Richard C. Kurten
Ph.D., Baylor College of Medicine
Office: (501) 686-8269, 364-2823
Lab: (501) 364-1060
Press Release: REL-Asthma Research-Kurten_PHYO
I codirect the Lung Cell Biology Laboratory at the Arkansas Childrens’ Hospital Research Institute with my research partner Stacie M Jones MD (Chief of Pediatric Allergy and Immunology). My laboratory work at ACHRI is focussed on better understanding human lung disease and improving clinical therapy. A critical element in this work is the use of viable human lungs collected from deceased organ transplant donors. Lungs from across the country are routinely received and processed in the Lung Cell Biology Laboratory to provide material for use in our research and for use in a variety of collaborative projects.
An especially powerful system we use for our studies is the human precision cut lung slice model. Slices can be prepared containing a variety of tissue types that include airways and alveoli. Importantly, these slices retain many of their functions (airway ciliary motility, mucus secretion, ion transport, etc.) when maintained under appropriate conditions in tissue culture. For example, cross-sectioned airways can be stimulated to constrict using acetycholine, histamine or by crosslinking IgE. The responses mimic those that occur in individuals with asthma and are studied in airways prepared from normal donors, those with a history of asthma, or those who died from an asthma attack. Using such samples, we are studying mechanisms by which medications commonly used to treat asthma may loose their effectiveness and what can be done to mitigate this problem. We are particularly interested in the problem of beta-agonist desensitization/resensitization and the mechanisms for the benficial effects of inhaled corticosteroid medications. This work is done in collaboration with Rey Panettieri MD (LINK) at the Perelman School of Medicine (University of Pennsylvania) and is supported by the UAMS TRI (LINK) and by an NIH-NHLBI Program Project Award.
While asthma is characterized by acute episodes of bronchoconstriction, it is also a chronic inflamatory disease that is aggravated by underlying sensitivity to inhaled or ingested allergens and by viral infection. In a collaboration with Joshua Kennedy MD (Pediatric Allergy and Immunology), we are using human rhinovirus to infect human PCLS as well as isolated airway epithelial cells to evalute bronchoconstriction, bronchodilation and the cellular production and secretion of inflamatory cytokines. We are especially interested in determining what makes asthmatic lung bronchoconstriction hypersensitive following infection by rhinovirus. We are also interested in understanding how hypersesentivity is modulated by allergy. To address this problem, we are capitalizing on expertise in ongoing clinical and animal studies of immunotherapy for food allergy (Stacie Jones MD, Amy Scurlock MD). For these studies, we plan to characterize the atopic (allergic) state of donors by evaluating antigen-specific IgE in serum and by using that data to design antigen challenges for combination with rhinoviral challenges to better model the asthma ‘attack’. Especially interesting is the idea that oral antigen exposure may predispose to pulmonary allergic responses to the same antigen. This could be mediated by cell lymphoid trafficking to and from the mediastinal lymph nodes shared between the esophagous, trachea and the lungs, so we are now collecting these tissues as well.
In addition to short-term culture studies with human PCLS, we have also devised ways to maintain them for months in culture. This capability makes it possible for a student of fellow to think about performing longitudinal studies to evaluate the effects of sequential insults on the structure of the airways, potentially mimicing the airway remodelling that characterizes chronic asthma.
Efforts are not restricted to building human models for allergic airway disease. We are also actively isolating and using human airway macrophages and PCLS to study mechanisms for Coxiella burnetti infections in collaboaration with Dan Voth PhD (UAMS Microbiology and Immunology). Coxiella burnetti is a highly infectious obligate intercellular pathogen whose in vivo target is the airway macrophage. This project is supported by a R29 Exploratory Grant from NIH-NIAID.
We also use PCLS to identify/evaluate new bronchodilators and potential toxicants and have developed semi-automated approaches to measuring changes airway cross-sectional area. We have recently shown that chloroquine, a model bitter compound, is a potent bronchodilater of human airways in PCLS that retains bronchdilatory activity even after desensitization to beta-agonist medications (An et al 2012). In another example, we have evaluated PCLS responses to the commonly used pain reliever and fever reducer acetominophen. While acetominophen is a safe drug when used at recommended dosages, it has a very narrow therapeutic window and overdose leads to fulminant hepatic failure. It is the drug of choice in prenancy and is widely used in infants and children. Recently, it has been linked epidemiologically to increased asthma incidence. In studies performed in collaboration with Laura James MD (Pediatric Pharmacology & Toxicology), we find that although acetominophen is metabilized to the toxic NAPQI and forms protein adducts in airways, it does not promote airway hyperreactivity. Rather, it is a bronchodilator.
Overall, our objective is to take information gleaned from cell culture and animal systems and to test those findings in the laboratory using human tissue to model human disease. There are numerous opportunites for student or fellow research peojects using these novel approaches in the ACHRI Lung Cell Biology Laboratory.
Macdonald LJ, Graham JG, Kurten RC, Voth DE, Coxiella burnetii Exploits Host cAMP-Dependent Protein Kinase Signaling to Promote Macrophage Survival. Cell Microbiol. 2013 Sep 13. doi: 10.1111/cmi.12213.
Graham JG, Macdonald LJ, Hussain SK, Sharma UM, Kurten RC, Voth DE. Virulent Coxiella burnetii pathotypes productively infect primary human alveolar macrophages. Cell Microbiol. 2013 Jun;15(6):1012-25.
Koryakina Y, Jones SM, Cornett LE, Seely K, Brents L, Prather PL, Kofman A, Kurten RC. The effects of the β-agonist isoproterenol on the down-regulation, functional responsiveness, and trafficking of β2-adrenergic receptors with amino-terminal polymorphisms. Cell Biol Int. 2012;36(12):1171-83. doi: 10.1042/CBI20120134.
An SS, Wang WC, Koziol-White CJ, Ahn K, Lee DY, Kurten RC, Panettieri RA Jr, Liggett SB. TAS2R activation promotes airway smooth muscle relaxation despite β2-adrenergic receptor tachyphylaxis. Am J Physiol Lung Cell Mol Physiol. 2012 Aug;303(4):L304-11. PubMed Central PMCID: PMC3423830.
MacDonald LJ, Kurten RC, Voth DE. Coxiella burnetii alters cyclic AMP-dependent protein kinase signaling during growth in macrophages. Infect Immun. 2012 Jun;80(6):1980-6. PMCID: PMC3370589.
Milesi-Hallé A, McCullough S, Hinson JA, Kurten RC, Lamps LW, Brown A, James LP. Echinomycin decreases induction of vascular endothelial growth factor and hepatocyte regeneration in acetaminophen toxicity in mice. Basic Clin Pharmacol Toxicol. 2012 Apr;110(4):327-34. doi: 10.1111/j.1742-7843.2011.00812.x. PubMed Central PMCID: PMC3289727.
Ye S, Fowler TW, Pavlos NJ, Ng PY, Liang K, Feng Y, Zheng M, Kurten R, Manolagas SC, Zhao H. LIS1 regulates osteoclast formation and function through its interactions with dynein/dynactin and Plekhm1. PLoS One. 2011;6(11):e27285. PMCID: PMC3207863.
Cooper PR, Kurten RC, Zhang J, Nicholls DJ, Dainty IA, Panettieri RA Jr. (2011) Formoterol and salmeterol induce a similar degree of β(2) -adrenoceptor tolerance in human small airways but via different mechanisms. Br J Pharmacol. 2011 Jun;163(3):521-32. PMCID: PMC3101615
Donahower B, McCullough S, Hennings L, Simpson PM, Stowe CD, Saad AG, Kurten RC, Hinson JA, James LP. (2010) Human recombinant Vascular Endothelial Growth Factor (hrVEGF) reduces necrosis and enhances hepatocyte regeneration in a mouse model of acetaminophen toxicity. J Pharmacol Exp Ther. 2010 Apr 2. PMCID: PMC2912052
Koryakina YA, Fowler TW, Jones SM, Schnackenberg BJ, Cornett LE, Kurten RC. (2008) Characterization of a panel of six beta2‑adrenergic receptor antibodies by indirect immunofluorescence microscopy. Respir Res 9:32. PMCID: PMC2383888
Schnackenberg BJ, Jones SM, Pate C, Shank B, Sessions L, Pittman L, Cornett L, Kurten RC. (2006). The beta-agonist isoproterenol attenuates EGF-stimulated wound closure in human airway epithelial cells. Am J Physiol: Lung Cell. Mol. Physiol. 290(3):L485-91. PMID: 16227322
Kurten RC, Chowdhury P, Sanders Jr RC, Pittman LM, Sessions LW, Chambers TC, Lyle CM, Schnackenberg BJ, Foreman S, Jones SM (2005). Coordinating epidermal growth factor induced motility promotes efficient wound closure. Am J Physiol: Cell Physiol. 288(1):C109-21. PMID: 15371256