Molecular Medicine. J Picot Ed. Humana Press, 2005.

Peer-Reviewed Journal Articles

Dejima K, Randell SH, Stutts JM, Senior BA, Boucher RC. Potential Role of Abnormal Ion Transport in the Pathogenesis of Chronic Sinusitis. Archives of Otolaryngology, Head and Neck Surgery. 2006, In Press.

Gomperts BN, Belperio JA, Rao PN, Randell SH, Fishbein MC, Burdick MD, Strieter RM. Circulating progenitor epithelial cells traffic via CXCR4/CXCL12 in response to airway injury. J Immunol. 2006 Feb 1;176(3):1916-27.

Grubb BR, Gabriel SE, Mengos A, Gentzsch M, Randell SH, Van Heeckeren AM, Knowles MR, Drumm ML, Riordan JR, Boucher RC. SERCA Pump Inhibitors Do Not Correct Biosynthetic Arrest of D F508CFTR in Cystic Fibrosis. Am J Respir Cell Mol Biol. 2006 Mar;34(3):355-63.

Yim HW, Slebos RJ, Randell SH, Umbach DM, Parsons AM, Rivera MP, Detterbeck FC, Taylor JA. Smoking is associated with increased telomerase activity in short-term cultures of human bronchial epithelial cells. Cancer Lett. 2006 Mar 3; [Epub ahead of print]

Koukoulis G, Caldwell R, Inokawa H, Button B, Sevala M, Lyles JD, Takashima S, Blackwell J, Randell SH, Egan TM. Trends in lung pH and PO2 after circulatory arrest: implications for non-heart-beating donors and cell culture models of lung ischemia-reperfusion injury. J Heart Lung Transplant. 2005 Dec;24(12):2218-25. Epub 2005 Nov 17.

Neuringer IP, Sloan J, Budd S, Chalermskulrat W, Park RC, Stonebraker JR, O'Neal WK, Aris RM, Randell SH. Calcineurin inhibitor effects on growth and phenotype of human airway epithelial cells in vitro. Am J Transplant. 2005 Nov;5(11):2660-70.

Matsui H. Verghese MW, Kesimer M, Schwab UE, Randell SH, Sheehan JK, Grubb BR, Boucher RC. Reduced three-dimensional motility in dehydrated airway mucus prevents neutrophil capture and killing bacteria on airway epithelial surfaces. J Immunol. 2005 Jul 15;175(2);1090-9.

Slebos RJ, Livanos E, Yim HW, Randell SH, Parsons AM, Detterbeck FC, Rivera MP, Taylor JA. Chromosomal abnormalities in bronchial epithelium from smokers, nonsmokers, and lung cancer patients. Cancer Genet Cytogenet. 2005 Jun;159(2):137-42.

Das S, Palmer OP, Leight WD, Surowitz JB, Pickles RJ, Randell SH, Buchman CA. Cytokine amplification by respiratory syncytial virus infection in human nasal epithelial cells. Laryngoscope. 2005 May;115(5):764-8.

Wu Q, Lu Z, Verghese MW, Randell SH. Airway epithelial cell tolerance to Pseudomonas aeruginosa. Respir Res. 2005 Apr 1;6(1):26.