Idiopathic pulmonary fibrosis (IPF) is characterized by an aberrant repair response with uncontrolled turnover of extracellular matrix involving mesenchymal cell phenotypes, where lung resident mesenchymal stem cells (LRMSC) have been supposed to have an important role. However, the contribution of LRMSC in lung fibrosis is not fully understood, and the role of LRMSC in IPF remains to be elucidated. Here, we performed transcriptomic and functional analyses on LRMSC isolated from IPF and control patients (CON). Both over-representation and gene set enrichment analyses indicated that oxidative phosphorylation is the major dysregulated pathway in IPF LRMSC. The most relevant differences in biological processes included complement activation, mesenchyme development, and aerobic electron transport chain. Compared to CON LRMSC, IPF cells displayed impaired mitochondrial respiration, lower expression of genes involved in mitochondrial dynamics, and dysmorphic mitochondria. These changes were linked to an impaired autophagic response and a lower mRNA expression of pro-apoptotic genes. In addition, IPF TGFβ-exposed LRMSC presented different expression profiles of mitochondrial-related genes compared to CON TGFβ-treated cells, suggesting that TGFβ reinforces mitochondrial dysfunction. In conclusion, these results suggest that mitochondrial dysfunction is a major event in LRMSC and that their occurrence might limit LRMSC function, thereby contributing to IPF development.

Lung-resident mesenchymal stem cells (LR-MSC) are thought to participate in idiopathic pulmonary fibrosis (IPF) by differentiating into myofibroblasts. On the other hand, LR-MSC in IPF patients present senescence-related features. It is unclear how they respond to a profibrotic environment. Here, we investigated the profibrotic response of LR-MSC isolated from IPF and control (CON) patients. LR-MSC were inoculated in mice 48 h after bleomycin (BLM) instillation to analyze their contribution to lung damage. In vitro, LR-MSC were exposed to TGFβ. Mice inoculated with IPF LR-MSC exhibited worse maintenance of their body weight. The instillation of either IPF or CON LR-MSC sustained BLM-induced histological lung damage, bronchoalveolar lavage fluid cell count, and the expression of the myofibroblast marker, extracellular matrix (ECM) proteins, and proinflammatory cytokines in the lungs. In vitro, IPF LR-MSC displayed higher basal protein levels of aSMA and fibronectin than CON LR-MSC. However, the TGFβ response in the expression of TGFβ, aSMA, and ECM genes was attenuated in IPF LR-MSC. In conclusion, IPF LR-MSC have acquired myofibroblastic features, but their capacity to further respond to profibrotic stimuli seems to be attenuated. In an advanced stage of the disease, LR-MSC may participate in disease progression owing to their limited ability to repair epithelial damage.

There is a paucity of in vivo assays to investigate the potential deleterious effects of plastic-laden compounds in the gastrointestinal tract of mammals, compared to in vitro testing and ecotoxicity assays in marine organisms. This work aims to fill this gap through a comprehensive evaluation of the acute toxicokinetics and bioavailability of bisphenol A (BPA)-adsorbed medium-density polyethylene (PE) microplastics (MPs) (ca. 3000 μg BPA/g), with a mean particle size of 136 μm, which were administered via oral gavage at a mere 0.67 mg BPA/kg body weight for 24 h using a murine model. The determination of plasma BPA-glucuronide revealed that BPA associated with MPs (PE-BPA) is bioavailable to a similar extent to that of freely dissolved BPA, with Area Under the Curves (AUC) values of 1249 ± 182 and 928 ± 276 μg h·L^-1 for the 0 → 6 h interval (AUC_0→6h), and 3586 ± 526 and 2325 ± 634 μg h·L^-1 for the 0 → 24 h interval (AUC_0→24h), corresponding to PE-BPA and free BPA, respectively. Several biomarker assays of the small intestine and liver, and the investigation of the gut barrier function were conducted to elucidate the potential deleterious effects of PE-BPA as compared to BPA and PE alone. Acute exposure to PE-BPA increased the expression of the detoxification biomarkers multidrug resistance protein 1 (MDR1) and UDP-glucuronosyltransferase 2b1 (UGT2b1) in the jejunum, particularly when PE and BPA occurred together, likely due to the extended intestinal residence time of the BPA-laden MPs. Oxidative stress markers, such as superoxide dismutase activity, and inflammatory responses, evaluated by myeloperoxidase activity, were also elevated in the PE-BPA group, suggesting a defensive response but without evidence of oxidative damage as determined by the malondialdehyde levels. In conclusion, the findings suggest that BPA associated with MPs exhibits similar bioavailability than that of freely dissolved BPA, with the subsequent activation of detoxification pathways and inflammatory responses.

Background/Objectives: The inconsistent clinical outcomes of platelet-rich plasma (PRP) therapy for knee osteoarthritis (KOA) highlight the need to elucidate PRP’s therapeutic potential and influencing factors. Real-world evidence can provide valuable insights in a broad patient population. This study aims to analyze real-world data from KOA patients treated with PRP. Methods: Real-world data from 86 KOA patients treated with intraosseous combined with intra-articular (IO + IA) PRP injections were utilized to retrospectively evaluate the long-term effectiveness of this procedure and the impact of PRP characteristics and patient variables on treatment response. Results: The WOMAC score was reduced 2 months after completing the treatment procedure. Such a reduction was sustained throughout the follow-up time points, up to 18 months. The percentage of responders was between 55 and 67%. The PRP erythrocyte and leukocyte counts negatively correlated with the change in WOMAC score (ΔWOMAC). The PRP platelet count did not correlate with the WOMAC or the ΔWOMAC scores. The KL severity degree did not affect the responsiveness to treatment. Women reported a higher WOMAC score than men, both before and 2 and 3 months after PRP treatment. However, the ΔWOMAC score was not different between sexes within this period. A negative correlation trend was detected between the patient’s age and the ΔWOMAC score. Conclusions: IO + IA PRP administration alleviated severe KOA symptoms with sustained relief for up to 18 months in most patients, potentially delaying the need for knee prostheses. The clinical efficacy was not influenced by narrow platelet dose variations but was negatively impacted by the leukocyte content in the long term, while sex and KOA severity had no influence.

Sepsis is characterized by a dysregulated host response to infection; this can lead to multiorgan dysfunction where liver and kidneys play a key role. This study evaluated whether long-term oral administration of A12C modulates hepatic and renal homeostasis under basal conditions and during polymicrobial sepsis. Forty-five male Sprague–Dawley rats were allocated to healthy control (SAN), healthy A12C-treated (STO), septic control (IC), or septic A12C-treated (IA) groups. A12C was administered in drinking water at 6×10⁸ CFU/mL for 30 days, and sepsis was induced by caecal ligation and puncture (CLP). Gene expression, protein abundance, antioxidant enzyme activities, and histopathological alterations were evaluated in liver and kidney. Under basal conditions, A12C reduced hepatic Tlr4 and Tgfb1 expression and TLR4, ICAM-1, and SOD2 protein abundance, whereas renal Tnf and Icam1 expression and SOD and GRd activities increased. During sepsis, A12C-treated rats showed lower hepatic expression of Tnf, Il6, Ccl2, Icam1, and Nos2, together with increased SOD1 protein abundance. In kidney, A12C reduced Tlr4, Il6 and Icam1 expression and increase CAT, GPx, and GRd activities. Reduced expression of several inflammatory and endothelial mediators was detected in both organs and a marked enhancement of renal antioxidant defences during sepsis. The present results support the potential of A12C to improve the host response to sepsis and limit sepsis-associated organ dysfunction, possibly through a preconditioning-like mechanism.