Reticular Basement Membrane Research Articles

Allergic rhinitis and asthma: inflammation in a one-airway condition

BackgroundAllergic rhinitis and asthma are conditions of airway inflammation that often coexist.DiscussionIn susceptible individuals, exposure of the nose and lungs to allergen elicits early phase and late phase responses. Contact with antigen by mast cells results in their degranulation, the release of selected mediators, and the subsequent recruitment of other inflammatory cell phenotypes. Additional proinflammatory mediators are released, including histamine, prostaglandins, cysteinyl leukotrienes, proteases, and a variety of cytokines, chemokines, and growth factors. Nasal biopsies in allergic rhinitis demonstrate accumulations of mast cells, eosinophils, and basophils in the epithelium and accumulations of eosinophils in the deeper subepithelium (that is, lamina propria). Examination of bronchial tissue, even in mild asthma, shows lymphocytic inflammation enriched by eosinophils. In severe asthma, the predominant pattern of inflammation changes, with increases in the numbers of neutrophils and, in many, an extension of the changes to involve smaller airways (that is, bronchioli). Structural alterations (that is, remodeling) of bronchi in mild asthma include epithelial fragility and thickening of its reticular basement membrane. With increasing severity of asthma there may be increases in airway smooth muscle mass, vascularity, interstitial collagen, and mucus-secreting glands. Remodeling in the nose is less extensive than that of the lower airways, but the epithelial reticular basement membrane may be slightly but significantly thickened.ConclusionInflammation is a key feature of both allergic rhinitis and asthma. There are therefore potential benefits for application of anti-inflammatory strategies that target both these anatomic sites.

Mast cell-mediated airway remodelling

Summary Airway structural changes (remodelling) in asthma include increased smooth muscle mass, mucus gland hypertrophy, deposition of extracellular matrix components, thickening of reticular basement membrane, and angiogenesis. The extent of remodelling correlates with severity of asthma, and since patients with extensive remodelling may be resistant to steroids therapy, prevention of airway remodelling is a promising therapeutic strategy for curing patients with severe asthma. Mast cells play a pivotal role in allergic inflammatory diseases including asthma and rhinitis. Both early-phase mediators such as tryptase and chymase and late-phase mediators such as cytokines released by mast cells are capable of modulating airway smooth muscle cell function and inducing goblet cell hyperplasia. Nasal remodelling in patients with rhinitis seems far less extensive than that which occurs in bronchi of asthmatic patients. Because cytokine production by smooth muscle cells may partly explain the differences in remodelling at these two sites, further investigation of the interaction between human mast cells and airway smooth muscle cells is required to identify new therapeutic strategies for reducing airway remodelling in asthma.

Ultrastructure of the reticular basement membrane in asthmatic adults, children and infants

Reticular basement membrane (RBM) thickening in asthma is considered to be the result of subepithelial fibrosis. Thus, the RBM in asthma should contain an excess of fibrils identified as interstitial collagen and the ratio of fibril to matrix should be increased above normal levels. Electron micrographs of the RBM were compared with those of interstitial collagen deeper in the bronchial wall using endobronchial biopsy specimens from adult asthmatics (aged 18-41 yrs (n = 10)), children with difficult asthma (aged 6-16 yrs (n = 10)), wheezy infants with reversible airflow limitation (aged 0.3-2 yrs (n = 10)) and age-matched nonasthmatic controls: 10 adults, nine children and nine symptomatic infants with normal lung function. Fibrils in the RBM were significantly thinner (median (range) width 39 (30-52) nm versus 59 (48-73) nm), and fewer fibrils were banded than in the interstitial collagen (ratio of banded to non-banded fibrils 0.08 (0-0.17) versus 0.22 (0-1.3)). The ratio of fibrils to matrix in the thickened RBM of asthmatics did not differ from that of their respective controls (1.34 (0.63-2.49) versus 1.18 (0.31-2.6)). The ratio of fibril to matrix in the thickened reticular basement membrane of asthmatics is normal, and, contrary to what is expected in fibrosis, the fibrils do not resemble those of interstitial collagen.

Exhaled breath condensate cysteinyl leukotrienes and airway remodeling in childhood asthma: a pilot study

BackgroundIt has been suggested that cysteinyl leukotrienes (cysLTs) play an important role in airway remodeling. Previous reports have indicated that cysLTs augment human airway smooth muscle cell proliferation. Recently, cysLTs have been measured in exhaled breath condensate (EBC). The aim of this study was to evaluate the relationship between cysLTs in EBC and another marker of airway remodeling, reticular basement membrane (RBM) thickening, in endobronchial biopsies in children.Methods29 children, aged 4–15 years, with moderate to severe persistent asthma, who underwent bronchoscopy as part of their clinical assessment, were included. Subjects underwent spirometry and EBC collection for cysLTs analysis, followed by bronchoscopy and endobronchial biopsy within 24 hours.ResultsEBC cysLTs were significantly lower in asthmatic children who were treated with montelukast than in those who were not (median (interquartile range) 36.62 (22.60–101.05) versus 249.1 (74.21–526.36) pg/ml, p = 0.004). There was a significant relationship between EBC cysLTs and RBM thickness in the subgroup of children who were not treated with montelukast (n = 13, r = 0.75, p = 0.003).ConclusionEBC cysLTs appear to be associated with RBM thickening in asthma.

Reply

To the Editor: In their correspondence, Saglani et al1Saglani S. Bush A. Payne D.N. The difference between groups and individuals.J Allergy Clin Immunol. 2006; 117: 955Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar argue that our bronchial wall thickening (BWT) score is a poor predictor of reticular basement membrane (RBM) thickness. We did not intend to replace bronchial biopsy by high-resolution computed tomography (HRCT) scan to evaluate airway inflammation/remodeling. Our messages are that we need to develop noninvasive techniques to evaluate such abnormalities and that HRCT scan may be one of them. The relationship we found between biopsy and BWT score was not strong, and we wrote that “the corresponding coefficient of determination of the change in BWT score explained by change of RBM thickening was 11%.” This was probably related to a lack of power, and certainly we need more patients and more accuracy signs with new generations of computed tomography scan. Saglani et al1Saglani S. Bush A. Payne D.N. The difference between groups and individuals.J Allergy Clin Immunol. 2006; 117: 955Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar state that in the figure from our article, patients with the same BWT score may have different values for RBM. This is not surprising, because parameters contributing to BWT score are not limited to RBM thickness, and conversely, RBM thickening is not the only character of airway remodeling. The author's group has shown that even in children with severe asthma, RBM may be not thickened.2Payne D.N. Rogers A.V. Adelroth E. Bandi V. Guntupalli K.K. Bush A. et al.Early thickening of the reticular basement membrane in children with difficult asthma.Am J Respir Crit Care Med. 2003; 167: 78-82Crossref PubMed Scopus (430) Google Scholar We do not assume that BWT score on HRCT scan is a surrogate marker of RBM thickness, but it might be used as a noninvasive approach to examining airway structural changes. Again, we need to develop such procedures even if there is no extremely strong relationship.

Links between allergic rhinitis and asthma

航线的过敏疾病，包括季节的鼻炎，长期的长期的鼻炎和气喘，作为航线 mucosa 的煽动性的混乱被认出，但是在煽动性的反应的地点和疾病的临床的表明不同。气喘和过敏鼻炎经常在一样的病人共存并且被认为分享普通预先安排与环境影响交往的基因因素。两疾病特别地在西洋化的国家在最近的十年在流行增加了。这增加过时的人或物大部分归因于象暴露那样的环境因素到天线污染物质，和早年生活事件，包括到可能影响 IgEproduction 的传染代理人的暴露的度，自从在基因水池的一个重要变化有不够的时间。

Tissue fibrocytes in patients with mild asthma: A possible link to thickness of reticular basement membrane?

BackgroundMyofibroblasts, proposed as being derived from circulating fibrocytes, are considered to be important cells in thickening of the basement membrane in patients with asthma. We have studied the correlation of tissue fibrocyte levels to basement membrane thickness and the presence of fibrocytes in bronchoalveolar lavage fluid (BALF) in steroid-naive patients with mild asthma and controls.MethodsPatients with mild asthma (n = 9) were recruited and divided into two categories based on whether or not fibroblast-like cells could be established from BALF. Non-asthmatic healthy subjects (n = 5) were used as controls. Colocalization of the fibrocyte markers CD34, CD45RO, procollagen I, and α-smooth muscle actin (α-SMA) were identified in bronchial biopsies from patients and controls by confocal microscopy. Kruskall-Wallis method was used to calculate statistical significance and Spearman coefficient of rank correlation was used to assess the degree of association.ResultsIn patients with BALF fibroblasts, a 14-fold increase of tissue cells expressing CD34/CD45RO/α-SMA and a 16-fold increase of tissue cells expressing CD34/procollagen I was observed when compared to controls (p < 0.05). In contrast, patients without BALF fibroblasts displayed a 2-fold increase when compared to controls (p < 0.05). Fibrocytes were localized close to the basement membrane which was significantly thicker in patients with BALF fibroblasts when compared to the other two groups of subjects. Furthermore, basement membrane thickness could be correlated to the number of fibrocytes in tissue (r = 0.711). Fibroblasts-like cells were cultured from BALF where 17.6% of these cells expressed CD34, CD45RO and α-SMA.ConclusionThese findings indicate a correlation between recruited fibrocytes in tissue and thickness of basement membrane. Fibroblast progenitor cells may therefore be important in airway remodeling in steroid-naive patients with mild asthma.

Can HRCT be used as a marker of airway remodelling in children with difficult asthma?

BackgroundWhole airway wall thickening on high resolution computed tomography (HRCT) is reported to parallel thickening of the bronchial epithelial reticular basement membrane (RBM) in adult asthmatics. A similar relationship in children with difficult asthma (DA), in whom RBM thickening is a known feature, may allow the use of HRCT as a non-invasive marker of airway remodelling. We evaluated this relationship in children with DA.Methods27 children (median age 10.5 [range 4.1–16.7] years) with DA, underwent endobronchial biopsy from the right lower lobe and HRCT less than 4 months apart. HRCTs were assessed for bronchial wall thickening (BWT) of the right lower lobe using semi-quantitative and quantitative scoring techniques. The semi-quantitative score (grade 0–4) was an overall assessment of BWT of all clearly identifiable airways in HRCT scans. The quantitative score (BWT %; defined as [airway outer diameter – airway lumen diameter]/airway outer diameter ×100) was the average score of all airways visible and calculated using electronic endpoint callipers. RBM thickness in endobronchial biopsies was measured using image analysis. 23/27 subjects performed spirometry and the relationships between RBM thickness and BWT with airflow obstruction evaluated.ResultsMedian RBM thickness in endobronchial biopsies was 6.7(range 4.6 – 10.0) μm. Median qualitative score for BWT of the right lower lobe was 1(range 0 – 1.5) and quantitative score was 54.3 (range 48.2 – 65.6)%. There was no relationship between RBM thickness and BWT in the right lower lobe using either scoring technique. No relationship was found between FEV1 and BWT or RBM thickness.ConclusionAlthough a relationship between RBM thickness and BWT on HRCT has been found in adults with asthma, this relationship does not appear to hold true in children with DA.

Correlation of reticular basement membrane thickness and airway wall remolding in asthma patients

To investigate the correlation between the reticular basement membrane thickness and the airway wall remolding in asthma patients. Lung tissues were obtained from 5 patients who died from asthma, 3 males and 2 females, aged 45 +/- 16 (fatal asthma group), 5 asthmatics who died of diseases unrelated to asthma, 3 males and 2 females, aged 47 +/- 13, (non-fatal asthma group), and 5 dead patients without asthma, 3 males and 2 females, aged 24 +/- 14 (control group) to select 41, 38, and 43 transverse sections of tracheae respectively. The samples of tracheae were divided into cartilaginous and membranous airways by light microscopy (x100). The thickness of reticular basement membrane and the dimensions of the airway wall, including the smooth muscle area, submucosal gland area, inner and outer wall areas, and lumen area were measured. The correlations of reticular basement membrane thickness with the airway changes were analyzed. The reticular basement membrane was significantly thicker in both cartilaginous and membranous airways in the fatal and non-fatal asthma groups than in the control group (all P < 0.05). The submucosal gland area of the fatal asthma group was significantly larger than those of the non-fatal asthma group and control group (both P < 0.05). The inner wall area of the cartilaginous airway of the fatal asthma group was significantly larger than that of the non-fatal asthma group (P < 0.05); however, the inner wall area of the membranous airway of the fatal asthma group was not significantly different from that of the non-fatal asthma group. The outer wall areas of cartilaginous and membranous airways of the fatal asthma group were both significantly larger than those of the other 2 groups (all P < 0.05). There was no significant difference in the lumen areas of cartilaginous and membranous airways between the fatal and non-fatal asthma groups. The reticular basement membrane thickness was correlated with the smooth muscle area (P < 0.05), submucosal gland area (P < 0.05), and inner wall area (P < 0.01) of the corresponding bronchi in regard to the cartilaginous airway; and was correlated with the smooth muscle area (P < 0.05) and inner wall area (P < 0.01) of the corresponding bronchi in regard to the membranous airway, but was not correlated with the airway size, lumen area, and outer wall area in regard to the 2 kinds of airways. The reticular basement membrane thickness of central airway reflects the airway remolding of the central airway and the changes of smooth muscle and inner wall of the peripheral airway. It is worthwhile to do end bronchial biopsy to measure the reticular basement membrane thickness so as to assess the pathology of the airway and to conduct long-term follow-up among the asthma patients.

Investigation of young children with severe recurrent wheeze: any clinical benefit?

The management of young children with severe recurrent wheeze is difficult because symptoms are often refractory to conventional asthma therapy and other diagnoses must be excluded. The present authors aimed to evaluate the outcome of detailed, invasive investigations in such patients. Children aged between 3 months and 5 yrs with severe recurrent wheezing, who had been referred to a tertiary centre, underwent a protocol of investigations including a chest computed tomography scan, blood tests, nasal ciliary brushings, fibreoptic bronchoscopy, bronchoalveolar lavage (BAL), endobronchial biopsy and passage of an oesophageal pH probe. A total of 47 children (25 males) with a median age of 26 (range 5-58) months underwent investigation. Of these, 39% were atopic, two-thirds had evidence of gastro-oesophageal reflux and 37 out of 47 had an abnormal bronchoscopy. Findings included structural abnormalities (13 out of 37), excessive mucus (20 out of 37) and macroscopic inflammation (10 out of 37). BAL revealed bacterial growth in 12 out of 44 (27%) patients. Good quality endobronchial biopsies were obtained from 36 out of 46 (78%) patients; of these, 44% had tissue eosinophilia and 28% had a thickened reticular basement membrane. Additional investigations (including bronchoscopy) in young children with severe wheeze may help to identify positive diagnoses and provide information to support a clinical diagnosis of asthma. This hypothesis-generating work should form the basis of future interventional studies.

Inter‐relationships between airway inflammation, reticular basement membrane thickening and bronchial hyper‐reactivity to methacholine in asthma; a systematic bronchoalveolar lavage and airway biopsy analysis

Asthma is accepted as a disease characterized by airway inflammation, with evidence that airway structural changes, or 'remodelling' occurs. There are few studies relating airway physiology, inflammation and remodelling, however. We have carried out a study of inter-relationships between airway inflammation, airway remodelling, reticular basement membrane (RBM) thickening, and bronchial hyper-reactivity (BHR), before and after high-dose inhaled corticosteroid (fluticasone propionate 750 microg b.d.), in a group of relatively mild but symptomatic, steroid naïve asthma patients. Double-blind, randomized, placebo-controlled, parallel group study of inhaled corticosteroid (ICS) in 35 asthmatics, with bronchoalveolar lavage (BAL) and airway endobronchial biopsy (EBB) for inflammatory cell profiles and EBB for airway remodelling carried out at baseline, 3 and 12 months. At baseline RBM thickening was related to BAL mast cells and EBB eosinophil counts. In turn baseline log EBB EG2 eosinophil count, log%BAL epithelial cells and log RBM thickness explained 55% of the variability in BHR. We provide new information that airway inflammation, remodelling, and BHR in asthma are inter-related and improved by ICS therapy. Our data potentially support the need for early and long-term intervention with ICS even in relatively mild asthmatics, and the need to further assess the potential merit of longitudinal BHR testing in management of some patients, as this may reflect both airway inflammation and remodelling.

A Descriptive Study of Small Airway Reticular Basement Membrane Thickening in Clinically Stable Lung Transplant Recipients

Chronic rejection functionally manifested by fixed airflow limitation, bronchiolitis obliterans syndrome (BOS), is a major problem for all lung allograft programs. The inclusion of a pre-BOS category (BOS(0 approximately p)) in the newly revised guidelines, recognizes the potential importance of early changes. We tested the hypothesis that small airway reticular basement membrane thickening exists even in clinically stable lung transplant recipients with some evidence of inflammation but who are BOS-free. A bronchoscopic study was performed on 30 clinically stable lung allograft recipients at >/=3 months post-allograft, who were BOS-free but with some evidence of airway inflammation indicated by a pathologic diagnosis of lymphocytic bronchiolitis or raised exhaled nitric oxide (NO). After baseline physiologic assessment, small airway reticular basement membrane (Rbm) thickening was quantified in transbronchial biopsy (TBB) using image analysis, with inflammation assessed by bronchoalveolar lavage (BAL) differential cell counts. Twenty-one patients had technically satisfactory measurements of Rbm thickness. We detected small airway Rbm thickening when compared with published data for control lung diseases. There was no correlation between Rbm thickening and lung function (forced expiratory volume in 1 second [FEV(1)] best post-operatively and Rbm r = -0.10, not significant). Our data suggest that airway remodeling can occur early in lung allografts and before development of airflow limitation and BOS. Longitudinal pathophysiologic studies are needed to elucidate potential relationships between airway inflammation, Rbm thickening and allograft failure. Airway biopsies would be of value in such studies.

Is a two‐week trial of oral prednisolone predictive of target lung function in pediatric asthma?

We used a 2-week trial of prednisolone to determine "target" lung function for subsequent asthma therapy. The aim of this study was to evaluate whether some children exceed their "target" forced expired volume in 1 sec (FEV1) on subsequent visits in the following year, and whether this is associated with particular clinical or pathological features. Children (aged 6-16 years) with difficult asthma underwent spirometry and exhaled nitric oxide (FE(NO)) measurements before and after 2 weeks of prednisolone 40 mg/day. At the end of the course, subepithelial eosinophils and reticular basement membrane thickness were assessed. The highest FEV1 obtained in a 1-year follow-up was compared with the poststeroid postbronchodilator ("target") FEV1. Four of 22 children (18%) demonstrated an increase of > 9% above their "target" FEV1 during follow-up. None of these children had been prescribed additional asthma medications. Three of 7 children with persistent airflow limitation (PAL; poststeroid postbronchodilator FEV1 < 80% predicted) recorded an FEV1 > 80% predicted during follow-up. The median (interquartile range) number of subepithelial eosinophils was significantly higher in children who exceeded their target FEV1 than in children who did not (12.4 (8.5-39.9) vs. 1.4 (0.0-4.8) cells/mm2, P = 0.018). In conclusion, a 2-week course of prednisolone is not necessarily predictive of "target" lung function. Definitions such as PAL should be regularly reviewed on individual basis.

Airway remodelling in asthma: models and supermodels?

Although currently anti-inflammatory treatments are effective for most of the 5 million patients treated in the UK they do not completely control symptoms, and a minority of asthmatics continue to experience severe debilitating disease [1]. Of note, although inhaled corticosteroids reduce the Th2type eosinophilic airway inflammation and airway hyperresponsiveness (AHR) that characterize asthma, they do not restore either variable to normal [2]. For this reason attention has been focused on structural changes in the asthmatic airway termed airway remodelling. These changes include epithelial damage and goblet cell hyperplasia [3], increased airway smooth muscle [4] and recruitment and activation of myofibroblasts [5]. Increased deposition of collagens and other extracellular matrix proteins such as tenascin and fibronectin occurs both in the reticular basement membrane (RBM) [6] and throughout the bronchial mucosa and this structural remodelling is accompanied by new blood vessel formation [7]. The clinical consequences of airway remodelling in asthma remain uncertain but contributions to AHR and fixed airflow obstruction have been suggested. Mathematical modelling predicts that airways with increased smooth muscle narrow to a much greater extent than airways with less smooth muscle volume for a given degree of circumferential smooth muscle shortening [8]. Asthmatic subjects show accelerated decline in lung function over time compared with non-asthmatic subjects, and this loss of lung function is more marked in asthmatic smokers [9, 10]. Although duration and severity of asthma are the most important risk factors for development of fixed obstruction the highest rate of loss of lung function is seen during the early course of the illness. Interestingly, remodelling changes are seen early in childhood and may even pre-date the onset of symptoms [11]. The impact of current anti-inflammatory treatment on remodelling is controversial. Although partial reversal of remodelling has been reported with inhaled corticosteroid treatment, responses are seen after prolonged therapy [12] and are not confirmed in all studies. The initial rapid improvement in AHR in asthma with inhaled corticosteroid treatment may be explained by reduction in airway inflammation [13], but additional improvements over many months may reflect changes in remodelling. Important questions about airway remodelling in asthma remain unanswered (see Fig. 1). These include:

Airway Remodeling and Inflammation in Symptomatic Infants with Reversible Airflow Obstruction

We hypothesized that the epithelial reticular basement membrane (RBM) thickening and eosinophilic inflammation characteristic of asthma would be present in symptomatic infants with reversible airflow obstruction. RBM thickness and numbers of inflammatory cells were determined in ultrathin sections of endobronchial biopsies obtained from 53 infants during clinical bronchoscopy for severe wheeze and/or cough. Group A: 16 infants with a median age of 12 months (range 3.4-26 months), with decreased specific airway conductance (sGaw) and bronchodilator reversibility; Group B: 22 infants with a median age of 12.4 months (5.1-25.9 months), with decreased sGaw but without bronchodilator reversibility; and Group C: 15 infants with a median age of 11.5 months (3.4-24.3 months) with normal sGaw. Additional comparisons were made with the following groups. Group D: 17 children, median age 10.3 years (6-16 years), with difficult asthma; Group E: 10 pediatric control subjects without asthma, median age 10 years (6-16 years); and Group F: nine adult normal, healthy control subjects, median age 27 years (21-42 years). There were no significant differences in RBM thickness or inflammatory cell number between the infant groups. RBM thickness was similar in the infants and Groups E and F. However, the RBM in all infant groups (Group A: median 4.3 microm [range 2.8-9.2 microm]; Group B: median 4.15 microm [range 2.7-5.8 microm]; Group C: median 3.8 microm [range 2.7-5.5 microm]) was significantly less thick than that in the older children with asthma (Group D: median 8.3 microm [range 5.3-12.7 microm]; p < 0.001). RBM thickening and the eosinophilic inflammation characteristic of asthma in older children and adults are not present in symptomatic infants with reversible airflow obstruction, even in the presence of atopy.

Benefit from anti-inflammatory treatment during clinical remission of atopic asthma

Subjects with atopic asthma often experience a disappearance of symptoms around puberty. However, airway inflammation and remodeling may persist. It is unknown whether those findings warrant prolonged anti-inflammatory treatment despite the absence of symptoms. In this study, we investigated whether a short course of combined anti-inflammatory treatment would, also in this specific patient population, diminish airway inflammation and/or remodeling. A double-blind, randomized placebo-controlled trial was conducted in 28 asymptomatic subjects with a history of atopic asthma, with established bronchial hyperresponsiveness to methacholine (MCh) as non-invasive indicator of ongoing airway pathology. Intervention consisted of the salmeterol/fluticasone propionate combination (SFC) product (50/250 microg bid via the Diskus inhaler) or placebo for 3 months. The change in lung function (FEV1), bronchial response to MCh and adenosine monophosphate (AMP), the fraction of nitric oxide in exhaled air (FENO) and quality of life (QOL) scores were measured. Also, bronchial biopsies were taken and cryo sections immunostained for eosinophils (major basic protein, MBP) and mast cells (tryptase and chymase) before and after treatment. The change in reticular basement membrane (RBM) thickness, one of the parameters of airway remodeling, was also determined. SFC treatment improved hyperresponsiveness to MCh (P = 0.014) as well as AMP (P = 0.011), and reduced FENO (P < 0.001) significantly as compared with placebo. Lung function tended to improve (NS). Furthermore, SFC treatment reduced tryptase in the subepithelium of bronchial biopsy specimens (P = 0.01), and slightly reduced RBM thickness (P = 0.05). However, eosinophils in (sub)epithelium were not significantly affected; neither were chymase levels, blood eosinophils or QOL scores. We found that 3 months of treatment with fluticasone propionate and salmeterol reduced airway hyperresponsiveness, FENO and tryptase density in the airway mucosa as markers of airway inflammation. MBP density in the airway mucosa and QOL were, however, unchanged. The clinical relevance of these findings, especially with respect to the long-term outcome, has not been determined yet.

Eosinophils in repair and remodelling

SummarySeveral studies in man suggest a role for the eosinophil in repair in remodelling. Skin biopsies taken at time intervals after allergen injection into human skin indicate that the formation of myofibroblast‐like cells and activation of fibroblasts, as shown by tenascin and procollagen‐1 production, may be partly under the control of infiltrating TGF‐β1+/IL‐13+ eosinophils. Studies involving the infusion of an anti‐IL‐5 monoclonal antibody to atopic subjects indicate that eosinophils are unlikely to be essential for the redness, swelling and induration characteristic of late‐phase allergic response but may play a role in repair/remodelling processes as shown by inhibition of tenascin deposition. Selective reduction of eosinophils by anti‐IL‐5 was also associated with a significant reduction in the up‐regulated expression of ECM proteins in the reticular basement membrane of asthmatics. Furthermore, this reduction in the expression of matrix proteins occurred over a relatively short time period and despite only partial eosinophil depletion. Taken together these data provide direct evidence of a causal association between eosinophils and ECM protein deposition in mild atopic asthma.

Reticular basement membrane thickening in airways of lung transplant recipients is not affected by inhaled corticosteroids

Chronic rejection is a major problem for all lung transplant programmes, which is functionally manifested by fixed airflow limitation, Bronchiolitis Obliterans Syndrome (BOS). The inclusion of a Pre-BOS category, BOS(0 approximately p), in newly revised guidelines, recognizes the potential importance of early changes. We have previously demonstrated reticular basement membrane (Rbm) thickening in clinically stable lung transplant recipients free from BOS. The present study extends this, testing the hypothesis that inhaled corticosteroid (ICS) therapy will lead to a decrease in Rbm thickness in lung transplant recipients. A parallel group, bronchoscopic intervention study of clinically stable lung allograft recipients, free from BOS, but with evidence of airway inflammation. Following baseline assessment of Rbm thickening, subjects were randomized to 3 months of either chlorofluorocarbon-driven beclomethasone diproprionate (BDP) 400 microg b.i.d., or a formulation designed to yield at least an equivalent dose, hydrofluoroalkane-driven BDP, 200 microg b.i.d. Three months treatment with a moderate dose of ICS, including a formulation designed for preferential small airway deposition, had no effect on Rbm thickening (13+/-3 vs. 14+/-5 microm post-ICS). Our data would suggest that airway remodelling can occur early in lung allografts and is not affected by moderate dose ICS therapy. Longitudinal studies are required to describe the pathophysiological processes involved in BOS, and specifically to elucidate potential relationships between airway remodelling, airflow obstruction and allograft failure.

Remodeling and Inflammation of Bronchi in Asthma and Chronic Obstructive Pulmonary Disease

Asthma and chronic obstructive pulmonary disease (COPD) are pathologically distinct in terms of their predominant inflammatory cells and structural alterations (i.e., remodeling). However, there are many cases of functional and pathologic overlap, supporting the author's view that use of the terms asthma or COPD is oversimplistic and fails to identify the range of phenotypes that exist. In general, there is epithelial fragility and thickening of the reticular basement membrane, even in mild asthma; increased airway smooth muscle mass, hypertrophy of mucus-secreting glands, increased vascularity, greater numbers of fibroblasts, and increased deposition of collagen in severe asthma and COPD; and mucous metaplasia, squamous metaplasia, and parenchymal destruction in COPD. Because of increased neutrophilia, patterns of inflammation become similar when exacerbations of asthma and COPD result in hospitalization. Moreover, in mild COPD, exacerbations of bronchitis are associated with mucosal eosinophilia and upregulation of RANTES, two features normally associated with asthma. The overlap may also be seen in intermediate thickening of the reticular basement membrane and eosinophilia in patients with COPD who demonstrate reversibility to oral steroid. Importantly, a recent study of "eosinophilic bronchitis" demonstrates a thickened reticular basement membrane and challenges our current concept of the histopathologic distinctions between asthma and COPD.

Effects of Inhaled Corticosteroids on Pathology in Asthma and Chronic Obstructive Pulmonary Disease

The effects of inhaled corticosteroids (ICSs) have been investigated in asthma and chronic obstructive pulmonary disease (COPD) using endobronchial biopsies. In asthma, most studies have shown reductions in infiltrating eosinophils, mast cells, and T lymphocytes. Cell-associated mediators, such as cytokines derived from type 2 T-helper lymphocytes, are decreased as assessed by immunostaining and molecular biology techniques. More recently, attention has been devoted to the effect of ICSs on structural changes. In asthma, ICSs have been shown in some studies to affect collagen deposition (size of the reticular basement membrane), the number of vessels, or epithelial integrity. The correlations between those findings and various clinical and functional outcomes are far from clear. A long-term study has shown a decrease in the basement membrane size in a group of patients with asthma treated according to their level of airway hyperreactivity. In COPD, ICSs generally do not decrease neutrophils, macrophages, and CD8(+) T lymphocytes. The effects of these drugs on structural changes in COPD have not been investigated extensively. Long-term prospective studies are needed to demonstrate the potential for ICSs to affect the natural history of chronic bronchial diseases.