Thomas M. Murphy, MD

Related Content

Locations

• Duke Asthma, Allergy and Airway Center

Services

• Asthma and Allergies
• Pulmonology and Respiratory Medicine

Department / Division:
Pediatrics / Pulmonary and Sleep Medicine

Address:
DUMC 2994
Durham, NC 27710

Appointment Telephone:
919-668-4000 or 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 (Washington, DC), 1973-1976
• Pediatric Pulmonology, Georgetown University (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.  Maturation and mechanisms of airway smooth muscle relaxation
4.  Mechanical plasticity of airway smooth muscle and its development
5.  Identity and function of airway smooth muscle NAD(P)H oxidase

Our laboratory leads in developing important models of the contributions of airway smooth muscle (ASM) to airway hyperresponsiveness in the young.  Four major paradigms have emerged in 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  Unpublished data suggest that an siRNA to MLCK genome suppresses MLCK content and shortening function without affecting active stress generation.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 and was recently funded.

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.

A long-term collaboration with the laboratory of Dr. John Hoidal at the University of Utah has shed light on the identity and function of NAD(P)H oxidase in airway smooth muscle.  A recent collaborative publication (Sturrock et al, Am J Physiol: Lung Cell Mol Physiol, 2007) provides evidence that the renal isoform of the nox paralog protein (NOX4) is constitutive in ASM NAD(P)H oxidase and is substantially upregulated by the growth factor transforming growth factor beta.  Key functions of the ASM NAD(P)H oxidase are to regulate cell growth and hyperplasia and to modulate its contraction (Brar et al, J Biol Chem 28:20017-20026, 1999) through mechanisms involving the AP-1 transcription factor and NF kappa B (Brar et al, Am J Physiol: Lung Cell Molec Physiol 282:L782-L795, 2002).

Future investigations will pursue these paradigms and will seek to take advantage of the increasing number of airway biology investigators at Duke University.

Representative Publications:
Wang L, Chitano P, Murphy TM. Maturation of guinea pig tracheal strip stiffness. Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L902-8. (2005) Abstract

Wang L, Chitano P, Murphy TM. A maturational model for the study of airway smooth muscle adaptation to mechanical oscillation. Can J Physiol Pharmacol. 2005 Oct;83(10):817-24. (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. Pediatr Pulmonol. 2005 Feb;39(2):108-16. (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. J Appl Physiol. 2004 Dec;97(6):2029-34. (2004) 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. J Appl Physiol. 2000 Apr;88(4):1338-45. (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. J Biol Chem. 1999 Jul 9;274(28):20017-26. (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. J Pharmacol Exp Ther. 1998 May;285(2):876-83. (1998) Abstract

Mitchell RW, Murphy TM, Leff AR. Physiological mechanisms mediating enhanced force generation during development and immune sensitization. Can J Physiol Pharmacol. 1992 Apr;70(4):615-23. (1992) Abstract

Ikeda K, Mitchell RW, Guest KA, Seow CY, Kirchhoff CF, Murphy TM, Leff AR. Ontogeny of shortening velocity in porcine trachealis. Am J Physiol. 1992 Mar;262(3 Pt 1):L280-5. (1992) Abstract

Murphy TM, Mitchell RW, Phillips IJ, Leff AR. Ontogenic expression of acetylcholinesterase activity in trachealis of young swine. Am J Physiol. 1991 Oct;261(4 Pt 1):L322-6. (1991) 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. Am J Physiol. 1991 Jun;260(6 Pt 1):L471-80. (1991) Abstract

Mitchell RW, Murphy TM, Kelly E, Leff AR. Maturation of acetylcholinesterase expression in tracheal smooth muscle contraction. Am J Physiol. 1990 Aug;259(2 Pt 1):L130-5. (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. Pediatr Infect Dis J. 1987 Feb;6(2):159-63. (1987) Abstract

Miller RW, Salcedo JR, Fink RJ, Murphy TM, Magilavy DB. Pulmonary hemorrhage in pediatric patients with systemic lupus erythematosus. J Pediatr. 1986 Apr;108(4):576-9. (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. Crit Care Med. 1986 Feb;14(2):125-7. (1986) 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. Med Pediatr Oncol. 1986;14(4):202-7. (1986) Abstract