<p>Copper-Heparin Inhalation Therapy To Repair Emphysema: A Scientific Rationale</p>

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.

Nutritional immunity: the impact of metals on lung immune cells and the airway microbiome during chronic respiratory disease

“…Copper deficiency induces emphysema in animal models [ 332 – 334 ] and the EBC of stable COPD patients contains lower copper levels than of controls an observation that is positively related to FEV1 in individuals with COPD [ 335 ]. Intriguingly, individuals with Menkes disease, an X-linked recessive disorder of mutations in the intracellular copper-transporter ATP7A display an increased incidence in emphysema [ 336 , 337 ]. A loss of copper directly impacts AEC integrity and copper directly regulates elastin synthesis via the copper dependent enzyme lysyl oxidase [ 334 , 338 ].…”

Associations of serum Cu, Zn, and Se with Chronic Respiratory Diseases in the American adults: Data from NHANES 2013–2016 and a bidirectional Mendelian randomization analysis

“…For instance, anomalous expression of genes associated with Cu metabolism in the study of lung adenocarcinoma unveils the role of Cu homeostasis in tumor development [90]. Similarly, both Cu de ciency and excess may impact the synthesis of pulmonary elastin, thus affecting lung structure and functionality [91,92]. Investigations into pulmonary Cu metabolism are pivotal for deciphering the pathogenesis of these diseases and also offer potential interventional avenues for the prevention and treatment of pulmonary disorders.…”

Control of the Lung Residence Time of Highly Permeable Molecules after Nebulization: Example of the Fluoroquinolones

“…The restoration of elastin increases the need for copper in the lungs to activate the enzymes responsible for its repair, such as the lysyl oxidase metalloenzymes. [67]. Similarly, COPD subjects have lower levels of copper than healthy subjects [68].…”

“…Co-administration of copper and CIP to COPD patients with lung infection may help fight infection and restore copper levels in these people. Likewise, copper-heparin inhalation therapy to repair emphysema has recently been investigated [67].…”