Acute pancreatitis (AP) is a prevalent clinical condition of the digestive system, with a growing frequency each year. Approximately 20% of patients suffer from severe acute pancreatitis (SAP) with local consequences and multi-organ failure, putting a significant strain on patients’ health insurance. According to reports, the lungs are particularly susceptible to SAP. Acute respiratory distress syndrome, a severe type of acute lung injury (ALI), is the primary cause of mortality among AP patients. Controlling the mortality associated with SAP requires an understanding of the etiology of AP-associated ALI, the discovery of biomarkers for the early detection of ALI, and the identification of potentially effective drug treatments. Exosomes are a class of extracellular vesicles with a diameter of 30–150 nm that are actively released into tissue fluids to mediate biological functions. Exosomes are laden with bioactive cargo, such as lipids, proteins, DNA, and RNA. During the initial stages of AP, acinar cell-derived exosomes suppress forkhead box protein O1 expression, resulting in M1 macrophage polarization. Similarly, macrophage-derived exosomes activate inflammatory pathways within endothelium or epithelial cells, promoting an inflammatory cascade response. On the other hand, a part of exosome cargo performs tissue repair and anti-inflammatory actions and inhibits the cytokine storm during AP. Other reviews have detailed the function of exosomes in the development of AP, chronic pancreatitis, and autoimmune pancreatitis. The discoveries involving exosomes at the intersection of AP and acute lung injury (ALI) are reviewed here. Furthermore, we discuss the therapeutic potential of exosomes in AP and associated ALI. With the continuous improvement of technological tools, the research on exosomes has gradually shifted from basic to clinical applications. Several exosome-specific non-coding RNAs and proteins can be used as novel molecular markers to assist in the diagnosis and prognosis of AP and associated ALI.
Background: Severe acute pancreatitis (SAP) is a severe form of acute pancreatitis with the potential to cause life-threatening complications. Patients with acute SAP require surgical intervention and are admitted to the intensive care unit for non-invasive ventilation. Dexmedetomidine (Dex) is currently used by intensive care clinicians and anaesthesiologists as an adjunctive sedative. Therefore, the clinical availability of Dex makes it easier to implement in SAP treatment than developing new drugs.Methods: Randomly dividing thirty rats into sham-operated (Sham), SAP, and Dex groups. The severity of pancreatic tissue injury in each rat was assessed by Hematoxylin and eosin (HE) staining. Serum amylase activity and inflammatory factor levels were measured using commercially available kits. The expressions of necroptosis-related proteins, myeloperoxidase (MPO), CD68, and 4-hydroxy-trans-2-nonenal (HNE) were detected using immunohistochemistry (IHC). Transferase-mediated dUTP nick-end labeling (TUNEL) staining was utilized to identify pancreatic acinar cell apoptosis. The subcellular organelle structure of pancreatic acinar cells was observed using transmission electron microscopy. The regulatory effect of Dex on the gene expression profile of SAP rat pancreas tissue was investigated using RNA sequencing. We screened for differentially expressed genes (DEGs). Quantitative real-time PCR (qRT-PCR) measured critical DEG mRNA expression in rat pancreatic tissues.Results: Dex attenuated SAP-induced pancreatic injury, infiltration of neutrophils and macrophages, and oxidative stress. Dex inhibited the expression of necroptosis-associated proteins RIPK1, RIPK3, and MLKL and alleviated apoptosis in acinar cells. Dex also mitigated the structural damage caused by SAP to mitochondria and endoplasmic reticulum. Dex inhibited SAP-induced 473 DEGs, as determined by RNA sequencing. Dex may regulate SAP-induced inflammatory response and tissue damage by inhibiting the toll-like receptor/nuclear factor κB (TLR/NF-κB) signaling pathway and neutrophil extracellular trap formation.Conclusion: This study elucidated the remarkable effect of Dex against SAP and investigated the potential mechanism of action, providing an experimental base for the future clinical application of Dex in the treatment of SAP.
Objective C/EBPβ, a crucial transcription factor, regulates innate immunity and inflammatory responses. However, the role played by C/EBPβ in alveolar macrophage (AM) inflammatory responses remains unknown. This study aimed to investigate the role and mechanism of C/EBPβ in alveolar macrophages (AMs) from the transcriptional level and to search for natural compounds targeting C/EBPβ. Methods Rat AMs were infected with Lv-sh-C/EBPβ and treated with LPS, and the expression levels of iNOS, TNF-α, IL-6, and IL-1β were measured by RT-qPCR, Western blotting, and ELISA. Mechanistically, transcriptome sequencing (RNA-seq) revealed changes in gene expression patterns in AMs after LPS stimulation and C/EBPβ knockdown. Functional enrichment analyses and rescue experiments identified and validated inflammation-associated cell signaling pathways regulated by C/EBPβ. Furthermore, virtual screening was used to search for natural compounds that inhibit C/EBPβ with the structure of helenalin as a reference. Results Following stimulation with LPS, AMs exhibited an increased expression of C/EBPβ. C/EBPβ knockdown significantly decreased the expression levels of inflammatory mediators. A total of 374 differentially expressed genes (DEGs) were identified between LPS-stimulated C/EBPβ knockdown and negative control cells. The NOD-like receptor signaling may be a key target for C/EBPβ, according to functional enrichment analyses of the DEGs. Further experiments showed that the muramyl dipeptide (MDP, NOD2 agonist) reversed the downregulation of inflammatory mediators and the NF-κB pathway caused by the C/EBPβ knockdown. The virtual screening revealed that N-caffeoyltryptophan, orilotimod, and petasiphenone have comparable pharmacological properties to helenalin (a known C/EBPβ inhibitor) and demonstrate a great binding capacity to C/EBPβ. Conclusion Ablation of C/EBPβ may attenuate LPS-induced inflammatory damage in AMs by inhibiting the NOD2 receptor signaling pathway. Three natural compounds, N-caffeoyltryptophan, orilotimod, and petasiphenone, may be potential C/EBPβ inhibitors.
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