Biology subjects

Gutbier, B.

Publications and source records attributed to Gutbier, B..

2 recordsLinked to original sources

bioRxiv2024

Neutrophil-chemoattractant CXCL5 induces lung barrier permeability in acute lung injury

RationaleAcute lung injury is frequently caused by pneumonia, and severity correlates with inflammatory cell recruitment and lung barrier failure. Deciphering drug-targetable pathways is of clinical importance. ObjectivesInvestigation of paracrine and autocrine effects of epithelial-derived chemokine CXCL5 in acute lung injury. MethodsWe assessed the role of CXCL5 and related chemokines in patients with severe pneumonia and primary cells or cell lines challenged with Streptococcus pneumoniae or exposed to mechanical stretch. Furthermore, we evaluated the role of CXCL5 in in vivo models of acute lung injury through use of Cxcl5-deficient mice and in vitro human lung barrier models. ResultsPneumococcal infection and mechanical ventilation were associated with CXCL5 production in human subjects and in mice. CXCL5 was produced by bronchial and alveolar epithelial cells. The alveolar-epithelial barrier was protected in acute lung injury models in Cxcl5-deficient mice, independent of alveolar neutrophil recruitment. Single-cell transcriptomics revealed enhanced cell junctional transcripts in epithelial, but not endothelial cells in Cxcl5-deficient mice. Accordingly, CXCL5 exposure disrupted the barrier function of TNF-primed human primary alveolar epithelial cells, but not pulmonary microvascular endothelial cells. ConclusionsWe describe a novel function of CXCL5 in acute lung injury. Besides its recognized role in recruiting highly inflammatory cells such as neutrophils, CXCL5 increases alveolar-epithelial barrier permeability. Thus, in severe bacterial pneumonia, targeting of CXCL5 as adjunctive therapy to antibiotics may aid in reducing overshooting inflammation as well as stabilizing lung barrier function.

immunology↗

bioRxiv2022

Spatial expression of an mRNA encoding Tie2-agonist in the capillary endothelium of the lung prevents pulmonary vascular leakage

Angiopoietin ligands Ang1 and Ang2 and the Tie2 receptor tyrosine kinases form an endothelial signaling pathway regulating vascular homeostasis and controlling vessel permeability, inflammation and angiogenic responses. Whereas Ang1-mediated Tie2 activation reduces inflammation and endothelial permeability, its antagonist, Ang2 increases it. Increased plasma Ang2 levels are associated with poor outcomes in patients with acute lung injury (ALI), as well as in acute respiratory distress syndrome (ARDS). In the study presented here we tested the effect of a novel synthetic, nucleoside-modified mRNA-76 encoding for a hyperactive Ang1 derived fusion protein (COMP-Ang1) on attenuating post-inflammation vascular leakage. COMP-Ang1 mRNA was formulated into a cationic lipid nanoparticle (cLNP) using an optimized mixture of three different lipids and a microfluidic mixing technology. After intravenous injection, the respective mRNA-loaded LNPs were found to be delivered predominantly to the endothelial cells of the lung, while sparing other vascular beds. Also, the specific multimeric folding of the COMP-Ang1 protein complex appeared to be pivotal for its activity in preventing vascular leakage and in restoring the alveolar-endothelial barrier function in the inflamed and injured pulmonary vasculature. The mode of action of mRNA-76, such as its activation of the Tie2 signal transduction pathway, was tested by pharmacological studies in vitro and in vivo by systemic administration in respective mouse models. mRNA-76 was found to prevent lung vascular leakage/lung edema as well as neutrophil infiltration in an LPS-challenging model.

molecular biology↗