Physicians

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

Training

• MD, University of Rochester School of Medicine and Dentistry (New York), 1973

Residency

• 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  Unpublished data suggest that an siRNA to MLCK genome suppresses MLCK content and shortening function without affecting active stress generation.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.

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 (TGFβ).  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).  A locally supported project is designed to examine the potential contributions of excessive expression of TGFβ on the airways of patients with Down Syndrome.  Using our background in TGFβ1 signaling we are currently examining its potential role in protecting the airways from excessive airway hyperresponsiveness via airway smooth muscle mechanisms.

The fifth paradigm, which is in an earlier stage of development, is that the high affinity IgE receptor of airway smooth muscle FcεRI, which binds non-specifidc and specific IgE molecules, appears to play a role both in generating long-term hyperresponsiveness and in mediating acute contraction from allergens. This work is being done in collaboration with Abdelilah Soussi Gounni PhD, an Associate Professor of Immunology at the University of Manitoba, who discovered the high affinity IgE receptor on human airway smooth muscle and described its upregulation in human asthma in 2005.  The work also involves an active collaboration with Dr. Wesley Burks MD, chief of the Division of Allergy-Immunology at Duke.  Other collaborators include Timothy Haystead PhD (proteomics); Weiguo Zhang PhD (expert on high affinity IgE receptors and adapter molecules); Jerry Eu MD (expert on mouse trachealis culture systems and calcium signaling). This collaboration will focus on the mechanisms of human airway smooth muscle sensitization and contractile provocation (i.e. asthmatic responses) caused by aeroallergens, food antigens or drugs.  Model systems for investigation include human airway smooth muscle and airway smooth muscle from mice with targeted mutations or deletions of linker and adapter molecules assocatied with the high affinity IgE receptor.

The sixth paradigm is the participatory role of airway smooth muscle in the genesis of asthma pathophysiology resulting from secreted products of pulmonary neuroendocrine cells, especially gastrin releasing peptide (GRP).  In work done in collaboration with the laboratory of Dr. Mary Sunday we recently discovered receptors for GRP and neuromedin B (NMB) on airway smooth muscle in mice and humans. The EC50 for GRP on mouse trachealis is approximately 10-9 molar.  The specific small molecule inhibitor of GRP knocks down this response by 85%.  Taken together with published (PNAS Feb 1, 2011) evidence of broad immune cellular inflammatory participation in asthmatic inflammation, we are working toward translation of this biology into potentially more powerful and better integrated therapy for asthma.

Industry Relationships and Collaborations (What's this?)

This physician has no reported relationships with industry.

Representative Publications
Rabinovich DE, Fels E, Shanahan J, Majure JM and Murphy TM.  Chapter 10, Rheumatoid Diseases.  In Turcios NL and Fink R eds. Pulmonary Manifestations of Pediatric Diseases.  WB Saunders (Elsevier Sciences USA), Philadelphia, 2009. (2009)

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. Am J Physiol Lung Cell Mol Physiol. 2008 Jan;294(1):L139-48. (2008) Abstract

Vandevanter DR, Rasouliyan L, Murphy TM, Morgan WJ, Ren CL, Konstan MW, Wagener JS, . Trends in the clinical characteristics of the U.S. cystic fibrosis patient population from 1995 to 2005. Pediatr Pulmonol. 2008 Jul 8. (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. Am J Physiol Lung Cell Mol Physiol. 2008 May;294(5):L964-73. (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. Eur Respir J. 2007 May;29(5):834-60. (2007) Abstract

Chitano P, Wang L, Murphy TM. Three paradigms of airway smooth muscle hyperresponsiveness in young guinea pigs. Can J Physiol Pharmacol. 2007 Jul;85(7):715-26. (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. Am J Physiol Lung Cell Mol Physiol. 2007 Jun;292(6):L1543-55. (2007) Abstract

Chitano P, Wang L, Murphy TM. Mechanisms of airway smooth muscle relaxation during maturation. Can J Physiol Pharmacol. 2005 Oct;83(10):833-40. (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

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

Wang L, Chitano P, Murphy TM. Length oscillation induces force potentiation in infant guinea pig airway smooth muscle. Am J Physiol Lung Cell Mol Physiol. 2005 Dec;289(6):L909-15. (2005) Abstract

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

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, 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. Pediatr Pulmonol. 2004 Dec;38(6):456-64. (2004) Abstract

Chitano P, Murphy TM. Maturational changes in airway smooth muscle shortening and relaxation. Implications for asthma. Respir Physiol Neurobiol. 2003 Sep 16;137(2-3):347-59. (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. Am J Physiol Lung Cell Mol Physiol. 2002 Apr;282(4):L782-95. (2002) Abstract

Chitano P, Cox CM, Murphy TM. Relaxation of guinea pig trachealis during electrical field stimulation increases with age. J Appl Physiol. 2002 May;92(5):1835-42. (2002) Abstract

Chitano P, Halayko AJ, Murphy TM, Stewart AG. Growing up and advancing in airway smooth muscle research. Trends Pharmacol Sci. 2002 Oct;23(10):450-1. (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. 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

Knight J, Murphy TM, Browning I. The lung in sickle cell disease. Pediatr Pulmonol. 1999 Sep;28(3):205-16. (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

Murphy TM, Ray DW, Alger LE, Phillips IJ, Roach JC, Leff AR, Solway J. Ontogeny of dry gas hyperpnea-induced bronchoconstriction in guinea pigs. J Appl Physiol. 1994 Mar;76(3):1150-5. (1994) 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

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

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

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

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, 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

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, 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