Fig. 8

Temporal dynamics of macrophage-specific CXCL10 expression in lungs of infants with or without bronchopulmonary dysplasia (BPD). A Representative co-localization of CD68 (red, immunofluorescent staining) with CXCL10 (green; in situ hybridization) in age-matched lungs of infants with and without BPD (Cnt vs BPD). B-D Linear regression analyses of the number of macrophages (MΦ; CD68⁺ cells; B), CXCL10 mRNA per cell and field of view (C), and CXCL10 mRNA per MΦ (CD68⁺ cells) and field of view (D) related to age (lungs of infants with BPD: red; lungs of infants without BPD, non-BPD: blue); r2 and p-value are indicated next to the respective graph; n = 5 per group; scale bar: 60X. E–G A proposed working model of the functional role of hyperoxia-related macrophage-derived CXCL10 in the pathogenesis of BPD: decreasing expression of CXCL10 during postnatal lung development in healthy lungs that is disrupted by prolonged hyperoxia, thus suggesting CXCL10 inhibition as a therapeutic strategy (E). Hyperoxia promotes the differentiation of macrophages towards a M1-like inflammatory phenotype with expression of IL-6 and CXCL10, and an imbalance of protease and proteolytic activity. This cytokine storm (e.g., IL-6 and CXCL10) together with elevated protease activity negatively affects the survival of alveolar epithelial type 2 cells (AT2), activates fibroblasts, and causes lung matrix remodeling (F). The release of CXCL10 from hyperoxia-activated macrophages adversely affects the regenerative alveolar niche and spatial distribution of elastic fibers and collagen. In contrast, CXCL10 deficiency protects from these changes and pharmacological inhibition of CXCR3 reduces the macrophage migration, offering a new therapeutic target to treat BPD