The discovery of inflammasomes has enriched our knowledge in the pathogenesis of multiple inflammatory diseases. The NLR pyrin domain-containing protein 3 (NLRP3) has emerged as the most versatile and well-characterized inflammasome, consisting of an intracellular multi-protein complex that acts as a central driver of inflammation. Its activation depends on a tightly regulated two-step process, which includes a wide variety of unrelated stimuli. It is therefore not surprising that the specific regulatory mechanisms of NLRP3 inflammasome activation remain unclear. Inflammasome-mediated inflammation has become increasingly important in acute pancreatitis, an inflammatory disorder of the pancreas that is one of the fatal diseases of the gastrointestinal tract. This review presents an update on the progress of research into the contribution of the NLRP3 inflammasome to acute pancreatic injury, examining the mechanisms of NLRP3 activation by multiple signaling events, the downstream interleukin 1 family of cytokines involved and the current state of the literature on NLRP3 inflammasome-specific inhibitors.

Role of aldehyde dehydrogenase 2 in ischemia reperfusion injury: An update

Hepatic ischemia reperfusion injury (HIRI) is a major hurdle in many clinical scenarios, including liver resection and transplantation. Various studies and countless surgical events have led to the observation of a strong correlation between HIRI induced by liver transplantation and early allograft-dysfunction development. The detrimental impact of HIRI has driven the pursuit of new ways to alleviate its adverse effects. At the core of HIRI lies mitochondrial dysfunction. Various studies, from both animal models and in clinical settings, have clearly shown that mitochondrial function is severely hampered by HIRI and that its preservation or restoration is a key indicator of successful organ recovery. Several strategies have been thus implemented throughout the years, targeting mitochondrial function. This work briefly discusses some the most utilized approaches, ranging from surgical practices to pharmacological interventions and highlights how novel strategies can be investigated and implemented by intricately discussing the way mitochondrial function is affected by HIRI.

The endoplasmic reticulum (ER) is involved in calcium homeostasis, protein folding and lipid biosynthesis. Perturbations in its normal functions lead to a condition called endoplasmic reticulum stress (ERS). This can be triggered by many physiopathological conditions such as alcoholic steatohepatitis, insulin resistance or ischemia-reperfusion injury. The cell reacts to ERS by initiating a defensive process known as the unfolded protein response (UPR), which comprises cellular mechanisms for adaptation and the safeguarding of cell survival or, in cases of excessively severe stress, for the initiation of the cell death program. Recent experimental data suggest the involvement of ERS in ischemia/reperfusion injury (IRI) of the liver graft, which has been considered as one of major problems influencing outcome after liver transplantation. The purpose of this review is to summarize updated data on the molecular mechanisms of ERS/UPR and the consequences of this pathology, focusing specifically on solid organ preservation and liver transplantation models. We will also discuss the potential role of ERS, beyond the simple adaptive response and the regulation of cell death, in the modification of cell functional properties and phenotypic changes.

Organ transplantation is a multifactorial process in which proper graft preservation is a mandatory step for the success of the transplantation. Hypothermic preservation of abdominal organs is mostly based on the use of several commercial solutions, including UW, Celsior, HTK and IGL-1. The presence of the oncotic agents HES (in UW) and PEG35 (in IGL-1) characterize both solution compositions, while HTK and Celsior do not contain any type of oncotic agent. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic and water-soluble polymers, which present a combination of properties of particular interest in the clinical context of ischemia-reperfusion injury (IRI): they limit edema and nitric oxide induction and modulate immunogenicity. Besides static cold storage (SCS), there are other strategies to preserve the organ, such as the use of machine perfusion (MP) in dynamic preservation strategies, which increase graft function and survival as compared to the conventional static hypothermic preservation. Here we report some considerations about using PEG35 as a component of perfusates for MP strategies (such as hypothermic oxygenated perfusion, HOPE) and its benefits for liver graft preservation. Improved liver preservation is closely related to mitochondria integrity, making this organelle a good target to increase graft viability, especially in marginal organs (e.g., steatotic livers). The final goal is to increase the pool of suitable organs, and thereby shorten patient waiting lists, a crucial problem in liver transplantation.

Acute pancreatitis is an inflammatory disorder of the pancreas. Its presentation ranges from self-limiting disease to acute necrotizing pancreatitis (ANP) with multiorgan failure and a high mortality. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic, and water-soluble chemicals composed of repeating units of ethylene glycol. The present article explores the effect of PEG35 administration on reducing the severity of ANP and associated lung injury. ANP was induced by injection of 5% sodium taurocholate into the biliopancreatic duct. PEG35 was administered intravenously either prophylactically or therapeutically. Three hours after ANP induction, pancreas and lung tissue samples and blood were collected and ANP severity was assessed. To evaluate the inflammatory response, gene expression of pro-inflammatory cytokines and chemokine and the changes in the presence of myeloperoxidase and adhesion molecule levels were determined in both the pancreas and the lung. To evaluate cell death, lactate dehydrogenase (LDH) activity and apoptotic cleaved caspase-3 localization were determined in plasma and in both the pancreatic and lung tissue respectively. ANP-associated local and systemic inflammatory processes were reduced when PEG35 was administered prophylactically. PEG35 pre-treatment also protected against acute pancreatitis-associated cell death. Notably, the therapeutic administration of PEG35 significantly decreased associated lung injury, even when the pancreatic lesion was equivalent to that in the untreated ANP-induced group. Our results support a protective role of PEG35 against the ANP-associated inflammatory process and identify PEG35 as a promising tool for the treatment of the potentially lethal complications of the disease.