Research Summary:

My research has been primarily directed at the pathogenesis of inflammatory airway disorders, in particular, mechanisms underlying severe asthma and the increased airways responsiveness (AHR) characteristic of asthma. The role of inhibitory neural pathways in limiting airway narrowing: We hypothesized that a defect in inhibitory neural mechanisms could explain AHR and showed that in the cat lung in vivo, interruption of the central connections of the inhibitory pathways increased airway narrowing (JAP 1985; ARRD 1986). Later, the efferent components of this pathway were shown for the first time by me to be fully functional in trachea from subjects dying of asthma, evidence against the existence of a functional defect in human asthma (ARRD 1990). We presented some of the earliest evidence that nitric oxide is one mediator of inhibitory neural pathways in human bronchi (AJP 1993). B2 adrenergic receptor (B2AR) in severe asthma: I demonstrated that airway smooth muscle functional responses to B2 agonists are decreased in fatal asthma, explaining in part the clinical problem of poor responses to these agents in severe attacks (ARRD 1990, 1991). We tested the hypothesis that B2AR number was decreased to explain the functional hyporesponsiveness. Quantitative autoradiography demonstrated, paradoxically, increased receptor numbers that were linearly related to hyporesponsiveness (AJRCMB 1992). We showed increased B2AR gene expression (AJRCMB 1993), and hypothesized that the receptors were uncoupled by cytokines, stimulating a large body of confirmatory work by others. We established an animal model to determine the effects of chronic B2 agonist exposure, and showed that chronic B2 AR stimulation increased in vitro airway smooth muscle contractility, in vivo AHR, and induced increased wall thickness to a degree similar to that induced by chronic antigen exposure (ARRD 1994, 1995). A similar effect in human asthmatics may explain the adverse effects observed during prolonged treatment with these drugs. Sensory Nerves : We tested the hypothesis that the tachykinin neuropeptides or their receptors are present in increased amounts in the airways of asthmatics by measuring extractable neuropeptide content (AJRCCM 1995), and demonstrated increased tachykinin receptor gene expression in lungs from both asthmatics and cigarette smokers (AJP 1995). Following, we have initiated study of interactions between the immune system and airway innervation, particularly the role of neurotrophic cytokines, such as LIF and NGF, determining that LIF is readily inducible in the lung (AJRCMB 1999), augments responses to neuropeptides (BJP 1997), and may be involved in bidirectional interactions between neuropeptides and eosinophils (JACI 1999). Lung Adenosine: We localized the newly discovered adenosine receptor subtype (A3) for the first time in human and sheep lung (to eosinophils); defined the first role for this receptor in humans (inhibition of eosinophil chemotaxis, J. Leukocyte Biology, 1997) and demonstrated upregulation of A3 receptor gene expression in airways inflammation (AJRCMB 1997). Airway Remodelling: In one of the first systematic studies of airway smooth muscle function in severe asthma, I showed, in trachea, a post junctional increase in responsiveness probably due to increased smooth muscle mass (ARRD 1990). Since that finding, I, with others, have investigated the role of structural airway changes in determining AHR (ARRD 1993, 1995, 1997, Thorax, 1994, 1995, AJP 1994, JACI 1997, Clin Sci.2005). I found support for the hypothesis that there is an increase in airway wall area, including smooth muscle, and airway narrowing, with increasing duration of severe asthma [AJRCCM, 2000]. Using image analysis to evaluate luminal content in fatal asthma, we found asthmatics had more narrowed airways (> in large airways and older subjects), greater mucus occlusion, and more occlusion by cells. Greater lumen content was associated with a higher proportion of cells, and cells made up a higher proportion of the exudate in the small airways. Luminal mucus was greater in Polynesians &younger patients with asthma. Thus airway luminal obstruction by an exudate composed equally of mucus and cells is a major contributing cause of fatal asthma in most patients, but there were age and ethnicity-related related differences in the mechanism of death (Am J Med 2003). I have been evaluating pathways to increased smooth muscle mass and discovered gp130 cytokines and endothelin are capable of inducing hypertrophy of smooth muscle and inhibiting apoptosis of smooth muscle cells both in vitro and in explants [BJP 2003, AJP 2004]. Additional areas of research have included mechanisms of chronic cough, and clinical trials in asthma and pulmonary fibrosis.

Wellington Clinical School of Medicine, NZ Internal Medicine, FRACP
University of Otago, Dunedin, NZ, Respiratory Research, MD
University of British Columbia, Vancouver, Canada, Respiratory Medicine, FRACP(C)
St Thomas Hospital Medical School, London, UK Internal Medicine. , MRCP
University of Otago, Dunedin, New Zealand, Medicine, MBCHB
Recent Publications:

•Ernst P, McIvor A, Ducharme FM, Boulet LP, FitzGerald M, Chapman KR, Bai TR; Canadian Asthma Guideline Group.  Safety and effectiveness of long-acting inhaled beta-agonist bronchodilators when taken with inhaled corticosteroids.  Ann Intern Med. 145(9):692-4. Review. 2006.

•An SS, Bai TR, Bates JHT, 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 PSP, Smi

•Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbations predict excess lung function decline in asthma. Eur Respir J. 30:452-6. 2007.

•McWhinnie R, Pechkovsky DV, Zhou D, Lane D, Halayko AJ, Knight DA, Bai TR. Endothelin-1 induces hypertrophy and inhibits apoptosis in human airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 292:L278-L286. 2007.

•Ernst P, Franssen E, Chan CK, Okell M, O’Byrne P, Bai TR. Predictors of a more favourable response to combined therapy with salmeterol and fluticasone as initial maintenance therapy in asthma. Respir Med. 102:77-81. 2008.

•James AL, Green FH, Abramson MJ, Bai TR, Dolhnikoff M, Mauad T, McKay KO, Elliot JG. Airway basement membrane perimeter distensibility and airway smooth muscle area in asthma. J Appl Physiol. 104:1703-1708. 2008.

•McTaggart-Cowan HM, Shi P, Fitzgerald JM, Anis AH, Kopec JA, Bai TR, Soon JA, Lynd LD. An evaluation of patients’ willingness to trade symptom-free days for asthma-related treatment risks: a discrete choice experiment. J Asthma. 45:630-8. 2008.

•Sears MR, Boulet LP, Laviolette M, Fitzgerald JM, Bai TR, Kaplan A, Smiljanic-Georgijev N, Lee JS. Budesonide/formoterol maintenance and reliever therapy: impact on airway inflammation in asthma. Eur Respir J. 31:982-9. 2008.

•Hackett TL, Warner SM, Stefanowicz D, Shaheen F, Pechkovsky DV, Murray LA, Argentieri R, Kicic A, Stick SM, Bai TR, Knight DA. Induction of epithelial-mesenchymal transition in primary airway epithelial cells from patients with asthma by transforming growth factor-beta1. Am J Respir Crit Care Med. 180(2):122-133. 2009.

•James AL, Bai TR, Mauad T, Abramson MJ, Dolhnikoff M, McKay KO, Maxwell PS, Elliot JG, Green FH. Airway smooth muscle thickness in asthma is related to severity but not duration of asthma. Eur Respir J.34(5):1040-1045. 2009.

•Bai TR. Evidence for airway remodeling in chronic asthma. Curr Opin Allergy Clin Immunol. 10(1):82-86. 2010.