Desmosine: The Rationale for Its Use as a Biomarker of Therapeutic Efficacy in the Treatment of Pulmonary Emphysema

Abstract

Desmosine and isodesmosine (DID) are elastin-specific crosslinking amino acids that play a critical role in maintaining the structural integrity of elastic fibers, and their levels in body fluids may serve as biomarkers for alveolar wall injury. To support this concept, we present studies demonstrating the use of DID to detect elastic fiber damage that reflects distention and the rupture of airspaces. The emergence of airspace enlargement may be modeled by a percolation network describing the effect of changing proportions of intact and weak elastic fibers on the transmission of mechanical forces in the lung. Following the unraveling and fragmentation of weakened elastic fibers, the release of DID may correlate with an increasing alveolar diameter and provide an endpoint for clinical trials of novel agents designed to treat pulmonary emphysema. The limitations of the DID measurements related to specificity and reproducibility are also addressed, particularly regarding sample source and analytical techniques. Standardizing protocols to isolate and quantify DID may increase the use of this biomarker for the early detection of alveolar wall injury, which permits timely therapeutic intervention.

Keywords: desmosine; elastic fibers; elastin; hyaluronan; pulmonary emphysema.

Figure 1

Desmosine and Isodesmosine are crosslinks formed by the condensation of four lysine residues on adjacent elastin peptides. The only difference between them is the positioning of a lysine side chain on the central pyridinium ring. Reprinted with permission of Creative Commons (https://creativecommons.org/licenses/by-sa/4.0/, accessed on 2 October 2024).

Figure 2

Diagram of lung elastic fiber network showing intact (solid lines) and fragmented (dotted lines) fibers. The increased mechanical strain on the remaining intact fibers facilitates their fragmentation, producing foci of alveolar wall distention and rupture (arrows) that eventually become confluent.

Figure 3

Photomicrograph of unraveled (arrowhead) and fragmented (arrows) elastic fibers following treatment of the lung with elastase and LPS. The breakdown of these fibers releases proinflammatory elastin peptides that facilitate the progression of airspace enlargement. Reprinted with permission from [16]. Orcein stain; original magnification: 1000×.

Figure 4

A graphic representation of the self-perpetuating inflammatory process involving the release of elastin peptides from damaged elastic fibers. Tobacco smoke and other oxidants (A) enter biochemical machinery (B) and are broken down into free radicals (C) which turn on inflammatory engine (D) that activates elastases (E) which break down elastic fibers (F), fueling release of cytokines (G) that speed up inflammatory engine.

Figure 5

(A) Mass spectrometry profile showing the transitional ions used to identify desmosine. These ions result from the exposure of the chromatographically separated DID to a high-energy electromagnetic field. (B) The large chromatographic peak consists of DID derived from formalin-fixed tissue sections. The smaller coeluting peak is a deuterium-labeled DID standard used to identify the composition of the main peak. Reprinted with permission from [19].

Figure 6

Free urine DID was significantly decreased following a 28-day clinical trial of inhaled HA in patients with alpha-1 antitrypsin deficiency-induced COPD. Measurements were made one week after the completion of treatment. No significant difference was seen in the placebo group. The findings are consistent with the experimentally demonstrated effect of HA in preventing elastic fiber degradation. The paired t-test was used to determine statistical significance (p < 0.05). Reprinted with permission from [45].