Dysregulated intestinal epithelial apoptosis initiates gut injury, alters the intestinal barrier, and can facilitate bacterial translocation leading to a systemic inflammatory response syndrome (SIRS) and/or multi-organ dysfunction syndrome (MODS). A variety of gastrointestinal disorders, including inflammatory bowel disease, have been linked to intestinal apoptosis. Similarly, intestinal hyperpermeability and gut failure occur in critically ill patients, putting the gut at the center of SIRS pathology. Regulation of apoptosis and immune-modulatory functions have been ascribed to Thirty-eight-negative kinase 1 (TNK1), whose activity is regulated merely by expression. We investigated the effect of TNK1 on intestinal integrity and its role in MODS. TNK1 expression induced crypt-specific apoptosis, leading to bacterial translocation, subsequent septic shock, and early death. Mechanistically, TNK1 expression in vivo resulted in STAT3 phosphorylation, nuclear translocation of p65, and release of IL-6 and TNF-α. A TNF-α neutralizing antibody partially blocked development of intestinal damage. Conversely, gut-specific deletion of TNK1 protected the intestinal mucosa from experimental colitis and prevented cytokine release in the gut. Finally, TNK1 was found to be deregulated in the gut in murine and porcine trauma models and human inflammatory bowel disease. Thus, TNK1 might be a target during MODS to prevent damage in several organs, notably the gut.

The complement system is a major pillar of the humoral innate immune system. As a first line of defense against pathogens, it mediates early inflammatory response and links different branches of humoral and cellular immunity. Disorders affecting the exocrine pancreas, such as acute pancreatitis, potentially lead to a life-threatening systemic inflammatory response with aberrant activation of complement and coagulation cascades. Pancreatic proteases can activate key effectors of the complement system, which in turn drive local and systemic inflammation. Beyond that, the extent of pancreas–complement interaction covers complex pro- and anti-inflammatory mechanisms, which to this day remain to be fully elucidated. This review provides a comprehensive overview of the pathophysiological role of complement in diseases of the exocrine pancreas, based on existing experimental and clinical data. Participation of complement in acute and chronic pancreatitis is addressed, as well as its role in tumor immunology. Therapeutic strategies targeting complement in these diseases have long been proposed but have not yet arrived in the clinical setting.

Abdominal trauma (AT) is of major global importance, particularly with the increased potential for civil, terroristic, and military trauma. The injury pattern and systemic consequences of blunt abdominal injuries are highly variable and frequently underestimated or even missed, and the pathomechanisms remain still poorly understood. Therefore, we investigated the temporal-spatial organ and immune response after a standardized blast-induced blunt AT. Anesthetized mice were exposed to a single blast wave centered on the epigastrium. At 2, 6, or 24 h after trauma, abdominal organ damage was assessed macroscopically, microscopically, and biochemically. A higher degree of trauma severity, determined by a reduction of the distance between the epigastrium and blast inductor, was reflected by a reduced survival rate. The hemodynamic monitoring during the first 120 min after AT revealed a decline in the mean arterial pressure within the first 80 min, whereas the heart rate remained quite stable. AT induced a systemic damage and inflammatory response, evidenced by elevated HMGB-1 and IL-6 plasma levels. The macroscopic injury pattern of the abdominal organs (while complex) was consistent, with the following frequency: liver > pancreas > spleen > left kidney > intestine > right kidney > others > lungs and was reflected by microscopic liver and pancreas damages. Plasma levels of organ dysfunction markers increased during the first 6 h after AT and subsequently declined, indicating an early, temporal impairment of the function on a multi-organ level. The established highly reproducible murine blunt AT, with time-and trauma-severity-dependent organ injury patterns, systemic inflammatory response, and impairment of various organ functions, reflects characteristics of human AT. In the future, thisThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Thrombotic microangiopathy (TMA) is a rare but severe complication of tumors and their chemotherapeutic treatment. We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated. Additional studies need to determine the optimal duration of complement-directed therapies and validate effective monitoring strategies after discontinuation of such therapy.

Manual segmentation of hepatic metastases in ultrasound images acquired from patients suffering from pancreatic cancer is common practice. Semiautomatic measurements promising assistance in this process are often assessed using a small number of lesions performed by examiners who already know the algorithm. In this work, we present the application of an algorithm for the segmentation of liver metastases due to pancreatic cancer using a set of 105 different images of metastases. The algorithm and the two examiners had never assessed the images before. The examiners first performed a manual segmentation and, after five weeks, a semiautomatic segmentation using the algorithm. They were satisfied in up to 90% of the cases with the semiautomatic segmentation results. Using the algorithm was significantly faster and resulted in a median Dice similarity score of over 80%. Estimation of the inter-operator variability by using the intra class correlation coefficient was good with 0.8. In conclusion, the algorithm facilitates fast and accurate segmentation of liver metastases, comparable to the current gold standard of manual segmentation.