Probabilistic Prediction of Gastrointestinal Ischemia after Cardiothoracic Surgery.

BACKGROUND: Gastrointestinal ischemia (GIisch) is challenging to diagnose in patients after cardiothoracic surgery. Computed tomography angiography (CTA) carries substantial false-negative and false-positive rates. The aim of the study was to evaluate if a combination of readily available variables improves the diagnosis of GIisch after cardiothoracic surgery. METHODS: This retrospective study included patients receiving intensive care after cardiothoracic surgery. GIisch was confirmed by surgical and/or endoscopic findings. A GIisch prediction score was developed using the Spiegelhalter-Knill-Jones system in a training cohort then tested in a validation cohort (patients without obvious signs of GIisch on CTA). RESULTS: The training cohort comprised 125 consecutive patients with suspected GIisch in 2008 to 2019, including 85 with confirmed GIisch. CTA, performed in 92 patients, had a high false-negative rate of 17/60 (28%) and a lower false-positive rate of 7/32 (22%). The score included cardiopulmonary bypass, negatively associated with GIisch, and six variables positively associated with GIisch: intraoperative mean arterial pressure < 50 mm Hg, aspartate aminotransferase > 15 N, lactate increase in 24 hour > 20%, and 3 CTA findings, namely, bowel dilation, bowel wall thickening, and mesenteric vasoconstriction. The area under the receiver operating characteristic was 0.82 (95% confidence interval [CI], 0.51-0.93) in the training cohort and 0.82 (95% CI, 0.68-0.96) in the validation cohort (n = 34 patients). Reliability of the predicted probabilities was greatest for probabilities ≤ 30% or ≥ 70%. CONCLUSION: In patients receiving intensive care after cardiothoracic surgery, GIisch cannot be ruled out based solely on CTA findings. A scoring system combining CTA findings with other variables may improve the diagnosis of GIisch in this population.

LC3-associated phagocytosis protects against inflammation and liver fibrosis via immunoreceptor inhibitory signaling.

Sustained hepatic and systemic inflammation, particularly originating from monocytes/macrophages, is a driving force for fibrosis progression to end-stage cirrhosis and underlies the development of multiorgan failure. Reprogramming monocyte/macrophage phenotype has emerged as a strategy to limit inflammation during chronic liver injury. Here, we report that LC3-associated phagocytosis (LAP), a noncanonical form of autophagy, protects against hepatic and systemic inflammation during chronic liver injury in rodents, with beneficial antifibrogenic effects. LAP is enhanced in blood and liver monocytes from patients with fibrosis and cirrhosis. Pharmacological inhibition of LAP components in human monocytes from patients with cirrhosis or genetic disruption of LAP in mice with chronic liver injury exacerbates both the inflammatory signature in isolated human monocytes and the hepatic inflammatory profile in mice, resulting in enhanced liver fibrosis. Mechanistically, patients with cirrhosis showed increased monocyte expression of Fc fragment of IgG receptor IIA (FcγRIIA) and enhanced engulfment of immunoglobulin G in LC3+ phagosomes that triggers an FcγRIIA/Src homology region 2 domain-containing phosphatase-1 (SHP-1) inhibitory immunoreceptor tyrosine-based activation motif (ITAMi) anti-inflammatory pathway. Mice overexpressing human FcγRIIA in myeloid cells show enhanced LAP in response to chronic liver injury and resistance to inflammation and liver fibrosis. Activation of LAP is lost in monocytes from patients with multiorgan failure and restored by specifically targeting ITAMi signaling with anti-FcγRIIA F(ab')2 fragments, or with intravenous immunoglobulin (IVIg). These data suggest the existence of an ITAMi-mediated mechanism by which LAP might protect against inflammation. Sustaining LAP may open therapeutic perspectives for patients with chronic liver disease.

Mucosal-associated invariant T cells are a profibrogenic immune cell population in the liver.

Liver fibrosis is the common response to chronic liver injury, and leads to cirrhosis and its complications. Persistent inflammation is a driving force of liver fibrosis progression. Mucosal-associated invariant T (MAIT) cells are non-conventional T cells that display altered functions during chronic inflammatory diseases. Here, we show that circulating MAIT cells are reduced in patients with alcoholic or non-alcoholic fatty liver disease-related cirrhosis while they accumulate in liver fibrotic septa. Using two models of chronic liver injury, we demonstrate that MAIT cell-enriched mice show increased liver fibrosis and accumulation of hepatic fibrogenic cells, whereas MAIT cell-deficient mice are resistant. Co-culture experiments indicate that MAIT cells enhance the proinflammatory properties of monocyte-derived macrophages, and promote mitogenic and proinflammatory functions of fibrogenic cells, via distinct mechanisms. Our results highlight the profibrogenic functions of MAIT cells and suggest that targeting MAIT cells may constitute an attractive antifibrogenic strategy during chronic liver injury.