Airways hyperresponsiveness (AHR) is a central feature of asthma, strongly related to the severity of the disease. However, its mechanisms are not understood. In the first period of this grant, we examined how lung inflation (deep inspiration) influences airways responsiveness. We identified that lung inflation has two distinct beneficial effects in healthy humans: it acts as a bronchoprotector and as a bronchodilator against bronchoconstrictive stimuli. We also found that the bronchoprotective effect of lung inflation is lost in individuals with AHR and is also absent against the bronchoconstriction induced by an allergic reaction. Preliminary findings indicate that the bronchodilatory effect is lost in subjects with COPD and in those with severe asthma. We now propose 3 specific aims:
Specific aim 1 will test the hypothesis that nitric oxide (NO), which affects the airways smooth muscle by increasing the levels of cGMP, mediates the bronchoprotective effects of lung inflation and that the NO effect is impaired in AHR. This will be tested with the use of inhaled NO in healthy subjects and subjects with asthma with the intent to demonstrate that NO can mimic deep inspiration-induced bronchoprotection only in the former group. An analogous approach will be used by pre-treatment with sildenafil citrate, an approved inhibitor of PDE V, the enzyme responsible for cGMP degradation.
Specific aim 2 will be devoted to the understanding of the mechanisms behind the absence of bronchoprotection against a respiratory allergic reaction. We will first examine whether an allergic reaction leads to the loss of bronchoprotection against other stimuli, such as methacholine. By using inhaled NO, we will examine whether the bronchoprotective action of this molecule is absent against an allergic reaction. With antagonists to products of the allergic reaction (primarily antileukotrienes and antihistamines), we will test whether we can restore the bronchoprotective effects of lung inflation against allergen.
In specific aim 3 we will examine the reasons behind the loss of the bronchodilatory effect of lung inflation. Our hypothesis is that, in COPD, bronchodilation is lost as a result of impairment in lung elastic recoil, whereas in severe asthma, as a result of airway wall stiffness. To test this hypothesis, we will investigate these subject groups in comparison to healthy controls by simultaneously testing airways distensibility through high resolution computerized tomography imaging, recoil pressure at various lung volumes and bronchodilation by lung inflation.
| Pyrgos, George; Togias, Alkis; Brown, Robert H (2013) Phosphodiesterase V inhibition reduces airway responsiveness, but does not improve the beneficial effect of deep inspiration. Respiration 86:243-51 |
| Pyrgos, George; Scichilone, Nicola; Togias, Alkis et al. (2011) Bronchodilation response to deep inspirations in asthma is dependent on airway distensibility and air trapping. J Appl Physiol 110:472-9 |
| Skloot, Gwen S; Chandy, Dipak; Schachter, Neil et al. (2007) The bronchoprotective effect of deep inspiration is flow rate dependent. Respir Med 101:1376-82 |
| Scichilone, Nicola; Marchese, Roberto; Soresi, Simona et al. (2007) Deep inspiration-induced changes in lung volume decrease with severity of asthma. Respir Med 101:951-6 |
| Brown, Robert H; Pearse, David B; Pyrgos, George et al. (2006) The structural basis of airways hyperresponsiveness in asthma. J Appl Physiol 101:30-9 |
| Scichilone, Nicola; Permutt, Solbert; Bellia, Vincenzo et al. (2005) Inhaled corticosteroids and the beneficial effect of deep inspiration in asthma. Am J Respir Crit Care Med 172:693-9 |
| Pyrgos, George; Kapsali, Trisevgeni; Permutt, Solbert et al. (2003) Absence of deep inspiration-induced bronchoprotection against inhaled allergen. Am J Respir Crit Care Med 167:1660-3 |
| Skloot, Gwen; Togias, Alkis (2003) Bronchodilation and bronchoprotection by deep inspiration and their relationship to bronchial hyperresponsiveness. Clin Rev Allergy Immunol 24:55-72 |
| Peebles Jr, R S; Wagner, E M; Liu, M C et al. (2001) Allergen-induced changes in airway responsiveness are not related to indices of airway edema. J Allergy Clin Immunol 107:805-11 |
| Scichilone, N; Pyrgos, G; Kapsali, T et al. (2001) Airways hyperresponsiveness and the effects of lung inflation. Int Arch Allergy Immunol 124:262-6 |
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