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Diaphragm dysfunction in chronic obstructive pulmonary disease: a role for heparan sulphate?

Depts of ¹ Pulmonary Diseases, ⁴ Matrix Biochemistry and, ⁵ Intensive Care, Nijmegen Centre for Molecular Life Sciences, and, ² Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands, ³ Dept of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman, WA, USA. ⁶ C.A.C. Ottenheijm and G.J. Jenniskens contributed equally to the present study.

CORRESPONDENCE: C. A. C. Ottenheijm, Dept of Pulmonary Diseases, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Fax: 31 243610324. E-mail: c.ottenheijm{at}long.umcn.nl

Keywords: Chronic obstructive pulmonary disease, diaphragm muscle, glycosaminoglycan, heparan sulphate

Received: September 25, 2006
Accepted March 16, 2007

In the present study, phage display-derived antibodies were used to investigate the topology of glycosaminoglycan epitopes in the diaphragm of chronic obstructive pulmonary disease (COPD) and non-COPD patients. Furthermore, the potential physiological significance of changes in the occurrence of glycosaminoglycan epitopes in the diaphragm of COPD patients was studied by determining the overlap in epitope recognition of glycosaminoglycan antibodies and growth factors.

Diaphragm cryosections from non-COPD (n = 5) and COPD patients (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage I/II; n = 9) were incubated with antibodies directed against heparan sulphate, chondroitin sulphate and dermatan sulphate epitopes. Antibodies were visualised immunofluorescently. In addition, interference of antibody and growth factor binding with heparan sulphate epitopes was tested.

Specific glycosaminoglycan epitopes showed increased expression in the diaphragm of COPD patients, whereas other epitopes were decreased or unaffected. Interestingly, the anti-heparan sulphate antibody HS4C3, which is directed against a downregulated epitope, interfered with the binding of hepatocyte growth factor. Three patients with the most severe airway obstruction also demonstrated interference of heparan sulphate antibody A04B08 with hepatocyte growth factor binding.

Results indicate changes in glycosaminoglycan composition in the diaphragm of patients with chronic obstructive pulmonary disease. This may affect cellular physiology via alterations in growth factor handling and might be related to reduced levels of contractile protein in the diaphragm of these patients.

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