THE UNIVERSITY OF WESTERN AUSTRALIA
FACULTY OF MEDICINE, DENTISTRY AND HEALTH SCIENCES

OUR RESEARCH GROUP

Dr Lynette Fernandes
Professional profile
Senior Lecturer
Room 1.33A
Ph: 08-9346 4517

Mrs Tracy Mann
Professional profile
Research Associate
Ph: 08- 9346 3179

Mr Terence Peters
Honours Student 2007

Mr Samuel Fiddian
Honours Student 2007

Ms Amanda Chua
Honours Student 2007

Students Room:
Ph: 08- 9346 2350
Ph: 08- 9346 2708
Ph: 08- 9346 4728

OUR RESEARCH INTEREST

Our research program primarily focuses on investigating the distributionand function of novel receptor-effector systems within healthy and diseased lungs, with the expectation that these findings will be of strategic value in the pursuit of therapeutic targets in the treatment of obstructive lung diseases such as asthma.

Our group investigates receptor density, distribution and function within the airways through the use of a broad spectrum of approaches, including molecular, cellular, tissue and whole animal techniques. At the molecular level, radioligand binding studies investigating ligand-receptor interactions are routinely used to determine the density and binding characteristics of receptors within individual cell populations (using cell culture) and intact tissues (using frozen tissue sections).
Radioligand binding studies can be used in conjunction with autoradiography to reveal potential differences in receptor distribution and density between different cell types within the airways. Receptor distribution is also determined using immunocytochemical techniques and confocal microscopy.
Receptor function is assessed using a variety of approaches, ranging from Ca2+ mobilization in isolated cells, contraction of intact airway smooth musclepreparations, and lung function recordings in anaesthetized laboratory animals. These approaches have enabled us to investigate the density,distribution and function of numerous receptors, includingb- drenoceptors, endothelin receptors and protease-activated receptors, in healthy airways.
Moreover, we are interested in investigating the effects that airways inflammation caused by viral (e.g. influenza A virus, respiratory syncytial virus) and/or allergenic (e.g. house dust mite, ovalbumin) stimuli have on these receptor systems. This is of particular importance because airways inflammation is intimately associated with worsening airways function in asthmatics, and these receptor systems may exert important modulatory influences on airways function.

Protease-activated receptors, prostaglandin E2 and airways function

Protease-activated receptors (PARs) are a subfamily of seven-transmembrane domain, G protein-coupled receptors capable of mediating cellular signaling in response to proteases. PAR activation is dependent on the proteolytic cleavage of the extracellular amino terminus of the receptor, which reveals a new amino terminus that serves to act as a ?tethered ligand? to self-activate the receptor. Four different PARs, called PAR-1, -2, -3 and ?4 have been cloned, sequenced and characterised.
Of these, PAR-2 can be activated by trypsin and by the peptide SLIGRL, which mimics the tethered ligand sequence of PAR-2. We have shown that stimulation of PAR-2 by trypsin and SLIGRL induces relaxation of airway smooth muscle in vitro and in vivo (Cocks et al. (1999) Nature 398, 156). PAR-2-mediated relaxation responses in murine tracheal smooth muscle preparations were attenuated by inhibitors of cyclooxygenase-2, an enzyme involved in the synthesis of prostaglandins (Lan et al (2001)Br J Pharmacol 132, 93). Consistent with this, activation of PAR-2 caused elevated production of prostaglandin E2 by murine tracheal preparations, and exogenous prostaglandin E2 induced potent smooth muscle relaxation via activation of EP2 receptors.
Thus, in preparations from non-diseased animals, PAR-2 activation produced relaxation via the production of a potent smooth muscle relaxant prostaglandin E2.

Protease-activated receptors and respiratory tract viral infection

During his PhD candidature, Rommel Lan investigated the influence of respiratory tract viral infection on the distribution and function of PARs in mouse airways. Immunohistochemical staining revealed increased PAR-1 and PAR-2 expression on the apical airway epithelium of influenza A virus-infected tracheal preparations. Virus infection did not affect PAR- mediated responses in isolated tracheal preparations, but studies using whole animals showed that activation of PAR-1 and PAR-2 in virus-infected animals were functionally coupled to increased inhibitory responses against spasmogenic challenges in vivo. It is likely that PAR upregulation during a respiratory tract virus infection may mediate bronchoprotective functions in the airway.
A current PhD student, Richard Betts is investigating the potential effects of PAR-2 activators on the progression of respiratory tract viral infections
in mice.

Protease-activated receptors and allergic airways inflammation

Ben Decampo made the recent and exciting discovery that peptidic activators of PAR-2, such as SLIGRL-NH2,inhibited the development of airways hyperresponsiveness and pulmonary eosinophilia in a murine model of allergic airways inflammation. This response was mimicked by PGE2 and blocked by cyclooxygenase inhibitors, indicating that the SLIGRL-induced mediated via the production of endogenous prostanoids, such as PGE2.

Some of our recent publications in this area are listed below:

RESEARCH PUBLICATIONS

73 Judge, R.K., Henry, P.J., Mirtschin, P., Jelinek, G., Wilce, J.A. (2005). Toxins not neutralized by brown snake antivenom. Toxicol. Appl. Pharmacol. (in Press).

72 Henry, P.J. (2005). The protease-activated receptor2 (PAR2) – prostaglandin E2 – EP receptor axis: a potential bronchoprotective unit in the respiratory tract? Eur J Pharm (invited review, submitted 6/7/05)

71 De Campo, B.A. & Henry, P.J. (2005). Protease-activate receptors are partly pro-inflammatory and partly anti-inflammatory: Will PAR agonists or antagonists participate in future drug therapies? Curr Drug Targets (invited review, submitted 12/5/2005)

70 Henry, P.J., D’Aprile, A.C., Self, G.J., Hong, T., Mann, T.S. (2005). Inhibitors of prostaglandin transport and metabolism augment PAR2-mediated increases in PGE2 levels and smooth muscle relaxation in mouse isolated trachea. J. Pharmacol. Exp. Ther. 314, 995-1001.

69 Fernandes, L.B., Henry, P.J. & Goldie, R.G. (2005). Chapter 3: Beta-adrenoceptor agonists: basic pharmacology. (pages 47-60) In: Therapeutic Strategies in COPD. Editors: M Cazzola, B Celli, R Dahl, S Rennard. Publishers: Clinical Publishing, Oxford.

68 De Campo, B.A. & Henry, P.J. (2005). SLIGRL, a PAR2-activating peptide, inhibits airway eosinophilia and hyperresponsiveness in a murine model of allergic inflammation. Br. J. Pharmacol. 144, 1100-1108.

67 Henry, P.J., Mann, T.S. & Goldie, R.G. (2005). A rho kinase inhibitor, Y27632 inhibits pulmonary eosinophilia, bronchoconstriction and airways hyperresponsiveness in allergic mice. Pulm. Pharm. Ther. 18, 67-74.

66 Forbes, E., Smart, V., D’Aprile, A., Henry, P.J., Yang, M., Matthaei, K.I., Rothenberg, M.E., Foster, P.S. & Hogan, S.P. (2004). T helper-2 immunity regulates bronchial hyperresponsiveness in eosinophil-associated gastrointestinal disease in mice. Gastroenterology 127, 105-118.

65 Goldie, R.G. & Henry, P.J. (2004). New insights into selected mediators, pathways and pathologies in asthma and COPD. Curr. Opin Pharmacol. 4, 199-201.

64 Fernandes, L.B., Henry, P.J. & Goldie, R.G. (2004). Chapter 1: Beta-Adrenoceptor agonists. (pages 3-35) Series: Handbook of Experimental Pharmacology. Volume: Pharmacology and Therapeutics of Asthma and COPD. Editors: CP Page and PJ Barnes, Publisher: Springer, Berlin, London.

63 Lan, R.S., Stewart, G.A., Goldie, R.G. & Henry, P.J. (2004). Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice. Am. J. Physiol. 286, L388-L398.

62 Lam, C.F., Lan, R.S., van Heerden, P.V., Ilett, K.F. & Henry, P.J. (2003). Diethylenetriamine nitric oxide adduct relaxes precontracted mouse tracheal smooth muscle. Clin. Exp. Pharmacol. Physiol. 30, 709-711.

61 Henry, P.J., Mann, T.S., D’Aprile, A.C., Self, G.J. & Goldie, R.G. (2002). An endothelin receptor antagonist, SB217242 inhibits airway hyperresponsiveness in allergic mice. Am. J. Physiol., 283, 1072-1078.

60 Judge, R.K., Henry, P.J., D’Aprile, A.C., Lynch, D, Jalinek, G, Wilce, M.C.J. & Wilce, J.A. (2002). Identification of PLA2 and alpha-neurotoxin
proteins in the venom of Psuedonaja affinis (Dugite). Toxicol. Appl.
Pharmacol., 181, 184-191

61 Henry, P.J., Mann, T.S., D’Aprile, A.C., Self, G.J. & Goldie, R.G. (2002). An endothelin receptor antagonist, SB217242 inhibits airway hyperresponsiveness in allergic mice. Am. J. Physiol., (in Press).

60 Judge, R.K., Henry, P.J., D’Aprile, A.C., Lynch, D, Jalinek, G, Wilce, M.C.J. & Wilce, J.A. (2002). Identification of PLA2 and alpha-neurotoxin proteins in the venom of Psuedonaja affinis (Dugite). Toxicol. Appl. Pharmacol., 181, 184-191

59 Lan, R.S., Stewart, G.A. & Henry, P.J. (2002). Role of Protease-Activated Receptors (PARs) in airway function: a target for therapeutic intervention? Pharmacol. Ther. (in Press).

58 Decampo, B.A., Goldie, R.G., Jeng, A.Y. & Henry, P.J. (2002). Role of ECE, chymase and neutral endopeptidase in the processing of big ET-1, ET-1(1-21) and ET-1(1-31) in the trachea of allergic mice. Clin. Sci., (in Press).

57 Goldie, R.G., Rigby, P.J., Fernandes, L.B. & Henry, P.J. (2001). The impact of inflammation on bronchial neuronal networks.
Pulm. Pharmacol. Ther., 14, 177-182.

56 Yang, M., Hogan, S.P., Henry, P.J., Matthaei, K., McKenzie, A.N.J., Young, I.G., Rothenberg, M.E. & Foster, P.S. (2001).
Requirement for IL-4R alpha and STAT-6, and not IL-5, eotaxin and eosinophils in early and late-phase IL-13-mediated AHR Am. J. Resp Cell Mol. Biol., 25, 522-530.

55 Goldie, R.G. & Henry, P.J. (2001). Chapter 14: The involvement of endothelins in airway reactivity and disease (pages 357-387)
Series: Handbook of Experimental Pharmacology Volume: Endothelin and its inhibitors Ed: T. Warner Publ. Springer-Verlag

54 Henry, P.J. & Goldie, R.G. (2001). Chapter 4: Endothelin receptors (pages 69-114) Series: Handbook of Experimental Pharmacology Volume: Endothelin and its inhibitors Ed: T. Warner Publ. Springer-Verlag

53 Lan, R.S., Knight, D.A., Stewart, G.A. & Henry, P.J. (2001). Role of PGE2 in protease activated receptor-1, -2, and 4 mediated relaxation in the mouse trachea. Br. J. Pharmacol., 132, 93-100.

52 Lan, R.S., Stewart, G.A. & Henry, P.J. (2000). Modulation of airway smooth muscle tone by protease activated receptor-1, -2, -3 and -4 in trachea isolated from influenza A virus–infected mice. Br. J. Pharmacol., 129, 63-70.

51 Fernandes, L.B., D’Aprile, A.C., Henry, P.J., Spalding, L.J., Pudney, C.J. & Goldie, R.G. (1999). Detection of endothelin receptors inrat and guinea-pig airway nerves by immunohistochemistry. Pulm. Pharmacol. Ther., 12, 313-323.

50 Henry, P.J., Carr, M.J., Goldie, R.G. & Jeng, A.Y. (1999). Influence of an ECE inhibitor CGS 26303 on influenza A virus-induced
changes in endothelin content and ET­B receptor density in mouse airways. Eur. Respir. J., 14, 92-97.

49 Fernandes, L.B., Henry, P.J. & Goldie, R.G. (1999). Endothelin-1 potentiates cholinergic nerve-mediated contraction in human isolated bronchus. Eur. Respir. J., 13, 439-442.

48 Cocks, T.M., Fong, B., Chow, J.M., Anderson, G.P., Goldie, R.G., Henry, P.J., Carr, M.J., Fraumann, A., Hamilton, J.R. & Moffatt, J.D. (1999). A protective role for protease-activated receptors in the airways. Nature, 398, 156-160.

47 Henry, P.J. & King, S.H. (1999). Typical ETA receptors mediate atypical endothelin-1-induced contractions in sheep isolated tracheal smooth muscle. J. Pharmacol. Exp. Ther., 289, 1385-1390.

46 Goldie, R.G. & Henry, P.J. (1999). Endothelins and Asthma. Life Sci. 65, 1-15 .

45 Henry, P.J. (1999). Endothelin receptor distribution and function in the airway wall. Clin. Exp. Pharm. Physiol., 26, 162-167.

44 Henry, P.J. (1998). Respiratory viral infections and the endothelin system Pulmonary Pharmacol., 11, 133-140.

43 Maxwell, Goldie, R.G., & Henry, P.J. (1998). Ca2+ signalling by endothelin receptors in rat and human cultured airway smooth muscle cells. Br. J. Pharmacol., 125, 1768-1778.

42 Goldie, R.G., Henry, P.J., Rigby, P.J. & Knott, P.G. (1998). Influence of respiratory tract viral infection on endothelin-1-induced modulation of cholinergic nerve-mediated contractions in murine airway smooth muscle. J. Cardiovasc. Pharmacol., 31(Suppl 1), S219-S221.

41 Maxwell, M.J., Goldie, R.G. & Henry, P.J. (1998). Altered ETB- but not ETA-receptor density and function in sheep airway smooth muscle cells in culture. Am. J. Physiol., 274, L951-L957.

40 Fernandes, L.B., Henry, P.J., Spalding, L.J., Cody, S.H., Pudney, C.J. & Goldie, R.G. (1998). Immunocytochemical detection of endothelin receptors in rat cultured airway nerves. J. Cardiovasc. Pharmacol., 31(Suppl 1), S222-S224.

39 Henry, P.J. (1998). Endothelin receptor-linked signal transduction processes in the lung. In ‘Pulmonary actions of the endothelins’ Eds. R.G. Goldie & D.W.P. Hay, Publ. Birkhauser-Verlag, AG

38 Carr, M.J., Spalding, L.J., Goldie, R.G. & Henry, P.J. (1998). Distribution of immunoreactive endothelin in the lungs of mice during respiratory tract viral infection. Eur. Respir. J., 11, 79-85.

37 Devadason, P.S.S. & Henry, P.J. (1997). Comparison of the contractile effects and binding kinetics of endothelin-1 and sarafotoxin S6b in rat isolated renal artery. Br. J. Pharmacol., 121, 253-263.

POST-GRADUATE SUPERVISION

Michael Carr
Year 1993
The effects of glucocorticosteroids on endothelin receptor-mediated responses of airway smooth muscle

Peter Devadason
Year 1996
Pharmacological characterisation of endothelin receptors in the rat renal artery: Evidence for atypical ETA receptors?

Rommel Lan
Year 1998
Influence of influenza A virus infection on PAR and ET receptor-effector systems in the murine airway
Supervisor: Professor Geoff Stewart, Microbiology, UWA -

Genevieve Gimblett
Year 1998
Glucocorticoids enhance TNF-a production from TPA stimulated monocytoid THP-1 cells
Supervisor: Assoc. Prof. David Joyce, Pharmacology, UWA (Major supervisor)

Ben Decampo
Year 2000
Influence of ECE, NEP and chymase on the prossessing of ET-1 (1-31) and big ET-1 in the trachea of allergic and non-allergic mice
Supervisor: Professor Roy Goldie, Pharmacology, UWA

Amanda Shin
Year 2001
Does Oncostatin M play a role in virus-induced increases in endothelin-1 levels by airway epithelium?
Supervisor: Dr Darryl Knight, Medicine, UWA

Esther Ooi
Year 2002
Role of endothelin in RSV-induced airway inflammation and hyperresponsiveness

Tracy Hong
Year 2004
Effects of PAR-2 activation at selected time-points in a murine model of
allergic airway inflammation: sex differences in the model

Hilary Hii
Year 2005
Co-Supervisor: Assoc. Prof. Alan James
Airway dimensions in infants with and without a parental history of asthma

Matthew Moller
Year 2005
Co-Supervisor: Assoc. Prof. Alan James

PhD students

Michael MaxwellMichael Maxwell
1992-1997
Endothelin-1-induced calcium signalling in cultured airway smooth muscle
cells. (Distinction)
Co-Supervisor: Roy Goldie, Pharmacology, UWA

Michael Carr
1994-1998
The influence of respiratory tract viral infection on the distribution of
immunoreactive endothelin in the lung and on the function of endothelin
receptor-effector systems within the airways.
Co-Supervisor: Roy Goldie, Pharmacology, UWA

Rommel Lan
1999-2002
PARs in murine airways: expression, location and function
Co-Supervisor: Professor Geoff Stewart, Microbiology, UWA(Distinction)

Ben Decampo
2001-2005
The influence of Protease-activated receptors on allergic airway
inflammation in mice
Co-Supervisor: Professor Roy Goldie, Dr Paul Rigby, Pharmacology, UWA

Richard Betts
2003-2006
Stimulants of Protease-activated receptors-2 as modulators of respiratory
tract viral infection
|
Publications by undergraduate, Honours and PhD Students:

Undergraduate Students

• Henry, P.J. & King, S.H.  (1999). Typical ETA receptors mediate atypical endothelin-1-induced contractions in sheep isolated
  tracheal smooth muscle. J. Pharmacol. Exp. Ther., 289, 1385-1390.

• Devadason, P.S.S. & Henry, P.J. (1997). Comparison of the contractile effects and binding kinetics of endothelin-1 and
  sarafotoxin S6b in rat isolated renal artery. Br. J. Pharmacol., 121, 253-263.
• Lan, R.S., Stewart, G.A. & Henry, P.J. (2000). Modulation of airway smooth muscle tone by protease activated receptor-1,
  -2, -3 and -4 in trachea isolated from influenza A virus–infected mice.  Br. J. Pharmacol., 129, 63-70.
• Decampo, B.A., Goldie, R.G., Jeng, A.Y. & Henry, P.J. (2002)   Role of ECE, chymase and neutral endopeptidase in the
  processing of big ET-1, ET-1(1-21 and ET-1(1-31) in the trachea of allergic mice.  Clin. Sci., 103, 353-35
• Henry, P.J., D’Aprile, A.C., Self, G.J., Hong, T., Mann, T.S. (2005).
  Inhibitors of prostaglandin transport and metabolism augment PAR2-mediated
  increases in PGE2 levels and smooth muscle relaxation in mouse isolated
  trachea. J. Pharmacol. Exp. Ther. 314, 995-1001

• Carr, M.J., Goldie, R.G. & Henry, P.J. (1996). Time course changes in ETB receptor density and function in tracheal airway smooth muscle during respiratory tract viral infection. Br. J. Pharmacol., 117, 1222-1228.
• Goldie, R.G., Knott, P.G., Carr, M.J., Hay, D.W.P. & Henry, P.J. (1996). The endothelins in the pulmonary system.  Pulm.
  Pharmacol., 9, 69-93.
• Carr, M.J., Goldie, R.G. & Henry, P.J. (1996). Influence of respiratory tract viral infection on endothelin-1-induced potentiation of cholinergic nerve-mediated contraction in mouse isolated trachea. Br. J. Pharmacol., 119, 891-898.
• Carr, M.J., Spalding, L.J., Goldie, R.G. & Henry, P.J. (1998). Distribution of immunoreactive endothelin in the lungs of mice during respiratory tract viral infection.  Eur. Respir. J., 11, 79-85.
• Maxwell, M.J., Goldie, R.G. & Henry, P.J. (1998). Altered ETB- but not ETA-receptor density and function in sheep airway smooth
  muscle cells in culture. Am. J. Physiol., 274, L951-L957.
• Maxwell,M.J., Goldie, R.G., & Henry, P.J.  (1998). Ca2+ signalling by endothelin receptors in rat and human cultured airway
  smooth muscle cells. Br. J. Pharmacol., 125, 1768-1778.
• Cocks, T.M., Fong, B., Chow, J.M., Anderson, G.P., Goldie, R.G., Henry, P.J., Carr, M.J., Fraumann, A., Hamilton, J.R. & Moffatt, J.D.  (1999). A protective role for protease-activated receptors in the airways. Nature, 398, 156-160.
• Henry, P.J., Carr, M.J., Goldie, R.G. & Jeng, A.Y. (1999). Influence of an ECE inhibitor CGS 26303 on influenza A virus-induced
  changesin endothelin content and ET­B receptor density in mouse airways. Eur. Respir. J., 14, 92-97.
• Lan, R.S., Knight, D.A., Stewart, G.A. & Henry, P.J. (2001) Role of PGE2 in protease activated receptor-1, -2, and 4 mediated
  relaxation in the  mouse trachea. Br. J. Pharmacol., 132, 93-100.
• Lan, R.S., Stewart, G.A. & Henry, P.J. (2002)  Role of Protease-Activated Receptors (PARs) in airway function: a target for therapeutic intervention? Pharmacol.Ther. 95, 239-2
• Lam, C.F., Lan, R.S., van Heerden, P.V., Ilett, K.F. & Henry, P.J. (2003). Diethylenetriamine nitric oxide adduct relaxes precontracted mouse tracheal smooth muscle. Clin. Exp. Pharmacol. Physiol. 30, 709-711
• Lan, R.S., Stewart, G.A., Goldie, R.G. & Henry, P.J. (2004). Altered expression and in vivo lung function of protease-activated receptors during influenza A virus infection in mice. Am. J. Physiol. 286, L388-L398.
• De Campo, B.A. & Henry, P.J. (2005). SLIGRL, a PAR2-activating peptide, inhibits airway eosinophilia and hyperresponsiveness in a murine model of allergic inflammation. Br. J. Pharmacol. 144, 1100-1108.
• De Campo, B.A. & Henry, P.J. (2005). Protease-activate receptors are partly pro-inflammatory and partly anti-inflammatory: Will PAR agonists or antagonists participate in future drug therapies? Curr Drug Targets
  (invited review, submitted 12/5/2005