Lynette Fernandes | The University of Western Australia (original) (raw)

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Papers by Lynette Fernandes

Journal of Cardiovascular Pharmacology, 2004

We investigated the impact of respiratory syncytial virus (RSV) infection, an important asthma pr... more We investigated the impact of respiratory syncytial virus (RSV) infection, an important asthma precipitant, on endothelin receptor function and release in sheep bronchial explants. RSV infection was confirmed using polymerase chain reaction and immunohistochemistry. Since sheep airway smooth muscle contains only endothelin-A receptors, sarafotoxin (Stx) S6c did not cause airway contraction. In contrast, sarafotoxin S6c (300 nM) caused contraction in RSV-infected bronchial explants (8 ± 3% carbachol E max ). However, we could not detect airway smooth muscle endothelin-B receptors in explants using autoradiography. RSV infection per se did not alter the release of immunoreactive endothelin from sheep bronchial explants (control = 11.6 ± 0.9 pg versus RSV = 12.1 ± 0.9 pg). Interestingly, dexamethasone (1 µM) alone increased endothelin release in both control (17.9 ± 2.0 pg) and RSV-infected tissue (18.3 ± 3.1 pg). The combined presence of protease-activated receptor-2 (PAR-2) ligand (100 µM) and dexamethasone (1 µM) also increased endothelin release from control tissue (17.3 ± 1.4 pg), but endothelin release was suppressed by PAR-2 ligand in RSV-infected tissue (10.3 ± 0.8 pg), probably because PAR-2 expression was increased by RSV. In summary, the novel expression of endothelin-B receptors triggered by RSV might be relevant to RSV-associated asthma. Furthermore, activation of airway PAR-2 may be protective in asthma where endothelin levels are elevated in part via endothelin release suppression.

Current Opinion in Pharmacology, 2003

European Respiratory Journal, 1999

Respirology, 2009

Background and objective: In adults, respiratory movements, such as tidal and deep breaths, redu... more Background and objective: In adults, respiratory movements, such as tidal and deep breaths, reduce airway smooth muscle force and cause bronchodilation. Evidence suggests that these beneficial effects of oscillatory strain do not occur in children, possibly because of reduced coupling of the airways to lung tissue or maturational differences in the intrinsic response of the airways to oscillatory strain.Methods: The bronchodilator effects of oscillatory strain were compared in isolated airway segments from immature (3–4 weeks and 8–10 weeks old) and mature (18–20 weeks old) pigs. The lumen of fluid-filled bronchi was volume-oscillated to simulate tidal breaths and 0.5×, 2× and 4× tidal volumes. Contractions to acetylcholine and electrical field stimulation were recorded from the lumen pressure and were compared under oscillating and static conditions. Airway stiffness was determined from the amplitude of the lumen pressure cycles and the volume of oscillation.Results: Volume oscillation reduced contractions to acetylcholine and electrical field stimulation in an amplitude-dependent manner and the percentage reduction was the same for the different stimuli across all age groups. There was no difference in the relaxed dynamic stiffness of airways from the different age groups.Conclusions: The intrinsic response of the airway wall to equivalent dynamic strain did not differ in airways from pigs of different ages. These findings suggest that mechanisms external to the airway wall may produce age-related differences in the response to lung inflation during development.

Journal of Cardiovascular Pharmacology, 1998

Endothelin-1 (ET-1) has been shown to potentiate cholinergic neurotransmission in human bronchus ... more Endothelin-1 (ET-1) has been shown to potentiate cholinergic neurotransmission in human bronchus as well as in airways from a variety of animal species, suggesting that ET receptors exist prejunctionally on airway cholinergic nerves. We have successfully isolated and maintained rat tracheal para-sympathetic neurons in culture. Most cultured cells were associated with specific fluorescence for the nerve cell marker protein gene product 9.5 (PGP 9.5). These cultures contained a high proportion of parasympathetic neurons. Importantly, specific immunofluorescent antibodies for ETB receptors were colocalized with those for PGP 9.5. Therefore, for the first time, ETB receptors have been shown to exist on airway parasympathetic neurons in culture.

Trends in Pharmacological Sciences, 1990

Various bronchoactive agents can induce the release from the airway epithelium of an inhibitory s... more Various bronchoactive agents can induce the release from the airway epithelium of an inhibitory substance that is able to relax certain tissues including rat aorta and possibly also airway smooth muscle. This substance, whose existence has recently been confirmed using a new bioassay system, is distinct from nitric oxide (EDRF) and is also known to be non-prostanoid in nature. Roy Goldie and colleagues describe the properties of this factor, and its potential clinical significance.

Pulmonary Pharmacology & Therapeutics, 1999

We investigated the existence of endothelin (ET) receptor subtypes in airway neurones from the ra... more We investigated the existence of endothelin (ET) receptor subtypes in airway neurones from the rat and guinea-pig and determined the ability of these receptors to modulate contractile function. Rat tracheal neuron cultures as well as rat and guinea-pig whole mount preparations were labelled with antibodies to the cholinergic nerve marker choline acetyltransferase (ChAT), the neuron specific marker protein gene product 9.5 (PGP 9.5) and to ET A and ET B receptors. Following incubation with fluorescent secondary antibodies, fluorescence was detected using confocal microscopy with dual emission protocols. Specific fluorescence was detected both in whole mount preparations and neuron cultures, in association with the primary antibodies. Specific fluorescence associated with either ET A and ET B receptors was colocalized with that for PGP 9.5. Despite the presence of ET A and ET B receptors on airway nerves, ET-1 failed to significantly alter cholinergic, excitatory or inhibitory non-adrenergic-non-cholinergic nerve-mediated responses in guinea-pig airways. This is in sharp contrast to ET-1-induced potentiation of responses to cholinergic nerve-evoked contraction in rat trachea. Thus, although ET A and ET B receptors exist in airway cholinergic neurons in whole mount preparations and in primary neuron cultures from rat and guinea-pig trachea, the influence of these receptors on contractile function appears to be speciesdependent.

Asthma is a complex inflammatory disease of the airways involving reversible bronchoconstriction.... more Asthma is a complex inflammatory disease of the airways involving reversible bronchoconstriction. Chronic obstructive pulmonary disease is typified by inflammation and airflow limitation that has an irreversible component. There is now substantial evidence that Rho kinase is involved in many of the pathways that contribute to the pathologies associated with these respiratory diseases including bronchoconstriction, airway inflammation, airway remodelling, neuromodulation and exacerbations due to respiratory tract viral infection. Indeed the Rho kinase inhibitor Y-27632 causes bronchodilatation and reduces pulmonary eosinophilia trafficking and airways hyperresponsiveness. Furthermore, accumulating evidence suggests that inhibition of Rho kinase could have a major beneficial impact on symptoms and disease progression in asthma and COPD by modulating several other systems and processes. Thus, the Rho kinase pathway may indeed be a worthwhile therapeutic target in the treatment of asthma and chronic obstructive pulmonary disease.

Pulmonary Pharmacology & Therapeutics, 2001

It is well-recognized that the activities of airway neuronal systems can be modulated by various ... more It is well-recognized that the activities of airway neuronal systems can be modulated by various agonist molecules. This brief review examines some of the evidence that inflammation and some of the mediators relevant to the expression of inflammatory processes can also significantly alter the function and activities of airway nerves. The concept of neuronal plasticity and phenotype switching induced by inflammation is also examined, with particular emphasis on sensory airway nerves.

European Journal of Pharmacology, 2006

This study examined the effects of the selective Rho-kinase inhibitor Y-27632 [(+)-(R)-trans-4-(1... more This study examined the effects of the selective Rho-kinase inhibitor Y-27632 [(+)-(R)-trans-4-(1-aminoethyl)-(4-pyridyl)cyclohexanecarboxamide dihydrochloride]) on cholinergic nerve-mediated contraction and neurotransmitter release in murine and guinea-pig isolated tracheal preparations. In tracheal preparations obtained from both species, Y-27632 shifted carbachol concentration-effect curves to the right and reduced the maximal contractile response. Repeated electrical field stimulation (EFS) evoked transient, consistent and reproducible contractions in murine and guinea-pig tracheal preparations. Y-27632 inhibited these cholinergic nerve-mediated contractions in a concentration-dependent manner. EFS (0.1-30 Hz) elicited frequency-dependent cholinergic nerve-mediated contractile responses. In murine tracheal preparations, Y-27632 (3 μM and 10 μM) shifted frequency-response curves to EFS to the right by 5.5 and 13.0 fold respectively and markedly reduced the maximal contractile response. In murine and guinea-pig tracheal preparations loaded with [ 3 H]-choline, Y-27632 (10 μM) significantly increased the EFS-induced outflow of radioactivity from airway cholinergic nerves by 27% and 54% respectively. Thus, Y-27632 inhibited both carbachol-induced and cholinergic nerve-mediated contractile responses. Conversely, Y-27632 increased neurotransmitter release from airway cholinergic nerves. However, since antagonism of acetylcholine-induced contraction by Y-27632 overwhelmed the increased neurotransmitter release, the overall effect of this Rho-kinase inhibitor was to inhibit cholinergic nerve-mediated contraction.

Current Opinion in Pharmacology, 2002

nitric oxide synthase PGP 9.5 protein gene product 9.5 TEM transmission electron microscopy

Clinical and Experimental Pharmacology and Physiology, 1996

1. Airway smooth muscle receives cholinergic, adrenergic and non-adrenergic, non-cholinergic (NAN... more 1. Airway smooth muscle receives cholinergic, adrenergic and non-adrenergic, non-cholinergic (NANC) neural input. In guinea-pig airways cholinergic and NANC nerves provide contractile innervation, while adrenergic and NANC nerves provide nerves provide relaxant pathways. In contrast, the major relaxant innervation in human airways is NANC in nature.2. The present review describes the effects of selective phosphodiesterase (PDE) inhibitors on NANC relaxant and contractle responses in guinea-pig trachea as well as on NANC relaxations in human bronchus.3. The effects of endothelin-1 on cholinergic contractile responses obtained in a variety of species are also assessed.