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

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.

Keywords:

• collagen
• copper
• desmosine
• elastin
• emphysema
• fibulin-5
• heparin
• lysyl oxidase
• lysyl oxidase-like protein 1
• tropoelastin

Disclosure

Dr Rob Janssen reports a grant from Stichting Astma Bestrijding to study the effect of copper/heparin on emphysema formation in a mouse model, is one of the owners of Desmosine.com, and has a patent WO 2019/139479; Mr Paul Hagedoorn and Prof. Dr. Henderik W. Frijlink report that their employer has a license agreement with AstraZeneca on the Genuair inhaler and with PureIMS on the Twincer and Cyclops inhalers; Dr Frits M.E. Franssen report grants, personal fees from AstraZeneca, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from GlaxoSmithKline, grants, personal fees from Novartis, personal fees from TEVA, outside the submitted work. The authors report no other conflicts of interest in this work.