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

¹ Dept of Pulmonary Diseases; Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, the Netherlands; and Dept of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, U.S.A.
² Matrix Biochemistry at NCMLS
³ Dept of Pulmonary Diseases
⁴ Dept of Pulmonary Diseases; Intensive Care; and Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, the Netherlands
⁵ Dept of Pulmonary Diseases; and Institute for Fundamental and Clinical Human Movement Sciences, Radboud University Nijmegen Medical Centre, the Netherlands

^* To whom correspondence should be addressed. E-mail: c.ottenheijm{at}long.umcn.nl.

	Abstract

In the present study we used phage display-derived antibodies to investigate the topology of glycosaminoglycan epitopes in the diaphragm of COPD and non-COPD patients. Furthermore, a potential physiological significance of changes in the occurrence of glycosaminoglycan epitopes in COPD diaphragm 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 (GOLD I/II, n=9) were incubated with antibodies directed against heparan sulfate, chondroitin sulfate, and dermatan sulfate epitopes. Antibodies were visualized immunofluorescently. In addition, interference of antibody and growth factor binding to heparan sulfate epitopes was tested.

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

Results indicate changes in glycosaminoglycan composition in the diaphragm of patients with COPD. 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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