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Abstract Background Pulmonary fibrosis (PF) is an aging-related progressive lung disorder. The aged lung undergoes functional and structural changes termed immunosenescence and inflammaging, which facilitate the occurrence of fibrosis. Interleukin-10 (IL-10) is a potent anti-inflammatory and immunoregulatory cytokine, yet it remains unclear how IL-10 deficiency-induced immunosenescence participates in the development of PF. Methods Firstly we evaluated the susceptibility to fibrosis and IL-10 expression in aged mice. Then 13-month-old wild-type (WT) and IL-10 knockout (KO) mice were subjected to bleomycin(BLM) and analyzed senescence-related markers by PCR, western blot and immunohistochemistry staining of p16, p21, p53, as well as DHE and SA-β-gal staining. We further compared 18-month-old WT mice with 13-month-old IL-10KO mice to assess aging-associated cell senescence and inflamation infiltration in both lung and BALF. Moreover, proliferation and apoptosis of alveolar type 2 cells(AT2) were evaluated by FCM, immunofluorescence, TUNEL staining, and TEM analysis. Recombinant IL-10 (rIL-10) was also administered intratracheally to evaluate its therapeutic potential and related mechanism. For the in vitro experiments, 10-week-old naïve pramily lung fibroblasts(PLFs) were treated with the culture medium of 13-month PLFs derived from WT, IL-10KO, or IL-10KO + rIL-10 respectively, and examined the secretion of senescence-associated secretory phenotype (SASP) factors and related pathways. Results The aged mice displayed increased susceptibility to fibrosis and decreased IL-10 expression. The 13-month-old IL-10KO mice exhibited significant exacerbation of cell senescence compared to their contemporary WT mice, and even more severe epithelial-mesenchymal transition (EMT) than that of 18 month WT mice. These IL-10 deficient mice showed heightened inflammatory responses and accelerated PF progression. Intratracheal administration of rIL-10 reduced lung CD45 + cell infiltration by 15%, including a 6% reduction in granulocytes and a 10% reduction in macrophages, and increased the proportion of AT2 cells by approximately 8%. Additionally, rIL-10 significantly decreased α-SMA and collagen deposition, and reduced the expression of senescence proteins p16 and p21 by 50% in these mice. In vitro analysis revealed that conditioned media from IL-10 deficient mice promoted SASP secretion and upregulated senescence genes in naïve lung fibroblasts, which was mitigated by rIL-10 treatment. Mechanistically, rIL-10 inhibited TGF-β-Smad2/3 and PTEN/PI3K/AKT/ERK pathways, thereby suppressing senescence and fibrosis-related proteins. Conclusions IL-10 deficiency in aged mice leads to accelerated cell senescence and exacerbated fibrosis, with IL-10KO-PLFs displaying increased SASP secretion. Recombinant IL-10 treatment effectively mitigates these effects, suggesting its potential as a therapeutic target for PF. Graphical Abstract

Abstract Background Numerous studies have confirmed the involvement of extracellular vesicles (EVs) in various physiological processes, including cellular death and tissue damage. Recently, we reported that EVs derived from ischemia-reperfusion heart exacerbate cardiac injury. However, the role of EVs from healthy heart tissue (heart-derived EVs, or cEVs) on myocardial ischemia-reperfusion (MI/R) injury remains unclear. Results Here, we demonstrated that intramyocardial administration of cEVs significantly enhanced cardiac function and reduced cardiac damage in murine MI/R injury models. cEVs treatment effectively inhibited ferroptosis and maintained mitochondrial homeostasis in cardiomyocytes subjected to ischemia-reperfusion injury. Further results revealed that cEVs can transfer ATP5a1 into cardiomyocytes, thereby suppressing mitochondrial ROS production, alleviating mitochondrial damage, and inhibiting cardiomyocyte ferroptosis. Knockdown of ATP5a1 abolished the protective effects of cEVs. Furthermore, we found that the majority of cEVs are derived from cardiomyocytes, and ATP5a1 in cEVs primarily originates from cardiomyocytes of the healthy murine heart. Moreover, we demonstrated that adipose-derived stem cells (ADSC)-derived EVs with ATP5a1 overexpression showed much better efficacy on the therapy of MI/R injury compared to control ADSC-derived EVs. Conclusions These findings emphasized the protective role of cEVs in cardiac injury and highlighted the therapeutic potential of targeting ATP5a1 as an important approach for managing myocardial damage induced by MI/R injury.

Abstract Background Sepsis still remains a major challenge in intensive care medicine with unacceptably high mortality among patients with septic shock. Due to current limitations of human CD19+CD24hiCD38hi Breg cells (Bregs) studies among sepsis, here, we tried to evaluate Bregs in severity and prognostic value in patients with sepsis. Methods Peripheral blood from 58 patients with sepsis and 22 healthy controls was analyzed using flow cytometry to evaluate the frequency and number of Bregs. All cases were divided into non-survived or survived group after 28 days followed up. Spearman's correlation analysis was performed on Bregs frequency and clinical indices. The area under the curve was acquired using the receiver operating characteristic analysis to assess the sensitivity and specificity of Bregs for outcome of sepsis. Survival curve analysis and binary logistic regression were applied to estimate the value of Bregs in prognosis among cases with sepsis. Results Sepsis patients had decreased proportions and number of Bregs. Sepsis patients with low frequency of Bregs were associated with an increased risk of septic shock. Bregs frequency is inversely associated with lactate, SOFA, and APACHE II and positively correlated with Tregs frequency. Low levels of Bregs closely correlated with septic outcomes. Numbers of Bregs were prediction factors for poor prognosis. Conclusions Frequency and number of Bregs decreased, and Bregs deficiency revealed poor prognosis in patients with sepsis.