help button home button
AJRCCM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Published ahead of print on July 31, 2003, doi:10.1164/rccm.200305-650OC
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200305-650OCv1
168/7/798    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Barbato, A.
Right arrow Articles by Saetta, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barbato, A.
Right arrow Articles by Saetta, M.
American Journal of Respiratory and Critical Care Medicine Vol 168. pp. 798-803, (2003)
© 2003 American Thoracic Society

Original Article

Airway Inflammation in Childhood Asthma

Angelo Barbato, Graziella Turato, Simonetta Baraldo, Erica Bazzan, Fiorella Calabrese, Maria Tura, Renzo Zuin, Bianca Beghé, Piero Maestrelli, Leonardo M. Fabbri and Marina Saetta

Department of Pediatrics; Department of Clinical and Experimental Medicine, Section of Respiratory Diseases; Department of Respiratory Diseases and Radiology, University of Modena and Reggio Emilia; Institute of Pathology; and Department of Environmental Medicine and Public Health, University of Padua, Padua, Italy

Correspondence and requests for reprints should be addressed to Marina Saetta, M.D., Divisione di Pneumologia, Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Padova, via Giustiniani 3, 35128 Padua, Italy. E-mail: marina.saetta{at}unipd.it


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Airway pathology has been extensively investigated in adulthood asthma, whereas only few studies examined bronchial biopsies in childhood asthma. To evaluate the airway pathology in children with asthma, we analyzed bronchial biopsies obtained from 23 children undergoing bronchoscopy for clinical indications other than asthma. Nine had mild/moderate asthma. Six had atopy without asthma, and eight had no atopy or asthma. We measured basement membrane thickness and quantified the number of eosinophils, mast cells, neutrophils, macrophages, T lymphocytes, and positive cells for transforming growth factor-ß1 (TGF-ß1) and its receptors I and II (TGFß-RI and TGFß-RII) in subepithelium. Children with asthma had an increase in basement membrane thickness and in the number of eosinophils compared with control subjects, but not compared with children with atopy. They also had a decreased expression of TGFß-RII compared with both those with atopy and control subjects. In children with asthma, the number of eosinophils correlated negatively with TGFß-RII and positively with symptom duration. In conclusion, airway eosinophilia and basement membrane thickening, which are the pathologic features that are characteristic of adulthood asthma, are already present in children with mild asthma, and even in children with atopy without asthma. Moreover, in children with asthma but not in children with atopy without asthma, there is a downregulation of TGFß-RII.

Key Words: inflammation • remodeling • pediatric asthma • cytokines

Airway inflammation and remodeling play an important role in the pathophysiology of asthma. Although the airway pathology has been extensively investigated in adulthood asthma, only a few studies examined bronchial biopsies obtained from children with asthma (1). Investigating the airway pathology in childhood asthma may be of interest to clarify whether the pathologic features seen in adults begin early in the course of the disease and whether remodeling occurs in parallel with inflammation or sequential to it. Previous studies (2, 3) have described the presence of both inflammation and thickening of the basement membrane in children with asthma. However, in those studies, only a qualitative analysis was performed, and a control group of children without asthma was not included. More recently, Payne and coworkers (4), in a quantitative well-conducted study, demonstrated that children with difficult asthma had a thickened basement membrane as compared with pediatric control subjects and that this thickening was similar to that seen in adulthood asthma. However, as stated by the authors, the children examined in that study are not typical of the majority of children with asthma but represent those with the most severe disease, with persistent symptoms despite maximal steroid therapy. Furthermore, that study did not include a control group of children with atopy without asthma. Therefore, it is yet to be elucidated whether inflammation and remodeling can be already observed in children when the disease is mild or even when only atopy is present.

There is accumulating evidence to suggest that transforming growth factor-ß1 (TGF-ß1) may be involved in orchestrating both inflammatory and remodeling processes in asthma. TGF-ß1 is a pleiotropic cytokine that through binding to its type I and type II receptors (TGFß-RI and TGFß-RII) can exert a number of biological effects, including profibrotic and antiinflammatory activities (5, 6). Although some studies in human asthma have shown an increased expression of TGF-ß1 (7–9), underlining its profibrotic role, other studies have demonstrated an antiinflammatory activity of this cytokine (10, 11). It could be of interest to investigate the expression of TGF-ß1 and its receptors in childhood asthma, when the onset of inflammation and remodeling processes is probably occurring.

As far as we know, no study has addressed the issue to quantify the airway inflammatory and structural changes in children with mild/moderate asthma and to compare them with the appropriate pediatric control subjects, in particular with children with atopy without asthma. We therefore decided to measure the inflammatory cells and the basement membrane thickness in bronchial biopsies of children with mild/moderate asthma, of children with atopy but without asthma, and of children with no atopy or asthma. Moreover, to clarify the role of TGF-ß1 in airway inflammation and remodeling, we examined the expression of TGF-ß1, TGFß-RI, and TGFß-RII in the three groups of children. Some of the results of these studies have been previously reported in the form of an abstract at the 2003 Meeting of the American Thoracic Society (Seattle, WA) (12).


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Subjects
We recruited to the study 23 children who had undergone fiberoptic bronchoscopy for appropriate clinical indications other than asthma (13, 14). The study population included the following three groups: nine children with asthma (age of 4–12 years), six children with atopy without asthma (age of 3–13 years), and eight control children without asthma or atopy (age of 4–12 years). Children with asthma underwent bronchoscopy for persistent atelectasis (n = 3) or for recurrent pneumonia (n = 6). Children with atopy without asthma underwent bronchoscopy for stridor (n = 1), persistent atelectasis (n = 1), or recurrent pneumonia (n = 4). Children who were control subjects underwent bronchoscopy for stridor (n = 2), persistent atelectasis (n = 1), recurrent pneumonia (n = 3), or chronic cough (n = 2).

Asthma was diagnosed when the child had episodic cough, breathlessness, and a wheeze responsive to bronchodilators (15). The presence of atopy was defined by an increase in total (paper-radio-immunosorbent-test) or specific (radio-allergo-sorbent-test) IgE. All children of the three groups underwent paper-radio-immuno-sorbent-test, radio-allergo-sorbent-test, and routine blood tests, whereas spirometry was performed only in children who were able to cooperate with the test. FEV1 was measured using a 10-L bell spirometer (Biomedin, Padua, Italy), and the best of three maneuvers was expressed as a percentage of predicted values (16).

Performance of endobronchial biopsy for studying airway pathology was approved by local ethics committees. Informed consent was obtained from the children's parents. The study was performed according to the Declaration of Helsinki. Bronchoscopy was performed as previously described (17), except that the fiberoptic bronchoscope was inserted orally using a mouth Olympus MA-651 (K). One bronchial biopsy specimen was taken from the main carina using a bronchial forceps (Olympus FB 15 C-1) inserted through the service channel of the bronchoscope.

Sample Processing and Analysis
Biopsies were processed as previously described (18). Reticular basement membrane thickness was assessed on sections stained with hematoxylin and eosin by making measurements at 50-µm intervals along all the basement membrane, using a computer-aided image analysis (Casti Imaging, Venice, Italy). The infiltration of eosinophils, neutrophils, mast cells, macrophages, and CD4 T lymphocytes was assessed in the subepithelium by immunohistochemistry as previously described (19). The expression of TGF-ß1, TGFß-RI, and TGFß-RII was assessed in the subepithelium using immunohistochemical methods. Briefly, all biopsy sections were subjected to antigen retrieval by heating in a microwave oven on high power for 8 minutes in 0.01 mol/L citrate buffer (pH 6.0) and then incubated with a mouse monoclonal antibody anti–TGF-ß1 (150 µg/ml, dilution 1:20; Genzyme Diagnostics, Cambridge, MA) with a polyclonal antibody anti–TGF-ß1 receptor type I (200 µg/ml, dilution 1:200; Santa Cruz Biotechnology Inc., Santa Cruz, CA) or with a polyclonal antibody anti–TGFß-RII (200 µg/ml, dilution 1:200; Santa Cruz Biotechnology Inc.). Before incubation with primary antibody, the sections were treated with a biotin blocking kit (Vector Laboratories, Peterborough, UK) to inhibit endogenous biotin. The detection system was performed using the Vectastain ABC kit (Vector Laboratories) with 3-amino-9-ethylcarbazole as the chromogenic substrate. Sections were counterstained with Mayer's hematoxylin. The surface epithelial layer was not included in the count because of the frequent erosion or loss by technical misprocessing.

To avoid observer bias, the cases were coded, and the measurements were made without knowledge of clinical data. Differences between groups were analyzed using the analysis of variance for clinical data and the Kruskall-Wallis test for histologic data. The Mann-Whitney U test was performed after Kruskall-Wallis test when appropriate. Correlation coefficients were calculated using Spearman's rank method. Probability values of 0.05 or less were accepted as significant. Group data were expressed as means and SEM or as medians and range when appropriate.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical Findings
The characteristic of the children studied are shown in Table 1 . Spirometry was successfully performed in six of nine children with asthma, four of six children with atopy, and five of eight control subjects. Children with asthma had a FEV1 value (percentage of predicted) that was significantly lower than control children (p = 0.008). The three groups of children were similar with regard to age and sex. Six out of nine children with asthma were atopic. The bronchoscopy procedure was well tolerated by all children.


View this table:
[in this window]
[in a new window]
  		TABLE 1. Clinical characteristics of children with asthma, children with atopy, and control children

 
Seven of nine children with asthma had mild asthma and were treated with only inhaled salbutamol when needed. The remaining two children had moderate asthma and were treated regularly with combined salmeterol/fluticasone (50/100 twice a day in one child and 50/250 twice a day in the other child). All children with recurrent pneumonia (n = 13) were in treatment with antibiotics.

To confirm further the absence of asthma in children with atopy without asthma, we performed exercise challenge in those children who were able to cooperate with the test (three out of six). None of them had a fall in FEV1 that was 15% or more after exercise.

Biopsy Findings
Quantification of inflammatory cells was satisfactory in all children except in one of the group with asthma and in one of the control group in whom we could quantify only eosinophils and basement membrane thickness because of the limited amount of biopsy tissue. For the same reason, we were not able to quantify TGF-ß1 and its receptors in one child in the group with atopy.

Children with asthma had an increased reticular basement membrane thickness as compared with children who were control subjects (6.0, 4.5–9.5 vs. 4.2, 3.3–4.9; p = 0.001) (Figures 1 and 2) . Even if to a lesser extent, also children with atopy showed an increased basement membrane thickness as compared with children who were control subjects (4.9, 4.2–6.6 vs. 4.2, 3.3–4.9; p = 0.052) (Figure 1). In addition, both children with atopy without asthma and children with asthma had an increased number of eosinophils in the subepithelium as compared with children who were control subjects (p = 0.033 and p = 0.038, respectively) (Figures 3 and 4 and Table 2) . No significant difference was observed between children with atopy and with asthma in the reticular basement membrane thickness or in the eosinophilic infiltration. Of the two children taking inhaled steroids, one had a value of tissue eosinophils in the range of control subjects (48 cells/mm2), whereas the other had a prominent tissue eosinophilia (338 cells/mm2). No significant differences were observed among the three groups of subjects in the number of neutrophils, mast cells, CD4+ T lymphocytes, and macrophages (Table 2). The expression of TGF-ß1 and TGFß-RI was not significantly different in the three groups of children examined (Table 2). However, children with asthma had a decreased expression of TGFß-RII in the subepithelium as compared with both children with atopy and children who were control subjects (p = 0.004 and p = 0.047, respectively; Figure 5) .



View larger version (14K):
[in this window]
[in a new window]
  		Figure 1. Individual values for reticular basement membrane thickness in bronchial biopsies of children with asthma, children with atopy, and children who were control subjects. Horizontal bars represent median values. The asterisk indicates children with asthma who were not atopic; S indicates children with asthma who were treated with inhaled steroids.

 


View larger version (72K):
[in this window]
[in a new window]
  		Figure 2. Microphotograph showing bronchial biopsies from a child with asthma (A) and a control child (B), demonstrating an increased basement membrane thickness in the child with asthma. The tissue sections are stained with hematoxylin and eosin. Original magnification, x630.

 


View larger version (16K):
[in this window]
[in a new window]
  		Figure 3. Individual counts for eosinophils in bronchial biopsies of children with asthma, children with atopy, and control children. The results are expressed as number of cells per mm2 of tissue examined. Horizontal bars represent median values. The asterisk indicates children with asthma who were not atopic; S indicates children with asthma who were treated with inhaled steroids.

 


View larger version (66K):
[in this window]
[in a new window]
  		Figure 4. Microphotograph showing bronchial biopsies from a child with asthma (A) and a control child (B), demonstrating an increased number of eosinophils infiltrating the subepithelium in the child with asthma. Immunostaining with monoclonal antibody anti–EG-2 (positive cells are stained in red). Original magnification, x630.

 

View this table:
[in this window]
[in a new window]
  		TABLE 2. Cellular counts in the subepithelium

 


View larger version (15K):
[in this window]
[in a new window]
  		Figure 5. Individual counts for TGFß-RII+ cells in bronchial biopsies of children with asthma, children with atopy, and control children. The results are expressed as number of cells/mm2 of tissue examined. Horizontal bars represent median values.

 
When only the group of children with asthma was considered, the number of eosinophils in the airway wall showed a negative correlation with TGFß-RII expression (p = 0.035, r = -0.86) and a positive correlation with the duration of asthma symptoms (p = 0.020, r = 0.79). No other significant correlations were observed between cellular counts and functional data or between reticular basement membrane thickness and cellular counts or functional data.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
This study shows that the pathologic features characteristic of adulthood asthma, that is, airway eosinophilia and basement membrane thickening, are already present in children with mild/moderate asthma. Moreover, in children with asthma, these pathologic features are paralleled by a decreased expression of TGFß-RII. Children with atopy without asthma also exhibit an increase in number of eosinophils and, even if to a lesser extent, in basement membrane thickness.

By showing that basement membrane thickening is already present in childhood asthma, this study confirms the qualitative observations of previous reports (2, 3). The only study that provided quantitative measurements of basement membrane thickness in childhood asthma has been performed in children with difficult asthma, that is, in children with persistent symptoms despite maximal conventional therapy (4). Moreover, a group of children with atopy without asthma, which, according to the authors, would be the most appropriate control group, was not included in that report. Therefore, to the best of our knowledge, this is the first study to provide a quantification of basement membrane thickening in children with mild/moderate asthma and to compare the results with those of two appropriate pediatric control groups, that is, a group of children with atopy but without asthma and a group of children with no atopy or asthma.

Our observation of an increased number of eosinophils in bronchial biopsies of children with asthma may appear to be in disagreement with previous studies (3, 20). Cokugras and coworkers (3) showed that eosinophilic inflammation was present only in 1 of 10 children with moderate asthma, and Payne and coworkers (20) found that the number of eosinophils in children with difficult asthma was not different from that of children without asthma. However, children examined in those studies had been treated with high doses of inhaled (3) or oral steroids (20), which may have reduced the number of eosinophils. In our study, only two children with asthma were treated with inhaled steroids; thus in the majority of children, we obtained objective measurements of inflammatory cells without the influence of antiinflammatory drugs. The eosinophilic inflammation observed in our study is in keeping with the pioneer observation of Cutz and coworkers, who described a prominent eosinophilia in two endobronchial biopsies and two autopsy samples of children with asthma (2). Moreover, previous studies performed in bronchoalveolar lavage and induced sputum of children with asthma reported an increased number of eosinophils, which was related to the degree of bronchial hyperresponsiveness (21, 22). More recently, analysis of exhaled breath condensate confirmed the presence of an airway inflammatory process in childhood asthma (15, 23).

In this report, airway eosinophilia and, even if to a lesser extent, also basement membrane thickening were already present in children with atopy without asthma. The relationship between these pathologic changes, atopy, and asthma symptoms is difficult to establish, especially in children. Indeed, early allergic sensitization seems to play an important role in the development of persistent asthma in the first years of life (24). It can be hypothesized that airway inflammation and remodeling are early lesions that may occur even before the establishment of the disordered lung function characteristic of the disease. On the other hand, as not all children with atopy will eventually develop asthma (25, 26), it is also plausible that these pathologic lesions are not directly related to functional abnormalities. This hypothesis is consistent with the findings of previous studies that reported that basement membrane thickening and airway eosinophilia are present in adults with atopy without asthma (27–30).

One generally accepted hypothesis is that in asthma, airway remodeling is dependent on the prior development of chronic inflammation. Our observation of the presence of both thickening of basement membrane and airway eosinophilia in children with mild asthma suggests that remodeling processes begin early in the course of the disease and most likely occur in parallel with the establishment of the chronic inflammation rather than sequential to it.

To assess the role of TGF-ß1 in modulating the pathways leading to airway remodeling and inflammation, we examined the expression of this cytokine and its receptors in children with asthma. TGF-ß1 is a pleiotropic cytokine that can exert both profibrotic and antiinflammatory activities. The increased expression of TGF-ß1 observed in adults with asthma (7–9) has been traditionally related to tissue repairing processes occurring in the airways damaged by inflammatory cells. It has been hypothesized that the persistent activity of TGF-ß1, induced by chronic inflammation, might have detrimental consequences such as subepithelial fibrosis and airway remodeling (5). However, other studies have demonstrated that this cytokine may have antiinflammatory activities as well (10, 11), probably through the induction of apoptosis of inflammatory cells, particularly eosinophils (31). In our study, the expression of TGF-ß1 was similar in the three groups of children examined, whereas the expression of TGFß-RII was decreased in children with asthma as compared with both children with atopy and children who were control subjects. These findings suggest that TGF-ß1 signaling may be downregulated in childhood asthma and therefore may be unable to exert its antiinflammatory activity. This hypothesis is supported by the negative correlation observed between the number of TGFß-RII+ cells and the number of eosinophils in children with asthma. Conversely, neither TGF-ß1 nor its receptors were correlated with basement membrane thickness, suggesting that the profibrotic activity of this cytokine does not contribute to airway remodeling in childhood asthma.

Interestingly, in our population of children, the downregulation of TGFß-RII expression was the only pathologic feature that was able to differentiate children with asthma from children with atopy without asthma, despite the presence of a similar eosinophilia and a similar basement membrane thickening in the two groups of children. These findings suggest a possible role for the impaired TGF-ß signaling in the clinical manifestations of asthma in childhood.

A potential weakness of this study is that all children underwent bronchoscopy for specific clinical indications other than asthma (recurrent pneumonia, persistent atelectasis, chronic cough, and stridor) (13, 14), and the presence of these pathologic conditions, particularly pneumonia, could have influenced the results. However, because these conditions were equally distributed in children with asthma, children with atopy, and children who were control subjects, we feel rather confident that our observation of the presence of pathologic lesions in children with atopy and asthma but not in normal control subjects is valid. Moreover, biopsies from children undergoing bronchoscopy for clinical indications other than asthma are the only specimens allowing direct examination of airway pathology in children with mild asthma, which would be otherwise impossible for ethical reasons (32).

Another limitation of our report is the low power of the study because of the small number of subjects in each group. However, this is a common problem in biopsy studies, especially in children, in whom invasive maneuvers are more problematic. Even if only multicenter studies collecting high numbers of biopsies could overcome these difficulties, we believe that our study provides preliminary data that could prove useful for the design of future research in this field.

Finally, we should acknowledge that because our population included very young children, we performed only one biopsy per child, thus introducing a possible sample error. Despite all of these limitations, we believe that studies on bronchial biopsies provide a unique opportunity to investigate airway inflammation and remodeling in childhood asthma.

In conclusion, this study shows that airway eosinophilia and basement membrane thickening, which are the pathologic features characteristic of adulthood asthma, are already present in children with mild asthma and even in children with atopy without asthma. Moreover, we found that in children with asthma, but not in children with atopy without asthma, there is a downregulation of TGFß-RII.


   Acknowledgments
 
The authors thank Dr. Cristina Panizzolo for helping with the clinical selection of patients and Mrs. Elisabetta Baliello and Giuseppa Castriciano for assistance with staining the biopsies for TGF-ß.


   FOOTNOTES
 
Supported by the Ministry of University and Research.

Received in original form May 14, 2003; accepted in final form July 26, 2003


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Mckay OC, Hogg JC. The contribution of airway structure to early childhood asthma. Med J Aust 2002;177:S45–S47.
  2. Cutz E, Levison H, Cooper DM. Ultrastructure of airways in children with asthma. Histopathology 1978;2:407–421.[Medline]
  3. Cokugras H, Akcakaya N, Seckin I, Camcioglu Y, Sarimurat N, Aksoy F. Ultrastructural examination of bronchial biopsy specimens from children with moderate asthma. Thorax 2001;56:25–29.[Abstract/Free Full Text]
  4. Payne DNR, Rogers AV, Adelroth E, Bandi V, Guntupalli KK, Bush A, Jeffery PK. Early thickening of the reticular basement membrane in children with difficult asthma. Am J Respir Crit Care Med 2003;167:78–82.[Abstract/Free Full Text]
  5. Nakao A. Is TGF-ß1 the key to suppression of human asthma? Trends Immunol 2001;22:115–118.[CrossRef][Medline]
  6. Lawrence DA. Transforming growth factor-ß: a general review. Eur Cytokine Netw 1996;7:363–374.[Medline]
  7. Vignola AM, Chanez P, Chiappara G, Merendino A, Pace E, Rizzo A, La Rocca AM, Bellia V, Bonsignore G, Bousquet J. Transforming growth factor-ß expression in mucosal biopsies in asthma and chronic bronchitis. Am J Respir Crit Care Med 1997;156:591–599.[Abstract/Free Full Text]
  8. Redington AE, Madden J, Frew AJ, Djukanovic R, Roche WR, Holgate ST, Howarth TH. Transforming growth factor-ß1 in asthma. Am J Respir Crit Care Med 1997;156:642–647.[Abstract/Free Full Text]
  9. Minshall EM, Leung DYM, Martin RJ, Song YL, Cameron L, Ernst P, Hamid Q. Eosinophil-associated TGF-ß1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol 1997;17:326–333.[Abstract/Free Full Text]
  10. Haneda K, Sano K, Tamura G, Shirota H, Ohkawara Y, Sato T, Habu S, Shirato K. Transforming growth factor-beta secreted from CD4(+) T cells ameliorates antigen-induced eosinophilic inflammation: a novel high-dose tolerance in the trachea. Am J Respir Cell Mol Biol 1999;21:268–274.[Abstract/Free Full Text]
  11. Hansen G, McIntire JJ, Yeung VP, Berry G, Thorbecke GJ, Chen L, DeKruyff RH, Umetsu DT. CD4(+) T helper cells engineered to produce latent TGF-beta1 reverse allergen-induced airway hyperreactivity and inflammation. J Clin Invest 2000;105:61–70.[Medline]
  12. Barbato A, Turato G, Bazzan E, Baraldo S, Tura M, Panizzolo C, Zuin R, Calabrese F, Beghé B, Maestrelli P, et al. Cellular and structural changes in bronchial biopsies of children with asthma. American Thoracic Society 2003 International Conference, May 16–21 Seattle, USA. Am J Respir Crit Care Med 2003;167:A452.
  13. Green CG, Eisenberg J, Leong A, Nathanson I, Schnapf BM, Wood RE. Flexible endoscopy of pediatric airway. Am Rev Respir Dis 1992;145:233–235.[Medline]
  14. Barbato A, Magarotto M, Crivellaro M, Novello A Jr, Cracco A, de Blic J, Scheinmann P, Warner JO, Zach M. Use of pediatric broncoscope, flexible and rigid, in 51 European centres. Eur Respir J 1997;10:1761–1766.[Abstract]
  15. Shahid SK, Kharitonov SA, Wilson NM, Bush A, Barnes PJ. Increased interleukin-4 and decreased Interferon-{gamma} in exhaled breath condensate of children with asthma. Am J Respir Crit Care Med 2002;165:1290–1293.[Abstract/Free Full Text]
  16. Polgar G, Promadhat V. Pulmonary function testing in children: techniques and standards. Philadelphia: W.B. Saunders; 1971.
  17. Barbato A, Panizzolo C, Gheno M, Sainati L, Favero E, Faggian D, Giusti F, Pesscolderungg L, La Rosa M. Bronchoalveolar lavage in asthmatic children: evidence of neutrophil activation in mild-to-moderate persistent asthma. Pediatr Allergy Immunol 2001;12:73–77.[CrossRef][Medline]
  18. Saetta M, Di Stefano A, Maestrelli P, Turato G, Mapp CE, Pieno M, Zancuoghi G, Del Prete G, Fabbri LM. Airway eosinophilia and expression of Interleukin-5 protein in asthma and in exacerbations of chronic bronchitis. Clin Exp Allergy 1996;26:766–774.[CrossRef][Medline]
  19. Di Stefano A, Turato G, Maestrelli P, Mapp CE, Ruggieri MP, Roggeri A, Boschetto P, Fabbri LM, Saetta M. Airflow limitation in chronic bronchitis is associated with T-lymphocyte and macrophage infiltration of the bronchial mucosa. Am J Respir Crit Care Med 1996;153:629–632.[Abstract]
  20. Payne DNR, Adcock IM, Wilson NM, Oates T, Scallan M, Bush A. Relationship between exhaled nitric oxide and mucosal eosinophilic inflammation in children with difficult asthma, after treatment with oral prednisolone. Am J Respir Crit Care Med 2001;164:1376–1381.[Abstract/Free Full Text]
  21. Ferguson AC, Whitelaw M, Brown H. Correlation of bronchial eosinophil and mast cell activation with bronchial hyperresponsiveness in children with asthma. J Allergy Clin Immunol 1992;90:609–613.[CrossRef][Medline]
  22. Twaddell SH, Gibson PG, Carty K, Woolley KL, Henry RL. Assessment of airway inflammation in children with acute asthma using induced sputum. Eur Respir J 1996;9:2104–2108.[Abstract]
  23. Csoma Z, Kharitonov SA, Balint B, Bush A, Wilson NM, Barnes PJ. Increased leukotrienes in exhaled breath condensate in childhood asthma. Am J Respir Crit Care Med 2002;166:1345–1349.[Abstract/Free Full Text]
  24. Martinez FD. Development of wheezing disorders and asthma in preschool children. Pediatrics 2002;109:362–367.[Abstract/Free Full Text]
  25. Martinez FD, Wright AN, Taussing LM, Holberg KJ, Halonen M, Morgan WJ. Asthma and wheezing in the first six years of life. N Engl J Med 1995;332:133–138.[Abstract/Free Full Text]
  26. Taussing LM, Wright AN, Holberg KJ, Halonen M, Morgan WJ, Martinez FD. Tucson Children's Respiratory Study: 1980 to present. J Allergy Clin Immunol 2003;111:661–675.[CrossRef][Medline]
  27. Djukanovic R, Lai CKW, Wilson JW, Britten KM, Wilson SJ, Roche WR, Howarth PH, Holgate ST. Bronchial mucosal manifestations of atopy: a comparison of markers of inflammation between atopic asthmatics, atopic non asthmatics and healthy controls. Eur Respir J 1992;5:538–544.[Abstract]
  28. Shaver JR, O'Connor JJ, Pollice M, Cho SK, Kane GC, Fish JE, Peters SP. Pulmonary inflammation after segmental ragweed challenge in allergic asthmatic and nonasthmatic subjects. Am J Respir Crit Care Med 1995;152:1189–1197.[Abstract]
  29. Crimi E, Milanese M, Oddera S, Mereu C, Rossi GA, Riccio A, Canonica GW, Brusasco V. Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis. J Appl Physiol 2001;91:1029–1034.[Abstract/Free Full Text]
  30. Milanese M, Crimi E, Scordamaglia A, Riccio A, Pellegrino R, Canonica GW, Brusasco V. On the functional consequences of bronchial basement membrane thickening. J Appl Physiol 2001;91:1035–1040.[Abstract/Free Full Text]
  31. Alam R, Forsythe P, Stafford S, Fukuda Y. Transforming growth factor beta abrogates the effects of hematopoietins on eosinophils and induce their apoptosis. J Exp Med 1994;179:1041–1045.[Abstract/Free Full Text]
  32. Bush A, de Jongste JC, Carlsen K-H. Ultrastructural examination of bronchial specimens from children with moderate asthma. Thorax 2003;58:187–188.[Free Full Text]



This article has been cited by other articles:


Home page
 Ther Adv Respir DisHome page
M. M. del Giudice, A. Pezzulo, C. Capristo, E. Alterio, S. Caggiano, D. de Benedictis, and A. F. Capristo
Leukotriene modifiers in the treatment of asthma in children
Therapeutic Advances in Respiratory Disease, October 1, 2009; 3(5): 245 - 251.
[Abstract] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
S. Saglani, S. A. Mathie, L. G. Gregory, M. J. Bell, A. Bush, and C. M. Lloyd
Pathophysiological Features of Asthma Develop in Parallel in House Dust Mite-Exposed Neonatal Mice
Am. J. Respir. Cell Mol. Biol., September 1, 2009; 41(3): 281 - 289.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
G. Turato, A. Barbato, S. Baraldo, M. E. Zanin, E. Bazzan, K. Lokar-Oliani, F. Calabrese, C. Panizzolo, D. Snijders, P. Maestrelli, et al.
Nonatopic Children with Multitrigger Wheezing Have Airway Pathology Comparable to Atopic Asthma
Am. J. Respir. Crit. Care Med., September 1, 2008; 178(5): 476 - 482.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
T. N Hilliard, N. Regamey, J. K Shute, A. G Nicholson, E. W F W Alton, A. Bush, and J. C Davies
Airway remodelling in children with cystic fibrosis
Thorax, December 1, 2007; 62(12): 1074 - 1080.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. Saglani, D. N. Payne, J. Zhu, Z. Wang, A. G. Nicholson, A. Bush, and P. K. Jeffery
Early Detection of Airway Wall Remodeling and Eosinophilic Inflammation in Preschool Wheezers
Am. J. Respir. Crit. Care Med., November 1, 2007; 176(9): 858 - 864.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
C. M. Swaisgood, M. A. Aronica, S. Swaidani, and E. F. Plow
Plasminogen Is an Important Regulator in the Pathogenesis of a Murine Model of Asthma
Am. J. Respir. Crit. Care Med., August 15, 2007; 176(4): 333 - 342.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
A. A. Colin and T. Ali-Dinar
Endobronchial Biopsy in Childhood
Chest, June 1, 2007; 131(6): 1626 - 1627.
[Full Text] [PDF]

Home page
 ThoraxHome page
G. Turato, S. Baraldo, R. Zuin, and M. Saetta
The laws of attraction: chemokines, neutrophils and eosinophils in severe exacerbations of asthma
Thorax, June 1, 2007; 62(6): 465 - 466.
[Full Text] [PDF]

Home page
 ChestHome page
N. Regamey, T. N. Hilliard, S. Saglani, J. Zhu, M. Scallan, I. M. Balfour-Lynn, M. Rosenthal, P. K. Jeffery, E. W. F. W. Alton, A. Bush, et al.
Quality, Size, and Composition of Pediatric Endobronchial Biopsies in Cystic Fibrosis
Chest, June 1, 2007; 131(6): 1710 - 1717.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Cell Mol. Bio.Home page
N. R. Locke, S. G. Royce, J. S. Wainewright, C. S. Samuel, and M. L. Tang
Comparison of Airway Remodeling in Acute, Subacute, and Chronic Models of Allergic Airways Disease
Am. J. Respir. Cell Mol. Biol., May 1, 2007; 36(5): 625 - 632.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
A. Shibata, T. Katsunuma, M. Tomikawa, A. Tan, K. Yuki, K. Akashi, and Y. Eto
Increased Leukotriene E4 in the Exhaled Breath Condensate of Children With Mild Asthma
Chest, December 1, 2006; 130(6): 1718 - 1722.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
A. Barbato, G. Turato, S. Baraldo, E. Bazzan, F. Calabrese, C. Panizzolo, M. E. Zanin, R. Zuin, P. Maestrelli, L. M. Fabbri, et al.
Epithelial Damage and Angiogenesis in the Airways of Children with Asthma
Am. J. Respir. Crit. Care Med., November 1, 2006; 174(9): 975 - 981.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
S. Saglani, C. Molyneux, H. Gong, A. Rogers, K. Malmstrom, A. Pelkonen, M. Makela, E. Adelroth, A. Bush, D. N. R. Payne, et al.
Ultrastructure of the reticular basement membrane in asthmatic adults, children and infants
Eur. Respir. J., September 1, 2006; 28(3): 505 - 512.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
A. Bush
Update in pediatrics 2005.
Am. J. Respir. Crit. Care Med., March 15, 2006; 173(6): 585 - 592.
[Full Text] [PDF]

Home page
 ThoraxHome page
Spoken sessions
Thorax, December 1, 2005; 60(suppl_2): ii4 - ii52.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. W. Pijnenburg, E. M. Bakker, W. C. Hop, and J. C. De Jongste
Titrating Steroids on Exhaled Nitric Oxide in Children with Asthma: A Randomized Controlled Trial
Am. J. Respir. Crit. Care Med., October 1, 2005; 172(7): 831 - 836.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
C. E. Mapp, P. Boschetto, P. Maestrelli, and L. M. Fabbri
Occupational Asthma
Am. J. Respir. Crit. Care Med., August 1, 2005; 172(3): 280 - 305.
[Abstract] [Full Text] [PDF]

Home page
 NEJMHome page
I. Berti, G. Longo, S. Visintin, B. A. Chowdhury, C. R. Jenkins, G. B. Marks, H. K. Reddel, D. K.C. Lee, A. Raghupathy, B. Brashier, et al.
Treatment of Mild Asthma
N. Engl. J. Med., July 28, 2005; 353(4): 424 - 427.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. J. Szefler
Airway Remodeling: Therapeutic Target or Not?
Am. J. Respir. Crit. Care Med., April 1, 2005; 171(7): 672 - 673.
[Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
S. Saglani, K. Malmstrom, A. S. Pelkonen, L. P. Malmberg, H. Lindahl, M. Kajosaari, M. Turpeinen, A. V. Rogers, D. N. Payne, A. Bush, et al.
Airway Remodeling and Inflammation in Symptomatic Infants with Reversible Airflow Obstruction
Am. J. Respir. Crit. Care Med., April 1, 2005; 171(7): 722 - 727.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
H. Bisgaard, S. Zielen, M. L. Garcia-Garcia, S. L. Johnston, L. Gilles, J. Menten, C. A. Tozzi, and P. Polos
Montelukast Reduces Asthma Exacerbations in 2- to 5-Year-Old Children with Intermittent Asthma
Am. J. Respir. Crit. Care Med., February 15, 2005; 171(4): 315 - 322.
[Abstract] [Full Text] [PDF]

Home page
 Proc Am Thorac SocHome page
P. K. Jeffery
Remodeling and Inflammation of Bronchi in Asthma and Chronic Obstructive Pulmonary Disease
Proceedings of the ATS, November 1, 2004; 1(3): 176 - 183.
[Abstract] [Full Text] [PDF]

Home page
 ChestHome page
A. F. Gelb, A. Schein, E. Nussbaum, C. M. Shinar, Y. Aelony, H. Aharonian, and N. Zamel
Risk Factors for Near-Fatal Asthma
Chest, October 1, 2004; 126(4): 1138 - 1146.
[Abstract] [Full Text] [PDF]

Home page
 ThoraxHome page
D N R Payne, Y Qiu, J Zhu, L Peachey, M Scallan, A Bush, and P K Jeffery
Airway inflammation in children with difficult asthma: relationships with airflow limitation and persistent symptoms
Thorax, October 1, 2004; 59(10): 862 - 869.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
A. F. Gelb, C. F. Taylor, E. Nussbaum, C. Gutierrez, A. Schein, C. M. Shinar, M. J. Schein, J. D. Epstein, and N. Zamel
Alveolar and Airway Sites of Nitric Oxide Inflammation in Treated Asthma
Am. J. Respir. Crit. Care Med., October 1, 2004; 170(7): 737 - 741.
[Abstract] [Full Text] [PDF]

Home page
 Eur Respir JHome page
P.J.F.M. Merkus, W. van Pelt, J.C. van Houwelingen, L.E.M. van Essen-Zandvliet, E.J. Duiverman, K.F. Kerrebijn, and P.H. Quanjer
Inhaled corticosteroids and growth of airway function in asthmatic children
Eur. Respir. J., June 1, 2004; 23(6): 861 - 868.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
M. J. Tobin
Pediatrics, Surfactant, and Cystic Fibrosis in AJRCCM 2003
Am. J. Respir. Crit. Care Med., January 15, 2004; 169(2): 277 - 287.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
200305-650OCv1
168/7/798    most recent
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Barbato, A.
Right arrow Articles by Saetta, M.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Barbato, A.
Right arrow Articles by Saetta, M.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
Copyright © 2003 American Thoracic Society