Selective airway responsiveness in asthma

O’Connor, Brian; Crowther, Simon D; Costello, John; Morley, John E.

doi:10.1016/s0165-6147(98)01280-2

Cited by 24 publications

(13 citation statements)

References 32 publications

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“…However, whilst there is a separation in airway responsiveness to these agents between asthmatic subjects and healthy individuals, there is also a considerable degree of overlap, and it has been suggested that airway responses to these agents may not be sensitive indicators of the asthma phenotype (Avital et al 1995; O’Connor et al 1999). In contrast, asthmatic subjects invariably bronchoconstrict in response to the indirect-acting stimuli described earlier, which provoke little if any response in otherwise healthy individuals or in subjects with other respiratory diseases (Avital et al 1995; Van Schoor et al 2000).…”

Section: Adenosine: An Important Signaling Molecule In Asthmamentioning

confidence: 99%

Adenosine Receptors and Asthma

Wilson

Nadeem

Spina

et al. 2009

Adenosine Receptors in Health and Disease

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The pathophysiological processes underlying respiratory diseases like asthma are complex, resulting in an overwhelming choice of potential targets for the novel treatment of this disease. Despite this complexity, asthmatic subjects are uniquely sensitive to a range of substances like adenosine, thought to act indirectly to evoke changes in respiratory mechanics and in the underlying pathology, and thereby to offer novel insights into the pathophysiology of this disease. Adenosine is of particular interest because this substance is produced endogenously by many cells during hypoxia, stress, allergic stimulation, and exercise. Extracellular adenosine can be measured in significant concentrations within the airways; can be shown to activate adenosine receptor (AR) subtypes on lung resident cells and migrating inflammatory cells, thereby altering their function, and could therefore play a significant role in this disease. Many preclinical in vitro and in vivo studies have documented the roles of the various AR subtypes in regulating cell function and how they might have a beneficial impact in disease models. Agonists and antagonists of some of these receptor subtypes have been developed and have progressed to clinical studies in order to evaluate their potential as novel antiasthma drugs. In this chapter, we will highlight the roles of adenosine and AR subtypes in many of the characteristic features of asthma: airway obstruction, inflammation, bronchial hyperresponsiveness and remodeling. We will also discuss the merit of targeting each receptor subtype in the development of novel antiasthma drugs.

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Section: Adenosine: An Important Signaling Molecule In Asthmamentioning

confidence: 99%

Adenosine Receptors and Asthma

Wilson

Nadeem

Spina

et al. 2009

Adenosine Receptors in Health and Disease

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“…6 7 Persistence varies according to test spasmogen-<24 hours for AMP and 1-7 days for MCh and histamine-while bradykinin shows large protracted changes in sensitivity of up to 3-5 doubling doses over 2 weeks. 8 Although not previously studied in man, dramatic increases in responsiveness to the cysteinyl-LTs have been shown following allergen challenge in guinea pigs. 9 It is generally accepted that the cysteinyl-LTs are important in allergen induced early asthmatic responses with increased levels detected in bronchoalveolar lavage (BAL) fluid and urine.…”

mentioning

confidence: 99%

Contrasting effects of allergen challenge on airway responsiveness to cysteinyl leukotriene D4 and methacholine in mild asthma

Ketchell

D’Amato²,

Jensen³

et al. 2002

Thorax

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Background: Cysteinyl leukotrienes (cysteinyl-LTs) have been implicated in the pathogenesis of allergen induced airway responses. Airway responsiveness (AR) to inhaled cysteinyl-LTs is dramatically increased following allergen challenge in animal studies. The effect in man has not been evaluated. Methods: Ten mild steroid-naïve asthmatic subjects with an isolated early asthmatic response (EAR) and 21 with an additional late asthmatic response (LAR) took part in a randomised controlled crossover study to assess AR to inhaled methacholine (MCh) and cysteinyl-LT D 4 (LTD 4 ) 22 and 24 hours, respectively, after allergen challenge. Eight subjects had two further LTD 4 challenges separated by a 2 week washout period to assess the reproducibility of inhaled LTD 4 challenge. Results: In subjects with an isolated EAR, non-significant mean (SE) increases in AR of 0.4 (0.4) doubling doses (DD) for MCh and 0.4 (0.5) DD for LTD 4 followed allergen challenge compared with control. A significant correlation between AR to MCh and LTD 4 followed both control (r=0.91, 95% CI 0.67 to 0.98; p=0.0002) and allergen challenge (r=0.79, 95% CI 0.32 to 0.95; p=0.0063). In subjects with an additional LAR there was a significant increase in AR to MCh (1.2 (0.3) DD, p=0.0005) following allergen challenge but no overall effect on AR to LTD 4 (0.69 (0.4) DD, p=0.11). A significant correlation between AR to MCh and LTD 4 was again observed (r=0.70; 95% CI 0.38 to 0.87; p=0.0004) following control, although it was reduced following allergen challenge (r=0.48; 95% CI 0.063 to 0.76; p=0.027). LTD 4 challenge was highly reproducible with a mean difference of 0.2 (0.3) DD between challenges. Conclusions: Allergen challenge significantly increases AR to inhaled MCh but not to LTD 4 in subjects with LAR. The lack of a comparable increase in AR to LTD 4 is surprising. Endogenous cysteinyl-LTs are produced in abundance following allergen challenge and may enhance AR to MCh or induce a degree of tachyphylaxis to LTD 4 .

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“…Measurement of bradykinin is not used routinely to evaluate airway sensitivity in asthma, but may become established in this role following recent recognition of the deficiencies of methacholine (O'Connor et al, 1998). In the present study, initial exposure to ES evoked a fall (>10%) of forced expiratory volume in 1 s (FEV 1.0 ) in only 1 of 10 subjects.…”

mentioning

confidence: 77%

Exaggerated Airway Responsiveness to Ethanolic Solutions

Costello

1998

Inhalation Toxicology

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While determining responsiveness of asthmatic airways to bradykinin, it became apparent that responsiveness to the ethanolic diluent might be a confounding factor. Hence, responsiveness was measured under the same conditions using bradykinin diluted in phosphate-buffered saline. Differences in sensitivity imply that responsiveness to ethanol can develop in asthmatic subjects and can persist for several weeks. This observation questions the desirability of using ethanol for delivery of materials ( e.g., bradykinin and peptidoleukotrienes) into asthmatic airways. 923Inhalation Toxicology, 10:923-929, 1998

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Selective airway responsiveness in asthma

Cited by 24 publications

References 32 publications

Adenosine Receptors and Asthma

Adenosine Receptors and Asthma

Contrasting effects of allergen challenge on airway responsiveness to cysteinyl leukotriene D4 and methacholine in mild asthma

Exaggerated Airway Responsiveness to Ethanolic Solutions

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