Removal of Inflammatory Ascites Is Associated With Dynamic Modification of Local and Systemic Inflammation Along With Prevention of Acute Lung Injury: In Vivo and In Silico Studies

• Published in: Shock (Augusta, Ga.) Ga.), 2014-04, Vol.41 (4), p.317-323
• Main Authors: Emr, Bryanna, Sadowsky, David, Azhar, Nabil, Gatto, Louis A, An, Gary, Nieman, Gary F, Vodovotz, Yoram
• Format: Article
• Language: English
• Subjects: Acute Lung Injury - etiology; Acute Lung Injury - pathology; Acute Lung Injury - prevention & control; Animals; Ascites - complications; Ascites - metabolism; Ascites - therapy; Computer Simulation; Female; Inflammation Mediators - metabolism; Models, Biological; Oxygen - blood; Partial Pressure; Principal Component Analysis; Respiratory Distress Syndrome, Adult - etiology; Respiratory Distress Syndrome, Adult - pathology; Respiratory Distress Syndrome, Adult - prevention & control; Sepsis - complications; Sepsis - metabolism; Suction - methods; Sus scrofa
• ISSN: 1073-2322; 1540-0514
• DOI: 10.1097/SHK.0000000000000121

ABSTRACTBackgroundSepsis-induced inflammation in the gut/peritoneal compartment occurs early in sepsis and can lead to acute lung injury (ALI). We have suggested that inflammatory ascites drives the pathogenesis of ALI and that removal of ascites with an abdominal wound vacuum prevents ALI. We hypothesized that the time- and compartment-dependent changes in inflammation that determine this process can be discerned using principal component analysis (PCA) and Dynamic Bayesian Network (DBN) inference. MethodsTo test this hypothesis, data from a previous study were analyzed using PCA and DBN. In that study, two groups of anesthetized, ventilated pigs were subjected to experimental sepsis via intestinal ischemia/reperfusion and placement of a peritoneal fecal clot. The control group (n = 6) had the abdomen opened at 12 h after injury (T12) with attachment of a passive drain. The peritoneal suction treatment (PST) group (n = 6) was treated in an identical fashion except that a vacuum was applied to the peritoneal cavity at T12 to remove ascites and maintained until T48. Multiple inflammatory mediators were measured in ascites and plasma and related to lung function (PaO2/FIO2 ratio and oxygen index) using PCA and DBN. ResultsPeritoneal suction treatment prevented ALI based on lung histopathology, whereas control animals developed ALI. Principal component analysis revealed that local to the insult (i.e., ascites), primary proinflammatory cytokines play a decreased role in the overall response in the treatment group as compared with control. In both groups, multiple, nested positive feedback loops were inferred from DBN, which included interrelated roles for bacterial endotoxin, interleukin 6, transforming growth factor β1, C-reactive protein, PaO2/FIO2 ratio, and oxygen index. von Willebrand factor was an output in control, but not PST, ascites. ConclusionsThese combined in vivo and in silico studies suggest that in this clinically realistic paradigm of sepsis, endotoxin drives the inflammatory response in the ascites, interplaying with lung dysfunction in a feed-forward loop that exacerbates inflammation and leads to endothelial dysfunction, systemic spillover, and ALI; PST partially modifies this process.