To explore the mechanism of mitochondrial uncoupling protein 2 (UCP2) mediating the protective of melatonin when septic cardiomyopathy. UCP2 knocked out mice and cardiomyocytes were used to study the effect of melatonin in response to LPS. Indicators of myocardial and mitochondria injury including mitochondrial membrane potential, mitochondrial permeability transition pore, calcium loading, ROS, and ATP detection were assessed. In addition cell viability and apoptosis as well as autophagy-associated proteins were evaluated. Melatonin was able to protect heart function from LPS, which weakened in the UCP2-knockout mice. Consistently, genipin, a pharmacologic inhibitor of UCP2, augmented LPS-induced damage of AC16 cells. In contrast, melatonin upregulated UCP2 expression and protected the cells from the changes in morphology, mitochondrial membrane potential loss, mitochondrial Ca²⁺ overload, the opening of mitochondrial permeability transition pore, and subsequent increased ROS generation as well as ATP reduction. Mitophagy proteins (Beclin-1 and LC-3β) were increased while apoptosis-associated proteins (cytochrome C and caspase-3) were decreased when UCP2 was up-regulated. In conclusion, UCP2 may play a protecting role against LPS by regulating the balance between autophagy and apoptosis of cardiomyocytes, and by which mechanisms, it may contribute to homeostasis of cardiac function and cardiomyocytes activity. Melatonin may protect cardiomyocytes through modulating UCP2.

Background: In sepsis, vitamin D binding protein (VDBP) has been shown to be low-expressed. The current study examined the relationship between serum VDBP level and liver injury in sepsis patients, as well as in a mouse model for sepsis and in cultured liver epithelial cell line exposed to lipopolysaccharide (LPS). Methods: The human study included 78 sepsis patients and 50 healthy volunteers. Sepsis patients were categorized into sepsis survivor group ( n = 43) and sepsis non-survivor group ( n = 35) based on 28-day mortality for data analysis. Adult male C57BL/6 mice were subjected to cecal ligation and puncture (CLP). Serum samples were collected on day 1, 3, 5 and 7 to determine the levels of VDBP, 25-hydroxyvitamin D [25(OH)D ₃ ], 1,25-dihydroxyvitamin D [1,25(OH) ₂ D ₃ ], interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α). Potential protective effects of VDBP overexpression against LPS-induced liver damage were examined in cultured THLE2 cells. Results: Serum levels of VDBP, 25(OH)D ₃ , and 1,25(OH) ₂ D ₃ were significantly lower in sepsis patients vs. the healthy control ( P < 0.001), as well as in the sepsis non-survivor group vs. the sepsis survivor group ( P < 0.001, P = 0.0338, or P = 0.0013, respectively). Lower serum VDBP level was associated with higher Acute Physiology and Chronic Health Evaluation (APACHE) II score ( r = − 0.2565, P = 0.0234) and Sequential Organ Failure Assessment score ( r = − 0.3522, P = 0.0016), but lower serum albumin (ALB, r = 0.4628, P < 0.001) and total protein (TP, r = 0.263, P = 0.02). In CLP mice, there was a 5-day period of serum VDBP reduction, followed by return towards the baseline on day 7. VDBP was also decreased in LPS-treated THLE2 cells ( P < 0.001). VDBP overexpression reduced LPS-induced THLE2 damage. Reduced damage was associated with decreased oxidative stress and inactivation of the c-Jun N-terminal kinase signaling pathway. Conclusion: VDBP may be protective against sepsis-induced liver injury.

This study was performed to visualize the hemodynamic effects of pulmonary microcirculation and ventilation/perfusion (V/Q) matching after mechanical ventilation under different cardiac outputs and positive end-expiratory pressures (PEEPs). Ten experimental pigs were randomly divided into high and low tidal volume groups, and ventilation/perfusion were measured by electrical impedance tomography (EIT) at different PEEPs. Then, all the pigs were redivided into high cardiac output (CO) and low CO groups and measured by EIT at different PEEP levels with a low tidal volume. Additionally, sidestream dark field (SDF) was used to measure pulmonary microcirculation. Hemodynamic parameters and respiratory mechanics parameters were recorded. As PEEP increased at high tidal volume, blood flow was impaired at a higher PEEP (20 cmH₂O) compared with low tidal volume (shunt: 30.01 ± 0.69% vs. 17.95 ± 0.72%; V/Q ratio: 65.12 ± 1.97% vs. 76.57 ± 1.25%, p < 0.01). Low tidal volume combined with an appropriate PEEP is the best option from the match between ventilation and pulmonary blood flow. Increasing PEEP can solve the problem of excessive shunt at high CO, and the V/Q ratio tends to match. At low CO, the increased dead space can reach as high as 64.64 ± 7.13% when PEEP = 20 cmH₂O. With increasing PEEP, the microcirculation index deteriorates, including total vessel density (TVD), proportion of perfused vessel (PPV), perfused vessel density (PVD), and microcirculatory flow index (MFI). The periodic collapse of pulmonary capillaries or interruption of blood flow obviously occurred with high PEEP. The hemodynamic parameters indicated that the transpulmonary capillary wall pressure (Pcap) of the low CO group was negative at PEEP = 5 cmH₂O, which determines the opening and closing of the pulmonary microcirculation and controls lung perfusion and the production of extravascular lung water. Therefore, it is essential to couple macrocirculation and pulmonary microcirculation during mechanical ventilation by improving shunting and optimizing Pcap.

Acute Respiratory Distress Syndrome (ARDS) is a sudden onset of lung injury characterized by bilateral pulmonary edema, diffuse inflammation, hypoxemia, and a low P/F ratio. Epithelial injury and endothelial injury are notable in the development of ARDS, which is more severe under mechanical stress. This review explains the role of alveolar epithelial cells and endothelial cells under physiological and pathological conditions during the progression of ARDS. Mechanical injury not only causes ARDS but is also a side effect of ventilator-supporting treatment, which is difficult to model both in vitro and in vivo. The development of lung organoids has seen rapid progress in recent years, with numerous promising achievements made. Multiple types of cells and construction strategies are emerging in the lung organoid culture system. Additionally, the lung-on-a-chip system presents a new idea for simulating lung diseases. This review summarizes the basic features and critical problems in the research on ARDS, as well as the progress in lung organoids, particularly in the rapidly developing microfluidic system-based organoids. Overall, this review provides valuable insights into the three major factors that promote the progression of ARDS and how advances in lung organoid technology can be used to further understand ARDS.

The inhalation of zinc chloride (ZnCl₂) smoke is one of common resources of lung injury, potentially resulting in severe pulmonary complications and even mortality. The influence of ZnCl₂ smoke on lysine succinylation (Ksucc) in the lungs remains uncertain. In this study, we used a ZnCl₂ smoke inhalation mouse model to perform global proteomic and lysine succinylome analyses. A total of 6781 Ksucc sites were identified in the lungs, with injured lungs demonstrating a reduction to approximately 2000 Ksucc sites, and 91 proteins exhibiting at least five differences in the number of Ksucc sites. Quantitative analysis revealed variations in expression of 384 proteins and 749 Ksucc sites. The analysis of protein-protein interactions was conducted for proteins displaying differential expression and differentially expressed lysine succinylation. Notably, proteins with altered Ksucc exhibited increased connectivity compared with that in differentially expressed proteins. Beyond metabolic pathways, these highly connected proteins were also involved in lung injury-associated pathological reactions, including processes such as focal adhesion, adherens junction, and complement and coagulation cascades. Collectively, our findings contribute to the understanding of the molecular mechanisms underlaying ZnCl₂ smoke-induced lung injury with a specific emphasis on lysine succinylation. These findings could pave the way for targeted interventions and therapeutic strategies to mitigate severe pulmonary complications and mortality associated with such injuries in humans.