Michele Baroffio

Noninflammatory mechanisms of airway hyper-responsiveness in bronchial asthma: an overview

Airway hyper-responsiveness (AHR) is a cardinal feature of asthma. Its absence has been considered useful in excluding asthma, whereas it may be present in other diseases such as atopic rhinitis and chronic obstructive pulmonary disease. AHR is often considered an epiphenomenon of airway inflammation. Actually, the response of airways to constrictor stimuli is modulated by a complex array of factors, some facilitating and others opposing airway narrowing. Thus, it has been suggested that AHR, and perhaps asthma, might be present even without or before the development of airway inflammation. We begin this review by highlighting some terminological and methodological issues concerning the measurement of AHR. Then we describe the neurohumoral mechanisms controlling airway tone. Finally, the pivotal role of airway smooth muscle and internal and external modulation of airway caliber in vivo are discussed in detail.

Cysteinyl-leukotrienes in the regulation of β2-adrenoceptor function: an in vitro model of asthma

BackgroundThe response to β2-adrenoceptor agonists is reduced in asthmatic airways. This desensitization may be in part due to inflammatory mediators and may involve cysteinyl-leukotrienes (cysteinyl-LTs). Cysteinyl-LTs are pivotal inflammatory mediators that play important roles in the pathophysiology of asthma, allergic rhinitis, and other inflammatory conditions. We tested the hypothesis that leukotriene D4 (LTD4) and allergen challenge cause β2-adrenoceptor desensitization through the activation of protein kinase C (PKC).MethodsThe isoproterenol-induced cAMP accumulation was evaluated in human airway smooth muscle cell cultures challenged with exogenous LTD4 or the PKC activator phorbol-12-myristate-13-acetate with or without pretreatments with the PKC inhibitor GF109203X or the CysLT1R antagonist montelukast. The relaxant response to salbutamol was studied in passively sensitized human bronchial rings challenged with allergen in physiological salt solution (PSS) alone, or in the presence of either montelukast or GF109203X.ResultsIn cell cultures, both LTD4 and phorbol-12-myristate-13-acetate caused significant reductions of maximal isoproterenol-induced cAMP accumulation, which were fully prevented by montelukast and GF109203X, respectively. More importantly, GF109203X also prevented the attenuating effect of LTD4 on isoproterenol-induced cAMP accumulation. In bronchial rings, both montelukast and GF109203X prevented the rightward displacement of the concentration-response curves to salbutamol induced by allergen challenge.ConclusionLTD4 induces β2-adrenoceptor desensitization in human airway smooth muscle cells, which is mediated through the activation of PKC. Allergen exposure of sensitized human bronchi may also cause a β2-adrenoceptor desensitization through the involvement of the CysLT1R-PKC pathway.

Assessment of extravascular lung water by quantitative ultrasound and CT in isolated bovine lung

Lung ultrasonography (LUS) and computed tomography (CT) were compared for quantitative assessment of extravascular lung water (EVLW) in 10 isolated bovine lung lobes. LUS and CT were obtained at different inflation pressures before and after instillation with known amounts of hypotonic saline. A video-based quantitative LUS analysis was superior to both single-frame quantitative analysis and visual scoring in the assessment of EVLW. Video-based mean LUS intensity was strongly correlated with EVLW density (r(2)=0.87) but weakly correlated with mean CT attenuation (r(2)=0.49) and physical density (r(2)=0.49). Mean CT attenuation was weakly correlated with EVLW density (r(2)=0.62) but strongly correlated with physical density (r(2)=0.99). When the effect of physical density was removed by partial correlation analysis, EVLW density was significantly correlated with video-based LUS intensity (r(2)=0.75) but not mean CT attenuation (r(2)=0.007). In conclusion, these findings suggest that quantitative LUS by video gray-scale analysis can assess EVLW more reliably than LUS visual scoring or quantitative CT.

Bronchodilator effects of exercise hyperpnea and albuterol in mild-to-moderate asthma

In asthmatic patients, either bronchodilatation or bronchoconstriction may develop during exercise. In 18 patients with mild-to-moderate asthma, we conducted two studies with the aims to 1) quantify the bronchodilator effect of hyperpnea induced by incremental-load maximum exercise compared with effects of inhaled albuterol (study 1, n=10) and 2) determine the time course of changes in airway caliber during prolonged constant-load exercise (study 2, n=8). In both studies, it was also investigated whether the bronchodilator effects of exercise hyperpnea and albuterol are additive. Changes in airway caliber were measured by changes in partial forced expiratory flow. In study 1, incremental-load exercise was associated with a bronchodilatation that was approximately 60% of the maximal bronchodilatation obtainable with 1,500 microg of albuterol. In study 2, constant-load exercise was associated with an initial moderate bronchodilatation and a late airway renarrowing. In both studies, premedication with inhaled albuterol (400 microg) promoted sustained bronchodilatation during exercise, which was additive to that caused by exercise hyperpnea. In conclusion, in mild-to-moderate asthmatic individuals, hyperpnea at peak exercise was associated with a potent yet not complete bronchodilatation. During constant-load exercise, a transient bronchodilatation was followed by airway renarrowing, suggesting prevalence of constrictor over dilator effects of hyperpnea. Finally, the bronchodilator effect of hyperpnea was additive to that of albuterol.

Does a Low-Density Gas Mixture or Oxygen Supplementation Improve Exercise Training in COPD?

BACKGROUND Low-density gas mixtures and oxygen (O₂) supplementation are known to improve physical performance and ventilatory adaptation during incremental maximal exercise in COPD. We investigated whether their combined use during intense physical training is also effective in ameliorating exercise tolerance in patients affected by moderate to severe COPD. METHODS Thirty patients (FEV₁ < 60% of predicted) underwent a 2-month rehabilitation program. Leg-cycle training was conducted thrice weekly at 80% of the initial peak work rate for at least 20 min breathing room air, a 60% helium and 40% O₂ mixture, or supplemental O₂ (40%) inhaled from a Douglas bag. The study was randomized with a double-blind design. Before and at the end of the training period the subjects were tested for spirometry, arterial gas tension, diffusing lung capacity for CO, and incremental and constant work rate exercise test on a cycle ergometer. RESULTS Physical training resulted in a significant improvement in peak oxygen consumption and power output (P < .01 for both) and in exercise endurance time (P < .05) independently of the kind of inhaled gas during the rehabilitation program (P ≥ .42). No changes were observed in lung function tests or gas exchange. CONCLUSIONS We concluded that the use of a low-density gas mixture or O₂ supplementation does not contribute to improved exercise performance in patients with moderate to severe COPD without a significantly decreased diffusion lung capacity for CO who are able to tolerate intense physical training.

Beta-Adrenergic Agonists.

Inhaled β2-adrenoceptor (β2-AR) agonists are considered essential bronchodilator drugs in the treatment of bronchial asthma, both as symptoms-relievers and, in combination with inhaled corticosteroids, as disease-controllers. In this article, we first review the basic mechanisms by which the β2-adrenergic system contributes to the control of airway smooth muscle tone. Then, we go on describing the structural characteristics of β2-AR and the molecular basis of G-protein-coupled receptor signaling and mechanisms of its desensitization/ dysfunction. In particular, phosphorylation mediated by protein kinase A and β-adrenergic receptor kinase are examined in detail. Finally, we discuss the pivotal role of inhaled β2-AR agonists in the treatment of asthma and the concerns about their safety that have been recently raised.

Review: Airway smooth muscle as a model for new investigative drugs in asthma

Bronchial asthma as such exists because airway smooth muscle (ASM) contracts excessively in response to various stimuli. After several decades during which research was mainly focused on airway inflammation, increasing attention is now being paid to a possible abnormal behaviour of ASM. Thus, ASM is regarded as a major target for anti-asthma treatments. This review first describes the mechanisms of ASM contraction and airway hyperresponsiveness, through cellular, animal and human models. The developments of new drugs targeting extra and/or intracellular pathway of ASM contraction are discussed.

Severity grading of chronic obstructive pulmonary disease: the confounding effect of phenotype and thoracic gas compression

Current guidelines recommend severity of chronic obstructive pulmonary disease be graded by using forced expiratory volume in 1 s (FEV1). But this measurement is biased by thoracic gas compression depending on lung volume and airflow resistance. The aim of this study was to test the hypothesis that the effect of thoracic gas compression on FEV1 is greater in emphysema than chronic bronchitis because of larger lung volumes, and this influences severity classification and prognosis. FEV1 was simultaneously measured by spirometry and body plethysmography (FEV1-pl) in 47 subjects with dominant emphysema and 51 with dominant chronic bronchitis. Subjects with dominant emphysema had larger lung volumes, lower diffusion capacity, and lower FEV1 than those with dominant chronic bronchitis. However, FEV1-pl, patient-centered variables (dyspnea, quality of life, exercise tolerance, exacerbation frequency), arterial blood gases, and respiratory impedance were not significantly different between groups. Using FEV1-pl instead of FEV1 shifted severity distribution toward less severe classes in dominant emphysema more than chronic bronchitis. The body mass, obstruction, dyspnea, and exercise (BODE) index was significantly higher in dominant emphysema than chronic bronchitis, but this difference significantly decreased when FEV1-pl was substituted for FEV1. In conclusion, the FEV1 is biased by thoracic gas compression more in subjects with dominant emphysema than in those with chronic bronchitis. This variably and significantly affects the severity grading systems currently recommended.

Effects of κ- and μ-opioid agonists on cholinergic neurotransmission and contraction in isolated bovine trachealis.

The effects of the selective μ-opioid agonist DAMGO and the selective κ-opioid agonist U-50488H on tritiated acetylcholine release ([(3)H]-ACh) and contractile responses to electrical stimulation (ES) were simultaneously determined in isolated bovine trachealis. The inhibitory effect of DAMGO 10(-5)M on [(3)H]-ACh release was not significantly different from the effect of the non-selective muscarinic agonist pilocarpine 10(-5)M, whereas the effect of U-50488H 10(-5)M was significantly greater. The effects of both opioids were not significantly different when muscles were pre- or co-incubated with the unselective muscarinic antagonist atropine 10(-7)M. Both DAMGO and U-50488H attenuated ES-induced contraction and this effect was significantly correlated with the inhibition of [(3)H]ACh-release (r(2)=0.8552). These data suggest that (1) opioids are important modulators of airway smooth muscle tone, (2) their effect is not altered by the activity of muscarinic autoregulation, and (3) their inhibitory effect of airway smooth muscle contraction can be almost totally explained by inhibition of ACh release.

Lung diffusing capacity for nitric oxide as a marker of fibrotic changes in idiopathic interstitial pneumonias.

Lung diffusing capacity for carbon monoxide (DLCO) is decreased in both usual interstitial pneumonia-idiopathic pulmonary fibrosis (UIP-IPF) and nonspecific interstitial pneumonia (NSIP), but is moderately related to computed tomography (CT)-determined fibrotic changes. This may be due to the relative insensitivity of DLCO to changes in alveolar membrane diffusive conductance (DMCO). The purpose of this study was to determine whether measurement of lung diffusing capacity for nitric oxide (DLNO) better reflects fibrotic changes than DLCO DLNO-DLCO were measured simultaneously in 30 patients with UIP-IPF and 30 with NSIP. Eighty-one matched healthy subjects served as a control group. The amount of pulmonary fibrosis was estimated by CT volumetric analysis of visually bounded areas showing reticular opacities and honeycombing. DMCO and pulmonary capillary volume (VC) were calculated. DLNO was below the lower limit of normal in all patients irrespective of extent and nature of disease, whereas DLCO was within the normal range in a nonnegligible number of patients. Both DLNO and DLCO were significantly correlated with visual assessment of fibrosis but DLNO more closely than DLCO DMCO was also below the lower limit of normal in all UIP-IPF and NSIP patients and significantly correlated with fibrosis extent in both diseases, whereas VC was weakly correlated with fibrosis in UIP-IPF and uncorrelated in NSIP, with normal values in half of patients. In conclusion, measurement of DLNO may provide a more sensitive evaluation of fibrotic changes than DLCO in either UIP-IPF or NSIP, because it better reflects DMCO.