👤 María Dolores Pizarro

Fibroblast growth factor (FGF) signaling plays an important role in the pathogenesis of various respiratory diseases, including idiopathic pulmonary fibrosis (IPF). FGF ligands can exert both pro- and anti-fibrotic effects, depending on the responding cell, the expression levels of FGF receptors (FGFR1-4) and the context of other signaling molecules such as Transforming growth factor β (TGF-β). We evaluated here the effect of a modified version of a soluble FGFR3 decoy receptor (designated as "sFGFR3-Fc"), that specifically sequesters pro-fibrotic FGFR3 ligands, FGF1, FGF2 and FGF9 as a potential anti-fibrotic drug. We showed that FGF2 stimulated proliferation and expression of various fibrotic markers in human pulmonary fibroblasts from healthy donors and IPF patients. The sFGFR3-Fc was able to reduce these FGF2-mediated responses and also partially attenuate the pro-fibrotic phenotype induced by TGF-β, including gel contraction. Furthermore, single cell transcriptomic analyses revealed heterogeneity of IPF-derived fibroblasts for FGF2 response and confirmed the potential efficacy of sFGFR3-Fc in decreasing the expression of a subset of TGF-β1 pathway genes. Finally, sFGFR3-Fc was shown to improve the progression of pulmonary fibrosis using both a preventive and therapeutic strategy, evaluated in the standard single bleomycin (BLM) instillation mouse model as well as in a more severe model of repeated BLM instillations, as evidenced by the reduction in ECM deposits, the recovery of body weight and the restoration of lung function. Our data highlight the interplay between the TGF-β and the FGF signaling pathways and demonstrate the potential of targeting pro-fibrotic FGFR3 ligands as therapeutic strategy for IPF. Show less

Elevated lipoprotein(a) [Lp(a)] levels are associated with increased cardiovascular risk and have been implicated in various inflammatory conditions. However, evidence regarding the role of Lp(a) in patients with inflammatory bowel disease (IBD) remains limited. This study aimed to evaluate Lp(a) levels in a group of patients with IBD. A cross-sectional study was conducted involving patients with IBD actively followed by a multidisciplinary team. As part of routine care, patients with cardiovascular risk factors were systematically referred for comprehensive cardiology evaluation. For comparison, a control group matched for age and sex in a 2:1 ratio was randomly selected from the hospital database. Seventy-eight patients with IBD and 156 controls (mean age 56.1 years; 59% male) were included. Among patients with IBD, 56.4% had ulcerative colitis and 43.6% Crohn's disease. The IBD group showed a non-significant trend toward higher Lp(a) levels compared to controls (median [IQR]: 19.1 [5.9-71.3] vs. 17.5 [7.0-39.0]mg/dL; p=0.274). A significantly greater proportion of IBD patients had high-risk Lp(a) levels (>50mg/dL) than controls (35.9% vs. 19.2%; p=0.02). Additionally, IBD patients with Lp(a)>50mg/dL exhibited a non-significant trend toward higher inflammatory marker values. A substantial proportion of IBD patients exhibited elevated Lp(a) levels. Given its inflammatory, prothrombotic, and proatherogenic properties, Lp(a) may contribute to the increased cardiovascular risk observed in this population. Show less

To determine the influence of the construction design over the biological component's performance in an experimental bio-artificial liver (BAL) device. Two BAL models for liver microorgans (LMOs) were constructed. First, we constructed a cylindrical BAL and tested it without the biological component to establish its correct functioning. Samples of blood and biological compartment (BC) fluid were taken after 0, 60, and 120 min of perfusion. Osmolality, hematocrit, ammonia and glucose concentrations, lactate dehydrogenase (LDH) release (as a LMO viability parameter), and oxygen consumption and ammonia metabolizing capacity (as LMO functionality parameters) were determined. CPSI and OTC gene expression and function were measured. The second BAL, a "flat bottom" model, was constructed using a 25 cm The cylindrical BAL showed a good exchange of fluids and metabolites between blood and the BC, reflected by the matching of osmolalities, and glucose and ammonia concentration ratios after 120 min of perfusion. No hemoconcentration was detected, the hematocrit levels remained stable during the whole study, and the minimal percentage of hemolysis (0.65% ± 0.10%) observed was due to the action of the peristaltic pump. When LMOs were used as biological component of this BAL they showed similar values to the ones obtained in a Normothermic Reoxygenation System (NRS) for almost all the parameters assayed. After 120 min, the results obtained were: LDH release (%): 14.7 ± 3.1 in the BAL and 15.5 ± 3.2 in the NRS ( In this work, we demonstrate the importance of adapting the BAL architecture to the biological component characteristics to obtain an adequate BAL performance. Show less