Journal of Pathology J Pathol 2005; 207: 102–110 Published online 22 July 2005 in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/path.1818 Original Paper Airway proteoglycans are differentially altered in fatal asthma Marcus de Medeiros Matsushita, 1 Luiz Fernando Ferraz da Silva, 1 Mario Adriano dos Santos, 1 Sandra Fernezlian, 1 Jasmijn A Schrumpf, 2 Peter Roughley, 3 Pieter S Hiemstra, 2 Paulo Hil´ ario Nascimento Saldiva, 1 Thais Mauad 1,2 and Marisa Dolhnikoff 1 * 1 Department of Pathology, School of Medicine, University of Sao Paulo, Brazil 2 Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands 3 Shriners Hospital for Children, McGill University, Montreal, Canada *Correspondence to: Marisa Dolhnikoff, Departamento de Patologia, Faculdade de Medicina da Universidade de S˜ ao Paulo, Av Dr Arnaldo, 455, 2 ◦ Andar, Sala 2118, S˜ ao Paulo SP, Brazil, CEP 01246-903. E-mail: maridol@usp.br Received: 4 March 2005 Revised: 16 April 2005 Accepted: 8 May 2005 Abstract It has been suggested that airway remodelling is responsible for the persistent airway obstruction and decline in lung function observed in some asthmatic patients. The small airways are thought to contribute significantly to this functional impairment. Proteoglycans (PGs) are important components of the extracellular matrix (ECM) in the lungs. Besides controlling biophysical properties of the ECM, they play important roles in the regulation of some cytokines. Increased subepithelial PG deposition in the airways of mild asthmatics has been reported. However, there are no data on the PG content in small airways in asthma. This study has compared the content and distribution of PGs in large and small airways of patients who died of asthma with those in control lungs. Immunohistochemistry and image analysis were used to determine the content of lumican, decorin, biglycan, and versican in large (internal perimeter >6 mm) and small (internal perimeter ≤6 mm) airways of 18 patients who had died of asthma (A) and ten controls (C). The results were expressed as PG area (μm 2 )/epithelial basement membrane length (μm). The main differences between asthmatics and controls were observed in the small airways. There was a significant decrease in decorin and lumican contents in the external area of small airways in asthmatics (decorin: A = 1.05 ± 0.27 μm, C = 3.97 ± 1.17 μm, p = 0.042; lumican: A = 1.97 ± 0.37 μm, C = 5.66 ± 0.99 μm, p = 0.002). A significant increase in versican content in the internal area of small and large airways in asthmatics was also observed (small: A = 7.48 ± 0.84 μm, C = 5.16 ± 0.61 μm, p = 0.045; large: A = 18.38 ± 1.94 μm, C = 11.90 ± 2.86 μm, p = 0.028). The results show that PGs are differentially expressed in the airways of fatal asthma and may contribute to airway remodelling. These data reinforce the importance of the small airways in airway remodelling in asthma. Copyright  2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. Keywords: asthma; proteoglycans; small airways; image analysis; autopsy, remodelling Introduction A number of asthmatic subjects show evidence of persistent airway obstruction and decline of lung func- tion with time [1]. It is believed that airway remod- elling may be responsible for the persistent func- tional changes observed in these patients [2]. Several structural changes are related to airway remodelling in asthma: muscle hypertrophy/hyperplasia; mucus gland hyperplasia; and changes in the extracellular matrix (ECM). All components of the lung ECM (collagen, elastic fibres, proteoglycans, and glycopro- teins) have been shown to be potentially altered in asthma [3,4]. It has been proposed that changes in the epithelial – mesenchymal trophic unit due to epithe- lial injury in asthma are responsible for increased secretion of pro-fibrogenic cytokines such as TGF-β , myofibroblast proliferation, and subepithelial deposi- tion of ECM components [5]. It has also been suggested that small airway alter- ations may contribute significantly to the functional impairment in asthma, especially in the most severely affected patients [6–8]. The peripheral airways are thought to be the major site of airway obstruction in asthmatic patients [9]. Airway remodelling has been largely investigated in the large airways in asthma and there are still relatively scarce data on the small air- ways. Proteoglycans (PGs) are major components of the ECM and present many different biological functions. PGs have been implicated in maintenance of the biophysical properties of many tissues, in the assembly of collagen fibrils, and in tissue regulation of water balance; they influence cell migration, act as growth Copyright  2005 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.