Extracellular nucleotides (e.g., ATP, ADP, UTP, UDP) released by inflammatory cells interact with specific purinergic P2 type receptors to modulate their recruitment and activation. The focus of this review is on stimuli and mechanisms of extracellular nucleotide release and its consequences during inflammation. Necrosis leads to non-specific release of nucleotides, whereas specific release mechanisms include vesicular exocytosis and channel-mediated release via connexin or pannexin hemichannels. These release mechanisms allow stimulated inflammatory cells such as macrophages, neutrophils, and endothelial cells to fine-tune autocrine/paracrine responses during acute and chronic inflammation. Key effector functions of inflammatory cells are therefore regulated by purinergic signaling in acute and chronic diseases, making extracellular nucleotide release a promising target for the development of new therapies.

Bacterial spillage into a sterile environment following intestinal hollow-organ perforation leads to peritonitis and fulminant sepsis. Outcome of sepsis critically depends on macrophage activation by extracellular ATP-release and associated autocrine signalling via purinergic receptors. ATP-release mechanisms, however, are poorly understood. Here, we show that TLR-2 and −4 agonists trigger ATP-release via Connexin-43 hemichannels in macrophages leading to poor sepsis survival. In humans, Connexin-43 was upregulated on macrophages isolated from the peritoneal cavity in patients with peritonitis but not in healthy controls. Using a murine peritonitis/sepsis model, we identified increased Connexin-43 expression in peritoneal and hepatic macrophages. Conditional Lyz2^cre/creGja1^flox/flox mice were developed to specifically assess Connexin-43 impact in macrophages. Both macrophage-specific Connexin-43 deletion and pharmacological Connexin-43 blockade were associated with reduced cytokine secretion by macrophages in response to LPS and CLP, ultimately resulting in increased survival. In conclusion, inhibition of autocrine Connexin-43-dependent ATP signalling on macrophages improves sepsis outcome.

Paracrine signalling mediated by cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. Interleukin‐22 (IL‐22) is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear whether IL‐22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy (PH). Here, we found that plasma levels of IL‐22 and its upstream cytokine, IL‐23, are highly elevated in patients after major liver resection. In a mouse model of PH, deletion of IL‐22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. UsingRag1^−/−andRag2−/−γc−/⁻mice, we show that the main producers of IL‐22 post‐PH are conventional natural killer cells and innate lymphoid cells type 1. Extracellular adenosine triphosphate (ATP), a potent danger molecule, is elevated in patients immediately after major liver resection. Antagonism of the P2‐type nucleotide receptors, P2X1 and P2Y6, significantly decreased IL‐22 secretionex vivo.In vivo, specific inhibition of P2X1 was associated with decreased IL‐22 secretion, elevated liver injury, and impaired liver regeneration.Conclusion:This study shows that innate immune cell‐derived IL‐22 is required for efficient liver regeneration and that secretion of IL‐22 in the regenerating liver is modulated by the ATP receptor, P2X1. (Hepatology2016;63:2004‐2017)

The toll-like receptor 5 (TLR5) agonist, CBLB502/Entolimod, is a peptide derived from bacterial flagellin and has been shown to protect against radiation-induced tissue damage in animal models. Here we investigated the protective mechanism of CBLB502 in the liver using models of ischemia-reperfusion injury and concanavalin A (ConA) induced immuno-hepatitis. We report that pretreatment of mice with CBLB502 provoked a concomitant activation of NF-κB and STAT3 signaling in the liver and reduced hepatic damage in both models. To understand the underlying mechanism, we screened for cytokines in the serum of CBLB502 treated animals and detected high levels of IL-22. There was no transcriptional upregulation of IL-22 in the liver, rather it was found in extrahepatic tissues, mainly the colon, mesenteric lymph nodes (MLN), and spleen. RNA-seq analysis on isolated hepatocytes demonstrated that the concomitant activation of NF-κB signaling by CBLB502 and STAT3 signaling by IL-22 produced a synergistic cytoprotective transcriptional signature. In IL-22 knockout mice, the loss of IL-22 resulted in a decrease of hepatic STAT3 activation, a reduction in the cytoprotective signature, and a loss of hepatoprotection following ischemia-reperfusion-induced liver injury. Taken together, these findings suggest that CBLB502 protects the liver by increasing hepatocyte resistance to acute liver injury through the cooperation of TLR5-NF-κB and IL-22-STAT3 signaling pathways.

Half of the patients with esophageal cancer, cancer of the gastro-esophageal junction and gastric cancer present metastasis at the time of diagnosis. In addition, even patients originally thought to be free of metastasis will present metachronous metastasis in the course of the disease. These patients are considered incurable and current standard of care for metastatic esophageal, gastro-esophageal junction and gastric cancers is a systemic therapy without curative intention. However, patients presenting only a low metastatic load are now defined as oligometastatic disease and should benefit from an aggressive, multimodal therapy. We present here a review of recent publications investigating multimodal therapies for oligometastatic disease and showing that a systemic therapy combined with a resection of the primary tumor together with metastasis is associated with a better prognosis than a systemic therapy alone. We also give a precise focus on esophageal squamous cell carcinomas and adenocarcinomas of the gastro-esophageal junction and of the stomach. Interestingly, patients with oligometastatic cancer of the esophago-gastric junction can even be treated in curative intention with such a multimodal therapy as we present here in a short case report. In conclusion, new therapeutic strategies including multimodal approaches for oligometastatic disease have shown promising results in the last years and ongoing randomized prospective trials will provide us the evidence to include them in future European guidelines.

Robotic surgery has become increasingly prevalent in UGI surgery over the last decade, particularly for treating hiatal hernias. Voluminous hiatal hernias, defined as the herniation of 30–50 % of the stomach into the thorax, often require surgical intervention due to associated dysphagia and potential severe complications. Given the challenges of repairing voluminous hiatal hernias, especially in elderly and fragile patients, the surgical technique should be optimal. Robotic surgery affords excellent visualization, allowing high mediastinal dissection and precise hiatus reconstruction. Despite the clear technical advantages, it remains to be demonstrated if the robotic approach matches the outcomes of conventional laparoscopic techniques. We review here the fundamentals of hiatal hernia surgery and describe our surgical technique using the da Vinci Xi robot to operate voluminous hiatal hernias. Additionally, we performed a systematic research analysis and selected recent publications focusing on robotic surgery for voluminous hiatal hernias. Recent studies report comparable complication rates, recurrence, and hospital stay lengths between robotic and laparoscopy surgery. Initial robotic procedures had longer operative times, which decreased with surgeon experience. Most of the studies were observational and retrospective, reporting the experience of a single center. Robotic surgery appears to be a viable option with similar complications rates to laparoscopic surgery under optimized conditions. Current literature supports the broader adoption of robotic surgery for voluminous hiatal hernias. However, prospective randomized studies are needed to further validate its use.