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Background: Persistent inflammation, immunosuppression, and catabolism syndrome (PICS) refers to the chronic critical illness phase of severe immunosuppression with persistent inflammatory response and repeated nosocomial infections, protein hypercatabolism, poor nutritional status, and persistent multiple organ injury in critical patients. These patients are difficult to treat and have a poor prognosis. Here, we established a new type of mouse PICS model to investigate its underlying pathophysiological mechanisms and its potential treatment.

Methods: We divided C57BL/6 male mice at 8-10 weeks into SHAM-operated group, DEXA group, CLP group and CLP + DEXA group. Each group had 10 mice. Sepsis was induced using a modified cecal ligation and perforation (CLP) model on day 1 (cecal ligation site to 30% away from the end of the cecal), and the inflammatory response was maintained by injection of dexamethasone (DEXA) at a dose of 2 mg/kg/day on day 3. Then ELISA, flow cytometry, western blotting and Q-PCR were used to detect inflammation, immunosuppression and catabolic indicators in mice.

Results: We found that at day 14, the levels of IL-6, TNF-α, and IL-1β in the CLP + DEXA group increased by approximately 3,000%, 400%, and 300%, respectively, compared to the CLP group. The proportions of MDSCs and CD4 + T cells in the CLP + DEXA group were about 31.2% and 5.7%, while the proportions in the CLP group were 22.97% and 8.03%. This result also suggests a severe immunosuppressive state in the CLP + DEXA group. Compared with the CLP group, the body weight and muscle mass of the CLP + DEXA group were reduced by about 3.6 g and 135 mg, respectively, and the expression of muscle atrophy related genes such as Atrogin-1 and MuRF-1 was also increased by more than 500%. By examining intestinal tight junction proteins such as ZO-1 and Occludin, we found that the intestinal barrier of CLP + DEXA mice was severely disrupted. The 16srRNA and blood coated plates also confirmed the presence of the gut microbiota dysbiosis and translocation in the CLP + DEXA mice, which was similar to those in critically ill patients.

Conclusions: Collectively, our work developed a new type of mouse PICS model and elucidated that bacterial translocation plays a critical role in PICS. It also sheds light on tryptophan derivatives as potential therapeutic targeting of PICS.

Introduction: Hemorrhagic shock (HS) and traumatic brain injury (TBI) are leading causes of death in trauma. It has been shown that a novel partially occluding resuscitative endovascular balloon occlusion of the aorta device (p-REBOA) can be deployed in the thoracic aorta for up to 2 h with minimal downstream ischemia. However, the impact of partial occlusion on the injured brain has not been studied. We hypothesized that the use of the p-REBOA in a model of TBI and HS would not worsen the brain lesion size.

Methods: Yorkshire, female swine (40-45 kg; n = 22) were subjected to controlled cortical impact TBI and 40% blood volume loss. After 1 h of shock, they were randomized to either (1) placement of p-REBOA for 2 h (p-REBOA group) or (2) no p-REBOA (control). Brain lesion size, survival rates, resuscitation requirements, and key laboratory values were used to compare the groups.

Results: Nineteen animals survived to the end of the experiment, with all three deaths in the p-REBOA group ( P  = 0.1336). The brain lesion size was similar between the groups (mean p-REBOA volume vs. control: 3,690.93 ± 1,027.21 mm 3 and 2,961.32 ± 807.31 mm 3 , respectively; P  = 0.1245). The p-REBOA group showed more severe tissue ischemia, as defined by worse peak lactic acidosis ( P  < 0.000001). All animals in the p-REBOA group required vasopressor support during the critical care period compared to one in the control group ( P  = 0.0001).

Conclusion: Prolonged partial occlusion of the thoracic aorta in a combined model of HS and TBI results in significant hemodynamic instability, without an increase in the brain lesion size.

Epidermal growth factor (EGF) has healing effects on the intestinal mucosa and improves survival when administered systemically after the onset of preclinical sepsis. The intestine plays a key role in this improvement in mortality as transgenic mice that overexpress EGF only in the villus epithelium also have a survival benefit. However, EGF also has extraintestinal effects mediated via the adaptive immune system. To determine whether systemic EGF alters the T-cell response following sepsis, splenic flow cytometry was assayed in mice randomized to receive systemic EGF or vehicle. CD4 + T-cell frequency was increased, whereas CD8 + T-cell frequency was decreased in septic mice following EGF, associated with a significant decrease in activated CD4 + T memory cells. Further, the exhaustion marker TIGIT was significantly upregulated following EGF on both conventional and regulatory CD4 + T cells. Based on these findings and known crosstalk between the gut epithelium and the adaptive immune system, we asked whether the beneficial effects of systemic and intestine-specific EGF were dependent on the presence of an adaptive immune system. Rag1-/- mice lacking mature lymphocytes were randomized to receive either systemic EGF or vehicle following sepsis. In contrast to its beneficial effect in immunocompetent mice, EGF markedly worsened 7-day mortality in Rag1 -/- mice. Similar to immunocompetent mice, EGF decreased gut epithelial apoptosis in Rag1 -/- mice but lost its ability to improve either permeability or villus length. Further, when transgenic mice that overexpress intestine-specific EGF were crossed to Ra g1 -/- mice, intestine-specific EGF had no impact on survival following sepsis despite retaining its ability to decrease sepsis-induced gut epithelial apoptosis and permeability. Thus, although EGF is a potentially novel therapeutic in sepsis via improving gut integrity, EGF also changes T-cell biology, and the survival advantage of EGF following sepsis is dependent, at least in part, on interactions between the gut and the adaptive immune system.

Background: Cardiomyopathy is a common complication of sepsis that contributes to increased morbidity and mortality. However, the molecular mechanisms underlying septic cardiomyopathy are poorly understood. Dichloroacetate (DCA) improves mitochondrial respiration and survival in a mouse model of sepsis by inhibiting pyruvate dehydrogenase kinase, which inactivates pyruvate dehydrogenase (PDH) through phosphorylation of its subunits. In this study, we explore the role of DCA in septic cardiac dysfunction using a murine sepsis model.

Methods: Cecal ligation and puncture (CLP) was performed in mice to investigate molecular and echocardiographic response to sepsis. DCA was administered to test the effects of PDH activation on cardiac performance during early and late sepsis and myocardial metabolic substrate production. Matrix-assisted laser desorption/ionization imaging mass spectrometry was used to reveal spatial alterations in metabolism.

Results: CLP significantly increased phosphorylation of the PDH E1α subunit (PDH inactivation), and DCA treatment reduced PDH E1α phosphorylation (PDH activation) to baseline without affecting total PDH E1α levels. Administration of DCA at the time of CLP improved cardiac preload and stroke volume without affecting cardiac contractility at 12 h after CLP. However, there was a significant increase in cardiac contractility at 30 h after DCA administration independent of cardiac loading conditions. This improved cardiac function after DCA administration was associated with a trend toward decreased production of metabolic intermediates such as ketogenic amino acids, succinate, and palmitoyl carnitine. Imaging mass spectrometry revealed an increase in itaconate expression upon CLP that was mitigated by DCA administration.

Conclusion: Our findings revealed that sepsis decreased PDH activity in cardiac tissue. Rebalancing PDH activity with DCA improved cardiac performance after CLP. While imaging mass spectrometry identified changes in itaconate concentration and enabled detection of tricarboxylic acid cycle metabolites, further investigation is necessary to determine whether DCA is an effective therapeutic agent for septic cardiomyopathy.

Background: Prone positioning (PP) improves survival in severe acute respiratory distress syndrome (ARDS), but its prolonged effects on pulmonary and extrapulmonary organs remain unclear. This study aimed to investigate the pathophysiological effects of 24-h PP in a porcine ARDS model.

Methods: Ten female Bama mini swine (49.5 ± 3.7 kg) underwent severe ARDS induction via repeated saline lavage and were randomized to PP (n = 5) or supine position (SP, n = 5). Respiratory parameters, electrical impedance tomography, hemodynamics, and biochemical serum analysis were performed. After 24 h, regional lung injury was assessed via histopathology and wet-dry weight ratio, and extrapulmonary injury was evaluated by histopathology, apoptosis, oxidative stress, and organ-specific injury biomarkers.

Results: Nine swine were analyzed (PP, n = 5; SP, n = 4). PP significantly improved the PaO 2 /FiO 2 ratio. Electrical impedance tomography showed sustained improvements in ventilation, perfusion, and ventilation-perfusion matching (V/Q matching), particularly in the dorsal regions. Wet-dry weight ratio in the dorsal lung was significantly lower in the PP group, with no significant differences in respiratory mechanics or histopathological lung injury. Hemodynamic parameters, intra-abdominal pressure, and serum biochemical analyses showed no significant differences. Extrapulmonary injury analysis revealed no differences, except for a higher apoptotic index in renal tissue in the PP group.

Conclusions: Prolonged PP improved oxygenation by improving ventilation, perfusion, and V/Q matching, while reducing dorsal lung edema, without significantly affecting respiratory mechanics or histopathological lung injury. Additionally, PP showed no significant damage on hemodynamics and extrapulmonary organ function. However, attention should be given to potential renal impairment during prolonged PP administration.