The Relations between Structural Changes in Small Airways and Pulmonary-Function Tests

Cosio, Manuel G.; Ghezzo, Heberto; Hogg, James C.; Corbin, Richard P.; Loveland, M.; Dosman, James A.; Macklem, Peter T.

doi:10.1056/nejm197806082982303

Cited by 761 publications

(454 citation statements)

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“…4). This observation is very similar to that previously reported in human smokers [3] where the small airways (i.e., internal diameter <2 mm) were found to be affected, primarily by airway fibrosis and inflammatory infiltrate. Table 1 shows that both cigarette smoke exposed groups had a smaller weight gain than the Control group, the average of CS and CS+NAC groups amounting to 75% of the weight gain of the Control animals.…”

Section: Morphometrysupporting

confidence: 91%

“…The phase III slope of the N 2 single breath washout (SBW) test became a popular index of small airways alteration since the work by COSIO et al [3] showed its correlation with morphological scores of small airways abnormalities in smokers with normal spirometry. A later SBW study by VAN MUYLEM et al [4], which included helium and sulphur hexafluoride tracer concentrations, also revealed distinct correlations between indices derived from He and SF 6 slopes and airway pathology scores.…”

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confidence: 99%

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N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats

et al. 2000

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This study investigated the effect of cigarette smoke exposure and the potential protection N-acetylcysteine (NAC) in rat lungs.Forty-eight rats were exposed to cigarette smoke (CS) for 10 weeks, without (CS group) or with (CS+NAC group) oral intake of NAC 200 mg . rat -1 . day -1 , or to fresh air (Control). All rat lungs were assessed in terms of lung function, ventilation distribution (nitrogen, helium and sulphur hexafluoride phase III slopes), and morphometry (airway wall thickening of small, medium and large bronchi).The small bronchi, defined as the airways with an internal perimeter <1,000 mm showed significantly thicker airway walls in the CS than in the Control group. By contrast, no airway wall thickening was observed in the CS+NAC group with respect to Control. Except for decreased lung volumes and compliance in CS and CS+NAC groups, which were entirely attributable to smaller body weight gain, lung function was indistinguishable from Control. Phase III slopes were significantly increased only in the CS group.In conclusion, smoke-induced alterations in the rat lungs were reflected in wall thickening of the small bronchi and increased ventilation maldistribution. These smoke-induced morphometric and ventilation distribution alterations were prevented by N-acetylcysteine. Eur Respir J 2000; 15: 505±511. In humans, a major site of inflammatory action of cigarette smoke has been attributed to the so-called small airways, stimulating a number of studies aimed at characterizing and detecting structural change in the lung periphery [1,2]. The phase III slope of the N 2 single breath washout (SBW) test became a popular index of small airways alteration since the work by COSIO et al. [3] showed its correlation with morphological scores of small airways abnormalities in smokers with normal spirometry. A later SBW study by VAN MUYLEM et al. [4], which included helium and sulphur hexafluoride tracer concentrations, also revealed distinct correlations between indices derived from He and SF 6 slopes and airway pathology scores. Due to the fact that the diffusion front is located more peripherally for SF 6 than for He, the respective phase III slopes are indicative of the site where ventilation inhomogeneities occur.Although animal studies are well-suited for the study of lung function in the diseased lung, the difficulty often resides in reproducing a lesion which is comparable to that encountered in the human lung [5]. Previous studies in rats have led to conflicting results as to whether the cigarette smoke induces emphysematous lesions [6,7] or not [8,9] and not all studies provide any information about the extent to which the nonalveolated airways are affected [10]. Despite these difficulties, rat lungs have been used to investigate the possible protective role of N-acetylcysteine (NAC) over cigarette smoke induced lesions. NAC is an antioxidant and can therefore be expected to change lung oxidant-antioxidant imbalance induced by cigarette smoke which is a source of oxidants. Previous histopathology...

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Section: Morphometrysupporting

confidence: 91%

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confidence: 99%

N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats

et al. 2000

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“…In addition, the putative role played by TGF-1 in airway wall thickening in asthma has been recently proposed in a study showing that levels of TGF-1 are increased in BAL fluid of asthmatic patients at baseline and after local allergen challenge [31]. In chronic bronchitis, airway wall fibrosis has also been demonstrated [32,33]. The elevated levels of TGF-and FN released by AM from patients with chronic bronchitis may be of importance in the regulation of fibrosis, since airways macrophages are increased in numbers in the bronchial mucosa [13].…”

Section: Discussionmentioning

confidence: 99%

Release of transforming growth factor-beta (TGF-β) and fibronectin by alveolar macrophages in airway diseases

Vignola¹,

Chanez

Chiappara³

et al. 1996

Clinical and Experimental Immunology

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SUMMARYAsthma and chronic bronchitis are associated with airway remodelling, and airway macrophages are present in bronchial inflammation. TGF-¯and fibronectin released by alveolar macrophages possess a fibrogenic potency. The potential role of alveolar macrophages in airway remodelling was studied in asthma and chronic bronchitis by the release of TGF-¯and fibronectin. Alveolar macrophages were isolated by bronchoalveolar lavage in 14 control subjects, 14 asthmatics and 14 chronic bronchitics. The spontaneous and lipopolysaccharide (LPS)-or concanavalin A (Con A)-induced release of TGF-¯and fibronectin was measured by ELISA. Alveolar macrophages from chronic bronchitics spontaneously release greater amounts of TGF-¯and fibronectin than those from asthmatic and control subjects. Alveolar macrophages from asthmatics release greater amounts of TGF-¯and fibronectin than those from control subjects. The spontaneous release of TGF-¯is significantly correlated with that of fibronectin. Fibronectin release was significantly reduced after LPS stimulation, and TGF-¯release was significantly increased after LPS stimulation, except in chronic bronchitis patients. Con A increased the release of TGF-¯in cells from normal subjects. This study suggests that activated macrophages play a role in airway remodelling in chronic bronchitis and to a lesser extent in asthma.

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“…COPD is caused by the noxious effects of tobacco smoke, which leads to airway epithelial injury and the induction of changes such as squamous metaplasia (SM), the reversible replacement of the normal columnar epithelium by squamous epithelium (6). In 1978, Cosio et al noted that SM correlated with the severity of airway obstruction, suggesting that SM and airway obstruction may be linked (7).…”

Section: Introductionmentioning

confidence: 99%

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

Araya¹,

Cambier²,

Markovics³

et al. 2007

J. Clin. Invest.

232

228

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Squamous metaplasia (SM) is common in smokers and is associated with airway obstruction in chronic obstructive pulmonary disease (COPD). A major mechanism of airway obstruction in COPD is thickening of the small airway walls. We asked whether SM actively contributes to airway wall thickening through alteration of epithelial-mesenchymal interactions in COPD. Using immunohistochemical staining, airway morphometry, and fibroblast culture of lung samples from COPD patients; genome-wide analysis of an in vitro model of SM; and in vitro modeling of human airway epithelial-mesenchymal interactions, we provide evidence that SM, through the increased secretion of IL-1β, induces a fibrotic response in adjacent airway fibroblasts. We identify a pivotal role for integrin-mediated TGF-β activation in amplifying SM and driving IL-1β-dependent profibrotic mesenchymal responses. Finally, we show that SM correlates with increased severity of COPD and that fibroblast expression of the integrin α v β 8 , which is the major mediator of airway fibroblast TGF-β activation, correlated with disease severity and small airway wall thickening in COPD. Our findings have identified TGF-β as a potential therapeutic target for COPD.

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The Relations between Structural Changes in Small Airways and Pulmonary-Function Tests

Cited by 761 publications

References 13 publications

N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats

N-acetylcysteine prevents cigarette smoke induced small airways alterations in rats

Release of transforming growth factor-beta (TGF-β) and fibronectin by alveolar macrophages in airway diseases

Squamous metaplasia amplifies pathologic epithelial-mesenchymal interactions in COPD patients

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