Downregulation of PI3K-γ in a mouse model of sepsis-induced myocardial dysfunction.

A key component during sepsis is the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, of which the PI3K-γ isoform is a major regulator in many inflammatory responses. However, the role of PI3K-γ in the development of sepsis-induced myocardial dysfunction (SIMD) is unknown. In this study, we established a model of SIMD induced by lipopolysaccharide (LPS), subsequently used the selective inhibitor LY294002 and AS605240 to block the effect of PI3K and PI3K-γ, respectively. Cardiac function was evaluated by echocardiography, hearts were obtained for histological and protein expression examinations. ELISA was used to measure the serum levels of tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), cardiac troponin I (cTnI) and heart-type fatty acid binding protein (H-FABP). LPS-treated mice showed an increase to cardiac inflammation, myocardial damage and production of TNF-α, IL-6, NF-κB, cTnI and H-FABP. Administration of AS605240 to LPS-treated mice reduced some patho-physiological characteristics of SIMD and reduced TNF-α, IL-6, cTnI and H-FABP production. However, administration of LY294002 did not improve those same conditions. The results showed that PI3K-γ is likely a crucial element in SIMD by regulating the PI3K/Akt pathway, and become a new marker of myocardial injury. Inhibition of PI3K-γ might be a potential therapeutic target in SIMD.

Inflammation elevated IL-33 originating from the lung mediates inflammation in acute lung injury.

Excessive inflammatory reactions occur with acute respiratory distress syndrome (ARDS), however, the underlying mechanisms of ARDS remain incompletely understood. Here we investigated whether interleukin (IL)-33 was elevated in ARDS patients. Serum samples were obtained from 14 ARDS patients and 24 control healthy volunteers. ELISA was used to measure the concentrations of IL-33. Besides, we established pulmonary ARDS and extrapulmonary ARDS models in mice, and serum and lung tissue samples were collected for analyses. The results showed that serum IL-33 concentrations were significantly higher in pulmonary ARDS patients compared to controls. Also, the levels of IFN-γ and IL-2 were positively correlated with IL-33 levels. We also showed that there were increased IL-33 levels in both the serum and lungs in the pulmonary ARDS model. This was not the case, however, in the extrapulmonary ARDS model. Pulmonary inflammation and injury in the pulmonary ARDS model was reduced with IL-33 neutralizing antibody treatment.

Interleukin-27 is elevated in sepsis-induced myocardial dysfunction and mediates inflammation.

INTRODUCTION: Interleukin (IL)-27 is an important cytokine involved in many human inflammatory diseases. In this study, we investigated its role in the pathogenesis of sepsis-induced myocardial dysfunction (SIMD). METHODS: Twenty patients with SIMD and 24healthy donors were prospectively enrolled. Expression of IL-27 was detected in serum from SIMD patients by ELISA. Cardiac dysfunction was induced by administration of Escherichia coli lipopolysaccharide (LPS) to C57BL/6 (wild type) or IL-27R-/- mice. IL-27 mRNA in the myocardium was measured by RT-PCR. Cytokine levels in serum were determined by ELISA. RESULTS: Expression of IL-27 in the serum was markedly increased in patients with SIMD compared with that in controls. Serum IL-27 levels and cardiac IL-27 mRNA expression were significantly increased after LPS injection compared with control specimens. Compared with wild-type mice, IL-27R-/- mice had higher expression of brain natriuretic peptide, cardiac troponin I, IL-6, IL-12, tumor necrosis factor-α and transforming growth factor-ß. CONCLUSIONS: IL-27 is an important protective mediator of SIMD.

Short-term prone positioning for severe acute respiratory distress syndrome after cardiopulmonary bypass: A case report and literature review.

BACKGROUND: Aortic dissection is a complex and dangerous cardiovascular disease, with many complications in the perioperative period, including severe acute respiratory distress syndrome (ARDS), which affects prognosis and increases mortality. Despite the effect of prone positioning (PP) in improving oxygenation in patients with severe ARDS, reports about PP early after cardiac surgery are few and such an option may be an issue in cardiac surgery patients because of the recent sternotomy. CASE SUMMARY: A 40-year-old male patient diagnosed with acute type A aortic dissection on October 22, 2021 underwent ascending artery replacement plus total aortic arch replacement plus stent elephant trunk implantation under cardiopulmonary bypass. Unfortunately, he developed ARDS on postoperative day 1. Despite comprehensive treatment with aggressive pulmonary protective ventilation, fluid management with continuous renal replacement therapy, the condition continued to deteriorate and rapidly progressed to severe ARDS with a minimum oxygenation index of 51. We are ready to implement salvage therapy, including PP and extracorporeal membrane oxygenation (ECMO). Due to the large amount of pericardial mediastinal and thoracic drainage after thoracotomy, ECMO may result in massive postoperative bleeding. Prolonged prone ventilation is often inappropriate after thoracotomy. Therefore, we chose short-term PP for < 6 h. Finally, the oxygenation index greatly improved and the diffuse exudation in both lungs of the patient was significantly reduced with short-term prone positioning. CONCLUSION: Intermittent short-term PP can improve early postoperative severe ARDS after acute aortic dissection.

HMGB1 regulates IL-33 expression in acute respiratory distress syndrome.

The development and progression of acute respiratory distress syndrome (ARDS) has been shown to be regulated by cytokines. IL-33 and HMGB1 are conventionally considered as nuclear proteins and have a proinflammatory role. Studies have confirmed that HMGB1 has a significant role in ARDS, but few studies have provided direct evidence to confirm that IL33 is involved in ARDS. The purpose of our study was to determine whether IL-33 is elevated in ARDS and the relationship between IL-33 and HMGB1 in ARDS. We established a mouse model of LPS-induced lung inflammation/injury. Serum, bronchoalveolar lavage fluid (BALF) and lung tissues were obtained to determine the related indicators. IL-33 levels in both the serum, BALF and lungs were significantly increased at 24h after LPS administration compared to the control group. We also found that HMGB1 and other Th1 cytokine/chemokine levels in serum and BALF were also significantly elevated, but the Th2 cytokine levels in serum and BALF didn't increase. To further study the relationship between IL-33 and HMGB1, mice were pretreated with glycyrrhizin (an inhibitor of HMGB1) prior to LPS administration. We found that the expression of IL-33 and HMGB1 were markedly lower than those in the LPS group and the lung injury was ameliorated. The levels of other Th1 cytokines and chemokines in serum and BALF were also significantly decreased. The results showed that IL-33 is likely a major factor in ARDS, and the release of HMGB1 may be correlated with up-regulation of IL-33 expression.