Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale

Rob Janssen*, Emiel F. M. Wouters, Wim Janssens, Willeke F. Daamen, Paul Hagedoorn, Hugo A. J. M. de Wit, Jef Serre, Ghislaine Gayan-Ramirez, Frits M. E. Franssen, Niki L. Reynaert, Jan Hinrich von der Thusen, Henderik W. Frijlink

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Current pharmacotherapy of chronic obstructive pulmonary disease (COPD) aims at reducing respiratory symptoms and exacerbation frequency. Effective therapies to reduce disease progression, however, are still lacking. Furthermore, COPD medications showed less favorable effects in emphysema than in other COPD phenotypes. Elastin fibers are reduced and disrupted, whereas collagen levels are increased in emphysematous lungs. Protease/antiprotease imbalance has historically been regarded as the sole cause of emphysema. However, it is nowadays appreciated that emphysema may also be provoked by perturbations in the sequential repair steps following elastolysis. Essentiality of fibulin-5 and lysyl oxidase-like 1 in the elastin restoration process is discussed, and it is argued that copper deficiency is a plausible reason for failing elastin repair in emphysema patients. Since copper-dependent lysyl oxidases crosslink elastin as well as collagen fibers, copper supplementation stimulates accumulation of both proteins in the extracellular matrix. Restoration of abnormal elastin fibers in emphysematous lungs is favorable, whereas stimulating pulmonary fibrosis formation by further increasing collagen concentrations and organization is detrimental. Heparin inhibits collagen crosslinking while stimulating elastin repair and might therefore be the ideal companion of copper for emphysema patients. Efficacy and safety considerations may lead to a preference of pulmonary administration of copper-heparin over systemic administration.

Original languageEnglish
Pages (from-to)2587-2602
Number of pages16
JournalInternational Journal of Chronic Obstructive Pulmonary Disease
Volume14
DOIs
Publication statusPublished - 2019

Keywords

  • collagen
  • copper
  • desmosine
  • elastin
  • emphysema
  • fibulin-5
  • heparin
  • lysyl oxidase
  • lysyl oxidase-like protein 1
  • tropoelastin
  • OBSTRUCTIVE PULMONARY-DISEASE
  • SMALL-AIRWAY OBSTRUCTION
  • LYSYL OXIDASE
  • CADMIUM CHLORIDE
  • ELASTIC FIBERS
  • CROSS-LINKING
  • LUNG FIBROSIS
  • CENTRILOBULAR EMPHYSEMA
  • INHALED HEPARIN
  • GENE-EXPRESSION

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