Publikationsdatenbank

Enzymatic modulation of the pulmonary glycocalyx enhances susceptibility to Streptococcus pneumoniae (2024)

Art

Zeitschriftenartikel / wissenschaftlicher Beitrag

Autoren

Goekeri, Cengiz

Linke, Kerstin A. K.

Hoffmann, Karen

Lopez-Rodriguez, Elena

Gluhovic, Vladimir

Voß, Anne

Kunder, Sandra

Zappe, Andreas

Timm, Sara

Nettesheim, Alina

Schickinger, Sebastian M. K.

Zobel, Christian M.

Pagel, Kevin

Gruber, Achim D. (WE 12)

Ochs, Matthias

Witzenrath, Martin

Nouailles, Geraldine

Quelle

American journal of respiratory cell and molecular biology

Bandzählung: 71

Heftzählung: 6

Seiten: 646 – 658

ISSN: 1535-4989

Sprache

Englisch

Verweise

URL (Volltext): https://www.atsjournals.org/doi/10.1165/rcmb.2024-0003OC

DOI: 10.1165/rcmb.2024-0003OC

Pubmed: 39042016

Kontakt

Institut für Tierpathologie

Robert-von-Ostertag-Str. 15
14163 Berlin
+49 30 838 62450
pathologie@vetmed.fu-berlin.de

Abstract / Zusammenfassung

The pulmonary epithelial glycocalyx is rich in glycosaminoglycans such as hyaluronan and heparan sulfate. Despite their presence, the importance of these glycosaminoglycans in bacterial lung infections remains elusive. To address this, we intranasally inoculated mice with Streptococcus pneumoniae in the presence or absence of enzymes targeting pulmonary hyaluronan and heparan sulfate, followed by characterization of subsequent disease pathology, pulmonary inflammation, and lung barrier dysfunction. Enzymatic degradation of hyaluronan and heparan sulfate exacerbated pneumonia in mice, as evidenced by increased disease scores and alveolar neutrophil recruitment. However, targeting epithelial hyaluronan in combination with S. pneumoniae infection further exacerbated systemic disease, indicated by elevated splenic bacterial load and plasma concentrations of proinflammatory cytokines. In contrast, enzymatic cleavage of heparan sulfate resulted in increased bronchoalveolar bacterial burden, lung damage, and pulmonary inflammation in mice infected with S. pneumoniae. Accordingly, heparinase-treated mice also exhibited disrupted lung barrier integrity as evidenced by higher alveolar edema scores and vascular protein leakage into the airways. This finding was corroborated in a human alveolus-on-a-chip platform, confirming that heparinase treatment also disrupts the human lung barrier during S. pneumoniae infection. Notably, enzymatic pretreatment with either hyaluronidase or heparinase also rendered human epithelial cells more sensitive to pneumococci-induced barrier disruption, as determined by transepithelial electrical resistance measurements, consistent with our findings in murine pneumonia. Taken together, these findings demonstrate the importance of intact hyaluronan and heparan sulfate in limiting pneumococci-induced damage, pulmonary inflammation, and epithelial barrier function and integrity.