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Chronic pulmonary aspergillosis (CPA) is a devastating disease with increasing prevalence worldwide. The characteristic granulomatous-like inflammation poses as the major setback to effective antifungal therapies by limiting drug access to fungi. These inflammatory lung structures are reported to be severely hypoxic; nevertheless, the underlying mechanisms whereby these processes contribute to fungal persistence remain largely unknown. Hypoxia-inducible factor 1 alpha (HIF-1α), besides being the major cellular response regulator to hypoxia, is a known central immune modulator. Here, we used a model of Aspergillus fumigatus airway infection in myeloid-restricted HIF-1α knock-out (mHif1α-/-) mice to replicate the complex structures resembling fungal granulomas and evaluate the contribution of HIF-1α to antifungal immunity and disease development. We found that fungal-elicited granulomas in mHif1α-/- mice had significantly smaller areas, along with extensive hyphal growth and increased lung fungal burden. This phenotype was associated with defective neutrophil recruitment and an increased neutrophil death, therefore highlighting a central role for HIF-1α-mediated regulation of neutrophil function in the pathogenesis of chronic fungal infection. These results hold the promise of an improved capacity to manage the progression of chronic fungal disease and open new avenues for additional therapeutic targets and niches of intervention.

PURPOSE To study the role of serum biomarkers as prognostic factors for qualitative and quantitative response to anti-vascular endothelial growth factor injections for diabetic macular edema (DME). METHODS Sixty-seven eyes with DME were treated with intravitreal bevacizumab during a 12-month follow-up period. All cases underwent a baseline workup consisting of 12 inflammatory, metabolic and prothrombotic factors. The following outcomes were evaluated at 3-month intervals until 1 year of follow-up: visual acuity, central subfield thickness (CST), macular volume (MV), % of change from baseline in CST, occurrence of a CST change 20%, and a CST

A progressive fibrosing phenotype is critical in several lung diseases. It is irreversible and associated with early patient mortality. Growing evidence has revealed pulmonary macrophages’ role as modulators of the fibrotic processes. The proportion, phenotype, and function of alveolar (AM) and interstitial macrophages (IM) at the early stages of bleomycin-induced pulmonary fibrosis have not been clearly described. In this way, our study aimed to characterize these macrophage populations and investigate the effect on fibroblast activation. C57BL/6 mice were intratracheally injected with bleomycin and were sacrificed at day 3, 5, and 7 for the performance of flow cytometry and fluorescent-activated cell sorting analysis for protein and gene expression quantification. After bleomycin administration, the proportion of IM was significantly higher than that of AM, which showed a decay during the inflammatory phase, and peaked at day 7. At day 7 of the inflammatory phase, AM started shifting their phenotype from M1-like towards M2, while IM showed a M2-like phenotype. Conditioned medium derived from IM sorted at day 7 induced fibroblast activation and differentiation in myofibroblasts in vitro. Our findings indicate that IM are the largest macrophage population at the early stages of experimental pulmonary fibrosis and are secreted mediators able to activate fibroblasts, pointing to macrophage modulation as a potential therapeutic strategy to restrain progressive fibrosing lung disorders.

Pulmonary fibrosis (PF) is the end pathologic stage of several interstitial lung diseases associated with high morbidity and mortality rates. However, the treatments used in clinical practice are only capable to slow the disease progression rather than stop it. Evidences have shown critical roles of chronic inflammation in the progression of PF-associated diseases. However, the drivers of these effects are still unknown. Therefore, new insights about the immune regulation of PF are fundamental to develop more efficient therapeutic approaches. Growing evidences have shown the role of hepatocyte growth factor (HGF) and its receptor (c-Met) in modulation of immune cell’s migratory capacity and functions, namely its upon inflammatory stimuli and required for extravasation of neutrophil to inflamed tumours. Nevertheless, the effects of this signalling in immune cells in the context of PF-associated lung diseases remains unexplored. Therefore, we used a bleomycin‑induced PF model to understand the contribution of c‑Met‑expressing immune cells to PF progression. Interestingly, our data demonstrate that inflammatory cells and c-Met expression induction was specially observed on T cells and interstitial macrophages. Furthermore, in a cell‑specific transgenic mouse, in which c-Met was deleted in hematopoietic and endothelial cells, c-Met expression correlated with an increment in inflammatory infiltration, namely neutrophils and interstitial macrophages, and reduction of proinflammatory cytokines, along with higher tissue destruction and collagen deposition. Thus, our findings point out HGF/c‑Met signalling as a critical player in the pathogenesis of PF, probably through immune cells.