Nicola Solic1, John Wilson, Susan J Wilson, Janis K Shute. 1. Respiratory Cell and Molecular Biology Division, Southampton University School of Medicine, UK, and Department of Allergy, Immunology, and Respiratory Medicine, Alfred Hospital, Victoria, Australia.
Abstract
RATIONALE: Pulmonary disease in cystic fibrosis (CF) is characterized by an exaggerated interleukin (IL)-8-driven, neutrophilic, inflammatory response to infection. Binding of IL-8 to heparan sulfate (HS)-containing proteoglycans (HSPG) facilitates binding of the chemokine to its specific receptor, stabilizes and prolongs IL-8 activity, and protects it from proteolysis. We hypothesized that increased expression of HSPG contributes to the sustained inflammatory response in CF bronchial tissue. OBJECTIVES: Our objectives were to analyze the distribution and abundance of IL-8 and HS, in intact and cleaved forms, in bronchial tissue from adult patients with CF or chronic obstructive pulmonary disease (COPD) and a control group without inflammatory airway disease. METHODS: Immunostaining and quantitative image analysis were applied to ethanol-fixed and paraffin-embedded tissue obtained at transplant in patients with CF or COPD, or postmortem in the control group. MEASUREMENTS AND MAIN RESULTS: Quantitative immunohistochemical analysis demonstrated significant disease-related differences. Intact HS was significantly more abundant in epithelial and endothelial basement membranes in CF than in COPD or the control group. Conversely, cleaved HS was significantly more abundant in COPD than the other groups. More IL-8-positive blood vessels were observed in CF and COPD compared with the control group, whereas more extensive IL-8 expression in the epithelium was observed in CF compared with COPD. CONCLUSIONS: Sustained neutrophil recruitment in the CF airway may therefore be related not only to increased IL-8 expression but also to the increased stability and prolonged activity and retention of IL-8 when it is bound to HSPG in bronchial tissue.
RATIONALE: Pulmonary disease in cystic fibrosis (CF) is characterized by an exaggerated interleukin (IL)-8-driven, neutrophilic, inflammatory response to infection. Binding of IL-8 to heparan sulfate (HS)-containing proteoglycans (HSPG) facilitates binding of the chemokine to its specific receptor, stabilizes and prolongs IL-8 activity, and protects it from proteolysis. We hypothesized that increased expression of HSPG contributes to the sustained inflammatory response in CF bronchial tissue. OBJECTIVES: Our objectives were to analyze the distribution and abundance of IL-8 and HS, in intact and cleaved forms, in bronchial tissue from adult patients with CF or chronic obstructive pulmonary disease (COPD) and a control group without inflammatory airway disease. METHODS: Immunostaining and quantitative image analysis were applied to ethanol-fixed and paraffin-embedded tissue obtained at transplant in patients with CF or COPD, or postmortem in the control group. MEASUREMENTS AND MAIN RESULTS: Quantitative immunohistochemical analysis demonstrated significant disease-related differences. Intact HS was significantly more abundant in epithelial and endothelial basement membranes in CF than in COPD or the control group. Conversely, cleaved HS was significantly more abundant in COPD than the other groups. More IL-8-positive blood vessels were observed in CF and COPD compared with the control group, whereas more extensive IL-8 expression in the epithelium was observed in CF compared with COPD. CONCLUSIONS: Sustained neutrophil recruitment in the CF airway may therefore be related not only to increased IL-8 expression but also to the increased stability and prolonged activity and retention of IL-8 when it is bound to HSPG in bronchial tissue.
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