Thomas M. Murphy, MD
Department / Division
Pediatrics /
Pediatrics-Pulmonary and Sleep Med
Address
DUMC 102360
Durham, NC 27710
Appointment Telephone
919-668-4000, 919-681-3364
Office Telephone
919-684-3364
Fax Telephone
919-684-2292
- MD, University of Rochester School of Medicine and Dentistry (New York), 1973
- Internal Medicine, Georgetown University Hospital (Washington, DC), 1973-1976
- Pediatric Pulmonology, Georgetown University Hospital (Washington, DC), 1976-1978
Clinical Interests
Asthma, cystic fibrosis, chronic lung disease of infancy, bronchoscopy, recurrent pneumonia, exercise limitation
Research Interests
AREAS OF RESEARCH INTEREST
1. Maturation of airway contractile responses
2. Ontogenesis of airways hyperresponsiveness caused by inflammation
3. Role of the high affinity IgE receptor on airway smooth muscle in regulating long term hyperresponsiveness and acute allergic contraction
4. Maturation and mechanisms of airway smooth muscle relaxation
5. Mechanical plasticity of airway smooth muscle and its development
6. Identity and function of airway smooth muscle NAD(P)H oxidase
7. Role of Gastrin Releasing Peptide in the Pathogenesis of Asthma and its Therapeutic Targetability
Our laboratory leads in developing important models of the contributions of airway smooth muscle (ASM) to airway hyperresponsiveness in the young. Five major paradigms are emerging from our work at Duke.
The first is that while active stress changes little with age, shortening of ASM in guinea pigs is maximal at a few weeks of age and then declines substantially during adulthood (Chitano et al, J Appl Physiol 88:1338-1345, 2000). The changes in shortening appear related to parallel changes in myosin light phosphorylation (Chitano et al, Pediatr Pulmonol 39:108-116, 2005) and the content of myosin light chain kinase (Chitano et al, Pediatr Pulmonol 38:456-464, 2005). Unpublished data suggest that an siRNA to MLCK genome suppresses MLCK content and shortening function without affecting active stress generation. Additional data suggest that there is also a secondary role for the content of the 7 amino acid insert + isoforms of myosin heavy chain (SMB1 and SMB2; the “fast” isoforms) that are expressed to a greater extent in the newborn.
The second paradigm examines the impact of early sensitization (3 subcutaneous injections of ovalbumin in the first week of life) on late effects on ASM shortening. Extensive preliminary data demonstrate no effect on active stress and a small effect on shortening in the young, but a late effect on shortening in adults that is substantial. This effect appears to arise jointly from an increase (rather than a decrease) in the adult age group in the content of myosin light chain kinase and a parallel decrease (rather than the normal increase) in the internal resistance to shortening. The changes in MLCK content appear to parallel changes in a cytoskeletal enzyme protein-activating kinase PAK1, which is related to the phosphorylation and fragmentation of the intermediate filament vimentin, which in its long form appears to function as a stress fiber. An increase in phospho-vimentin is postulated to facilitate shortening by decreasing cytoskeletal stress fiber formation. These first two paradigms formed the core of our latest NIH R01 application which was awarded a ranking at the 7th percentile.
The third paradigm involves the failure of ASM from young guinea pigs to relax as efficiently as adult ASM during sustained stimulation (Chitano et al, J Appl Physiol 92:1835-1842, 2002). Further work demonstrates that mechanisms involved in this failure of relaxation include differences in secretion of prostaglandins and differences in acetyl cholinesterase function.
The fourth paradigm involves the failure of newborn trachealis to relax in the fashion of adult ASM following stretch. (In fact, there is demonstrated the potentiation of active stress rather than relaxation following stretch.) Developmental changes in the ASM cytoskeleton play a role in these differences (Am J Physiol: Lung Cell Molec Physiol 289:L909-L915, 2005).
An Editorial Focus in the American Journal of Physiology (“The Importance of Maturational Studies in Airway Smooth Muscle, Am J Physiol: Lung Cell Mol Physiol 289: L898-L901, 2005) discussed elements of paradigms 1 and 4 and pointed to the importance of the work and emphasized that our laboratory was unique in pursuing and elucidating these questions.
Industry Relationships and Collaborations (What's this?)
This faculty member (or a member of their immediate family) has a working relationship (i.e. consulting, research, and/or educational services) with the companies listed below. These relations have been reported to the health system leadership and, when appropriate, management plans are in place to address potential conflicts.
- Five Prime
- Gilead
- Merck
- Teva Pharmaceuticals
- Wiley-Blackwell Publishers (John Wiley & Sons Inc)
Representative Publications
Chitano, P; Wang, L; Mason, SN; Auten, RL; Potts, EN; Foster, WM; Sturrock, A; Kennedy, TP; Hoidal, JR; Murphy, TM. Airway smooth muscle relaxation is impaired in mice lacking the p47phox subunit of NAD(P)H oxidase. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2008;294:L139-L148.
(2008)
Abstract
VanDevanter, DR; Rasouliyan, L; Murphy, TM; Morgan, WJ; Ren, CL; Konstan, MW; Wagener, JS; Investigators, Coordinators of the Epidemiologic Study of Cystic Fibrosis. Trends in the clinical characteristics of the U.S. cystic fibrosis patient population from 1995 to 2005. Pediatric Pulmonology. 2008;43:739-744.
(2008)
Abstract
Wang, L; Pozzato, V; Turato, G; Madamanchi, A; Murphy, TM; Chitano, P. Reduced spontaneous relaxation in immature guinea pig airway smooth muscle is associated with increased prostanoid release. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2008;294:L964-L973.
(2008)
Abstract
An, SS; Bai, TR; Bates, JH; Black, JL; Brown, RH; Brusasco, V; Chitano, P; Deng, L; Dowell, M; Eidelman, DH; Fabry, B; Fairbank, NJ; Ford, LE; Fredberg, JJ; Gerthoffer, WT; Gilbert, SH; Gosens, R; Gunst, SJ; Halayko, AJ; Ingram, RH; Irvin, CG; James, AL; Janssen, LJ; King, GG; Knight, DA; Lauzon, AM; Lakser, OJ; Ludwig, MS; Lutchen, KR; Maksym, GN; Martin, JG; Mauad, T; McParland, BE; Mijailovich, SM; Mitchell, HW; Mitchell, RW; Mitzner, W; Murphy, TM; Paré, PD; Pellegrino, R; Sanderson, MJ; Schellenberg, RR; Seow, CY; Silveira, PS; Smith, PG; Solway, J; Stephens, NL; Sterk, PJ; Stewart, AG; Tang, DD; Tepper, RS; Tran, T; Wang, L. Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma. European Respiratory Journal. 2007;29:834-860.
(2007)
Abstract
Chitano, P; Wang, L; Murphy, TM. Three paradigms of airway smooth muscle hyperresponsiveness in young guinea pigs. Canadian Journal of Physiology and Pharmacology. 2007;85:715-726.
(2007)
Abstract
Sturrock, A; Huecksteadt, TP; Norman, K; Sanders, K; Murphy, TM; Chitano, P; Wilson, K; Hoidal, JR; Kennedy, TP. Nox4 mediates TGF-beta1-induced retinoblastoma protein phosphorylation, proliferation, and hypertrophy in human airway smooth muscle cells. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2007;292:L1543-L1555.
(2007)
Abstract
Chitano, P; Wang, L; Murphy, TM. Mechanisms of airway smooth muscle relaxation during maturation. Canadian Journal of Physiology and Pharmacology. 2005;83:833-840.
(2005)
Abstract
Chitano, P; Worthington, CL; Jenkin, JA; Stephens, NL; Gyapong, S; Wang, L; Murphy, TM. Ontogenesis of myosin light chain phosphorylation in guinea pig tracheal smooth muscle. Pediatric Pulmonology. 2005;39:108-116.
(2005)
Abstract
Wang, L; Chitano, P; Murphy, TM. A maturational model for the study of airway smooth muscle adaptation to mechanical oscillation. Canadian Journal of Physiology and Pharmacology. 2005;83:817-824.
(2005)
Abstract
Wang, L; Chitano, P; Murphy, TM. Length oscillation induces force potentiation in infant guinea pig airway smooth muscle. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2005;289:L909-L915.
(2005)
Abstract
Wang, L; Chitano, P; Murphy, TM. Maturation of guinea pig tracheal strip stiffness. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2005;289:L902-L908.
(2005)
Abstract
Bai, TR; Bates, JH; Brusasco, V; Camoretti-Mercado, B; Chitano, P; Deng, LH; Dowell, M; Fabry, B; Ford, LE; Fredberg, JJ; Gerthoffer, WT; Gilbert, SH; Gunst, SJ; Hai, CM; Halayko, AJ; Hirst, SJ; James, AL; Janssen, LJ; Jones, KA; King, GG; Lakser, OJ; Lambert, RK; Lauzon, AM; Lutchen, KR; Maksym, GN; Meiss, RA; Mijailovich, SM; Mitchell, HW; Mitchell, RW; Mitzner, W; Murphy, TM; Paré, PD; Schellenberg, RR; Seow, CY; Sieck, GC; Smith, PG; Smolensky, AV; Solway, J; Stephens, NL; Stewart, AG; Tang, DD; Wang, L. On the terminology for describing the length-force relationship and its changes in airway smooth muscle. Journal of Applied Physiology. 2004;97:2029-2034.
(2004)
Abstract
Chitano, P; Voynow, JA; Pozzato, V; Cantillana, V; Burch, LH; Wang, L; Murphy, TM. Ontogenesis of myosin light chain kinase mRNA and protein content in guinea pig tracheal smooth muscle. Pediatric Pulmonology. 2004;38:456-464.
(2004)
Abstract
Chitano, P; Murphy, TM. Maturational changes in airway smooth muscle shortening and relaxation. Implications for asthma. Respiratory Physiology and Neurobiology. 2003;137:347-359.
(2003)
Abstract
Brar, SS; Kennedy, TP; Sturrock, AB; Huecksteadt, TP; Quinn, MT; Murphy, TM; Chitano, P; Hoidal, JR. NADPH oxidase promotes NF-kappaB activation and proliferation in human airway smooth muscle. American Journal of Physiology: Lung Cellular and Molecular Physiology. 2002;282:L782-L795.
(2002)
Abstract
Chitano, P; Cox, CM; Murphy, TM. Relaxation of guinea pig trachealis during electrical field stimulation increases with age. Journal of Applied Physiology. 2002;92:1835-1842.
(2002)
Abstract
Chitano, P; Halayko, AJ; Murphy, TM; Stewart, AG. Growing up and advancing in airway smooth muscle research. Trends in Pharmacological Sciences. 2002;23:450-451.
(2002)
Abstract
Chitano, P; Wang, J; Cox, CM; Stephens, NL; Murphy, TM. Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis. Journal of Applied Physiology. 2000;88:1338-1345.
(2000)
Abstract
Brar, SS; Kennedy, TP; Whorton, AR; Murphy, TM; Chitano, P; Hoidal, JR. Requirement for reactive oxygen species in serum-induced and platelet-derived growth factor-induced growth of airway smooth muscle. Journal of Biological Chemistry. 1999;274:20017-20026.
(1999)
Abstract
Knight, J; Murphy, TM; Browning, I. The lung in sickle cell disease. Pediatric Pulmonology. 1999;28:205-216.
(1999)
Abstract
Dashtaki, R; Whorton, AR; Murphy, TM; Chitano, P; Reed, W; Kennedy, TP. Dehydroepiandrosterone and analogs inhibit DNA binding of AP-1 and airway smooth muscle proliferation. Journal of Pharmacology and Experimental Therapeutics. 1998;285:876-883.
(1998)
Abstract
Murphy, TM; Ray, DW; Alger, LE; Phillips, IJ; Roach, JC; Leff, AR; Solway, J. Ontogeny of dry gas hyperpnea-induced bronchoconstriction in guinea pigs. Journal of Applied Physiology. 1994;76:1150-1155.
(1994)
Abstract
Ikeda, K; Mitchell, RW; Guest, KA; Seow, CY; Kirchhoff, CF; Murphy, TM; Leff, AR. Ontogeny of shortening velocity in porcine trachealis. American Journal of Physiology. 1992;262:L280-L285.
(1992)
Abstract
Mitchell, RW; Murphy, TM; Leff, AR. Physiological mechanisms mediating enhanced force generation during development and immune sensitization. Canadian Journal of Physiology and Pharmacology. 1992;70:615-623.
(1992)
Abstract
Murphy, TM; Mitchell, RW; Halayko, A; Roach, J; Roy, L; Kelly, EA; Munoz, NM; Stephens, NL; Leff, AR. Effect of maturational changes in myosin content and morphometry on airway smooth muscle contraction. American Journal of Physiology. 1991;260:L471-L480.
(1991)
Abstract
Murphy, TM; Mitchell, RW; Phillips, IJ; Leff, AR. Ontogenic expression of acetylcholinesterase activity in trachealis of young swine. American Journal of Physiology. 1991;261:L322-L326.
(1991)
Abstract
Mitchell, RW; Murphy, TM; Kelly, E; Leff, AR. Maturation of acetylcholinesterase expression in tracheal smooth muscle contraction. American Journal of Physiology. 1990;259:L130-L135.
(1990)
Abstract
Rodriguez, WJ; Kim, HW; Brandt, CD; Fink, RJ; Getson, PR; Arrobio, J; Murphy, TM; McCarthy, V; Parrott, RH. Aerosolized ribavirin in the treatment of patients with respiratory syncytial virus disease. Pediatric Infectious Disease Journal. 1987;6:159-163.
(1987)
Abstract
Miller, RW; Fusner, JE; Fink, RJ; Murphy, TM; Getson, PR; Vojtova, JA; Reaman, GH. Pulmonary function abnormalities in long-term survivors of childhood cancer. Pediatric Blood and Cancer. 1986;14:202-207.
(1986)
Abstract
Miller, RW; Pollack, MM; Murphy, TM; Fink, RJ. Effectiveness of continuous positive airway pressure in the treatment of bronchomalacia in infants: a bronchoscopic documentation. Critical Care Medicine. 1986;14:125-127.
(1986)
Abstract
Miller, RW; Salcedo, JR; Fink, RJ; Murphy, TM; Magilavy, DB. Pulmonary hemorrhage in pediatric patients with systemic lupus erythematosus. Journal of Pediatrics. 1986;108:576-579.
(1986)
Abstract
