Induction and regulation of murine emphysema by elastin peptides

Abstract

Emphysema is the major component of chronic obstructive pulmonary disease (COPD). During emphysema, elastin breakdown in the lung tissue originates from the release of large amounts of elastase by inflammatory cells. Elevated levels of elastin-derived peptides (EP) reflect massive pulmonary elastin breakdown in COPD patients. Only the EP containing the GXXPG conformational motif with a type VIII β-turn are elastin receptor ligands inducing biological activities. In addition, the COOH-terminal glycine residue of the GXXPG motif seems a prerequisite to the biological activity. In this study, we endotracheally instilled C57BL/6J mice with GXXPG EP and/or COOH-terminal glycine deleted-EP whose sequences were designed by molecular dynamics and docking simulations. We investigated their effect on all criteria associated with the progression of murine emphysema. Bronchoalveolar lavages were recovered to analyze cell profiles by flow cytometry and lungs were prepared to allow morphological and histological analysis by immunostaining and confocal microscopy. We observed that exposure of mice to EP elicited hallmark features of emphysema with inflammatory cell accumulation associated with increased matrix metalloproteinases and desmosine expression and of remodeling of parenchymal tissue. We also identified an inactive COOH-terminal glycine deleted-EP that retains its binding-activity to EBP and that is able to inhibit the in vitro and in vivo activities of emphysema-inducing EP. This study demonstrates that EP are key actors in the development of emphysema and that they represent pharmacological targets for an alternative treatment of emphysema based on the identification of EP analogous antagonists by molecular modeling studies.

Impact of aging on inflammatory and immune responses during elastin peptide-induced murine emphysema

“…The correlation between lung elastin breakdown and aging is consistent with the hypothesis that aging is a major risk factor of COPD development through EP genesis and their consecutive deleterious effects. We previously described induction of emphysema-like phenotype in 6-wk-old mice after EP instillation (37). In the present study, we furthermore demonstrate that EP-induced emphysema is accelerated in elderly mice (15-moold mice) and that aging is exacerbating the emphysema-sections based on collection of second-harmonic generation (SHG) and two photons excited fluorescence (2PEF) signals, respectively, as previously described (37).…”

“…Lung inflammation is primarily due to the infiltration of inflamma-tory cells, mainly macrophages and neutrophils, gradually responsible for pulmonary elastin breakdown by secretion of elastinolytic proteases (30,33). Soluble elastin peptides (EP) produced in significant amounts during massive proteolytic degradation of lung (8,36) are able to drive the propagation and durability of the inflammatory process during COPD (23,37). Pathogenic T cells are also important in the orchestration and perpetuation of the inflammatory damages in a context of COPD.…”

“…The frequency of both CD4 ϩ T cells secreting T-helper (Th)-1 (19), Th-2 (35), or Th-17 (7) cytokines and CD8 ϩ T-cytotoxic (Tc) cells producing interferon-␥ (IFN-␥) (16) in various biological fluids correlates with activity and severity of the disease in patients with COPD. We previously demonstrated that instillation of EP to mice resulted in an acute emphysematous state (37) associated with a Th-1, Th-17, and Tc-1 proinflammatory response (31).…”

Lymphatic impairment leads to pulmonary tertiary lymphoid organ formation and alveolar damage

“…Immunostaining revealed reduced elastin in lungs from plt-Clec2-KO mice compared with those from control littermates, particularly in areas where the emphysema phenotype was most pronounced (Figure 8, E and F). Severe emphysema in humans is associated with the generation of elastin fragments, which are considered a marker of active disease (55) and may drive disease progression (56)(57)(58). We detected a significant increase in a 25-kDa elastin fragment and a nonsignificant increase in a 45-kDa elastin fragment in the lungs of 6-to 8-month-old plt-Clec2-KO mice compared with lungs of control animals ( Figure 8, G and H, and Supplemental Figure 9).…”

B cells in chronic obstructive pulmonary disease: moving to center stage

“…COPD is associated with proteolytic degradation of extracellular matrix proteins (Fig. 2) which contributes to emphysema development and also generates fragments of extracellular matrix (matrokines) that are chemotactic for inflammatory cells (1,69). However, injury to extracellular matrix proteins and cellular components of COPD lungs also generates neoepitopes against which autoantibodies can be generated.…”