Abstract
Rationale: Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury.Methods:LgalS3fl/fl mice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yield LysM-cre +/- /LgalS3 fl/fl and Pdgfrb-cre +/- /LgalS3 fl/fl mice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficient Gal-3 −/− mice.Results: Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed in Pdgfrb-cre +/- /LgalS3 fl/fl mice. Conclusions: Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation.
Highlights
Galectin-3 (Gal-3) is a pro-fibrotic, mammalian ß-galactoside binding lectin found to be highly upregulated in the injured lung, in patients with idiopathic pulmonary fibrosis (IPF) suffering acute exacerbations (MacKinnon et al, 2012)
Gal-3 is a marker of airway inflammation in bronchial asthma (Elkolaly and Ali, 2018) and is elevated in patients with chronic obstructive pulmonary disease (COPD), where it is associated with neutrophil accumulation in the small airways (Pilette et al, 2007)
We show that selective myeloid depletion decreased lung Gal-3 levels and diminished acute lung injury via a reduction in neutrophil recruitment and inflammation as well as reducing bleomycin-induced fibrosis, whereas depletion in the mesenchymal compartment had no effect
Summary
Galectin-3 (Gal-3) is a pro-fibrotic, mammalian ß-galactoside binding lectin found to be highly upregulated in the injured lung, in patients with idiopathic pulmonary fibrosis (IPF) suffering acute exacerbations (MacKinnon et al, 2012). Gal-3 is a marker of airway inflammation in bronchial asthma (Elkolaly and Ali, 2018) and is elevated in patients with chronic obstructive pulmonary disease (COPD), where it is associated with neutrophil accumulation in the small airways (Pilette et al, 2007). It has recently been implicated for its role in inflammatory and fibrotic responses following COVID-19 infection (Garcia-Revilla et al, 2020)
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