Copper as the most likely pathogenic divergence factor between lung fibrosis and emphysema

Abstract

Although fibrosis and emphysema are in many ways on opposite ends of the pulmonary parenchymal disease spectrum, they seem to share common pathomechanistic steps. This is illustrated by the coexistence of both entities in lungs of individuals with combined pulmonary fibrosis and emphysema. Macroproteins elastin and collagen are major constituents of the pulmonary extracellular matrix. The prevailing paradigm states that emphysema is caused by an imbalance between destructive proteolytic and protective antiproteolytic enzymes leading to accelerated degradation of elastin fibers in the lungs. Rates of elastin breakdown, however, are equally enhanced in patients with idiopathic pulmonary fibrosis (IPF) and emphysema. Excessive accumulation of collagen is a hallmark of IPF. Surprisingly, collagen levels in the lung parenchyma of patients with emphysema are also higher than in controls. The concentration of elastin fibers is elevated in fibrotic lungs, despite accelerated elastinolysis, suggesting that elastin repair is also enhanced in IPF. Since elastin concentrations are reduced in emphysematous lungs, the factor of divergence between emphysema and fibrosis seems to be the degree of elastin repair. Multiple elastin repair steps can be deduced of which tropoelastin synthesis and crosslinking of tropoelastin polymers by the copper dependent enzyme lysyl oxidase seem to be the most important ones. We suspect that the distinction in the pathogeneses of lung fibrosis and emphysema depends on the local availability of copper to activate sufficient lysyl oxidase for elastin crosslinking, and suggest assessing the effects of inhalation therapy with copper plus heparin in emphysema and heparin monotherapy in IPF.

Introduction

Although lung emphysema and fibrosis are opposite entities from radiological and pathological standpoints, remarkable similarity seems to exist between their disease mechanisms. Combined pulmonary fibrosis and emphysema (CPFE) is an intriguing disease entity in this regard, since it is characterized by emphysema in the lung apices and fibrosis in the bases (Fig. 1) [1]. The occurrence of both diseases in lungs of one individual is suggestive for the presence of common pathogenic steps. In the present manuscript, we will try to elucidate the divergent factor(s) between these two lung parenchymal conditions by comparing the sequential disease processes (Table 1).

Elastin is a unique protein that renders elasticity, resilience and deformability to the lungs, and is therefore a basic requirement for breathing [2]. Imbalance between enzymes with the ability to degrade elastin fibers, and those counteracting this, is seen as the main cause for the development of emphysema [3]. Accumulating evidence suggests, however, that proteases and antiproteases are also implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) [4].

The amino acids desmosine and isodesmosine (together referred to as DES) are unique to crosslinked elastin fibers [5]. DES levels in body fluids can therefore be used to quantify the rate of elastinolysis [6]. The chronic obstructive pulmonary disease (COPD) Biomarker Qualification Consortium regards DES as biomarkers with great potential [7]. Circulating levels of DES are correlated with mortality in COPD patients [8] and with progression of emphysema in individuals with alpha-1 antitrypsin (AAT) deficiency [9]. Although they are classically regarded as purely biomarkers of COPD, we recently discovered that plasma DES levels are equally elevated in IPF patients [10]. Apparently, enhanced elastinolysis is not responsible for the divergence between lung fibrotic and emphysematous pathogeneses.