Jorge-Luis Arias

Inflammation: a way to understanding the evolution of portal hypertension

BackgroundPortal hypertension is a clinical syndrome that manifests as ascites, portosystemic encephalopathy and variceal hemorrhage, and these alterations often lead to death.HypothesisSplanchnic and/or systemic responses to portal hypertension could have pathophysiological mechanisms similar to those involved in the post-traumatic inflammatory response.The splanchnic and systemic impairments produced throughout the evolution of experimental prehepatic portal hypertension could be considered to have an inflammatory origin. In portal vein ligated rats, portal hypertensive enteropathy, hepatic steatosis and portal hypertensive encephalopathy show phenotypes during their development that can be considered inflammatory, such as: ischemia-reperfusion (vasodilatory response), infiltration by inflammatory cells (mast cells) and bacteria (intestinal translocation of endotoxins and bacteria) and lastly, angiogenesis. Similar inflammatory phenotypes, worsened by chronic liver disease (with anti-oxidant and anti-enzymatic ability reduction) characterize the evolution of portal hypertension and its complications (hepatorenal syndrome, ascites and esophageal variceal hemorrhage) in humans.ConclusionLow-grade inflammation, related to prehepatic portal hypertension, switches to high-grade inflammation with the development of severe and life-threatening complications when associated with chronic liver disease.

Experimental obstructive cholestasis: the wound-like inflammatory liver response

Obstructive cholestasis causes hepatic cirrhosis and portal hypertension. The pathophysiological mechanisms involved in the development of liver disease are multiple and linked. We propose grouping these mechanisms according to the three phenotypes mainly expressed in the interstitial space in order to integrate them.Experimental extrahepatic cholestasis is the model most frequently used to study obstructive cholestasis. The early liver interstitial alterations described in these experimental models would produce an ischemia/reperfusion phenotype with oxidative and nitrosative stress. Then, the hyperexpression of a leukocytic phenotype, in which Kupffer cells and neutrophils participate, would induce enzymatic stress. And finally, an angiogenic phenotype, responsible for peribiliary plexus development with sinusoidal arterialization, occurs. In addition, an intense cholangiocyte proliferation, which acquires neuroendocrine abilities, stands out. This histopathological finding is also associated with fibrosis.It is proposed that the sequence of these inflammatory phenotypes, perhaps with a trophic meaning, ultimately produces a benign tumoral biliary process – although it poses severe hepatocytic insufficiency. Moreover, the persistence of this benign tumor disease would induce a higher degree of dedifferentiation and autonomy and, therefore, its malign degeneration.

The mast cell integrates the splanchnic and systemic inflammatory response in portal hypertension

Portal hypertension is a clinical syndrome that is difficult to study in an isolated manner since it is always associated with a greater or lesser degree of liver functional impairment. The aim of this review is to integrate the complications related to chronic liver disease by using both, the array of mast cell functions and mediators, since they possibly are involved in the pathophysiological mechanisms of these complications. The portal vein ligated rat is the experimental model most widely used to study this syndrome and it has been considered that a systemic inflammatory response is produced. This response is mediated among other inflammatory cells by mast cells and it evolves in three linked pathological functional systems. The nervous functional system presents ischemia-reperfusion and edema (oxidative stress) and would be responsible for hyperdynamic circulation; the immune functional system causes tissue infiltration by inflammatory cells, particularly mast cells and bacteria (enzymatic stress) and the endocrine functional system presents endothelial proliferation (antioxidative and antienzymatic stress) and angiogenesis. Mast cells could develop a key role in the expression of these three phenotypes because their mediators have the ability to produce all the aforementioned alterations, both at the splanchnic level (portal hypertensive enteropathy, mesenteric adenitis, liver steatosis) and the systemic level (portal hypertensive encephalopathy).This hypothetical splanchnic and systemic inflammatory response would be aggravated during the progression of the chronic liver disease, since the antioxidant ability of the body decreases. Thus, a critical state is produced, in which the appearance of noxious factors would favor the development of a dedifferentiation process protagonized by the nervous functional system. This system rapidly induces an ischemia-reperfusion phenotype with hydration and salinization of the body (hepatorenal syndrome, ascites) which, in turn would reduce the metabolic needs of the body and facilitate its temporary survival.

The value of microsurgery in liver research

The use of an operating microscope in rat liver surgery makes it possible to obtain new experimental models and improve the already existing macrosurgical models. Thus, microsurgery could be a very valuable technique to improve experimental models of hepatic insufficiency. In the current review, we present the microsurgical techniques most frequently used in the rat, such as the portacaval shunt, the extrahepatic biliary tract resection, partial and total hepatectomies and heterotopic and orthotopic liver transplantation. Hence, reducing surgical complications allows for perfecting the resulting experimental models. Thus, liver atrophy related to portacaval shunt, prehepatic portal hypertension secondary to partial portal vein ligation, cholestasis by resection of the extrahepatic biliary tract, hepatic regeneration after partial hepatectomies, acute liver failure associated with subtotal or total hepatectomy and finally complications derived from preservation or rejection in orthotopic and heterotopic liver transplantation can be studied in more standardized experimental models. The results obtained are therefore more reliable and facilitates the flow of knowledge from the bench to the bedside. Some of these microsurgical techniques, because of their simplicity, can be performed by researchers without any prior surgical training. Other more complex microsurgical techniques require in‐depth surgical training. These techniques are ideal for achieving a complete surgical training and more select microsurgical models for hepatology research.

Bile duct ligation: step-by-step to cholangiocyte inflammatory tumorigenesis.

Chronic liver inflammation after murine bile duct ligation could evolve according to three interrelated phenotypes, which would have different metabolic, functional and histologic characteristics. Liver injury secondary to extrahepatic cholestasis would induce an early ischemic-reperfusion phenotype with cholangiocyte depolarization, abnormal ion transport, hypometabolism with anaerobic glycolysis and hepatocytic apoptosis. This phenotype, in turn, could trigger the switch to a leukocytic phenotype by the cholangiocytes, with an intense anaplerotic activity, hypermetabolism, extracellular matrix degradation and moderated proliferation to create a pseudotissue with metabolic autonomy and paracrine functions. In the long-term cholestasis-drive tumorigenesis, the tumorous tissue would principally consist of cholangiocyte parenchyma, with an impressive biosynthetic activity through the tricarboxylic cell cycle. In terms of the tumorous stroma, made up by fibroplasia and angiogenesis, it would favor the tumor trophism. In conclusion, the great intensity and persistence in the expression of these phenotypes by the cholestatic cholangiocyte would favor chronic inflammatory tumorigenesis.

A half century (1961-2011) of applying microsurgery to experimental liver research.

The development of microsurgery has been dependent on experimental animals. Microsurgery could be a very valuable technique to improve experimental models of liver diseases. Microdissection and microsutures are the two main microsurgical techniques that can be considered for classifying the experimental models developed for liver research in the rat. Partial portal vein ligation, extrahepatic cholestasis and hepatectomies are all models based on microdissection. On the other hand, in portacaval shunts, orthotopic liver transplantation and partial heterotopic liver transplantation, the microsuture techniques stand out. By reducing surgical complications, these microsurgical techniques allow for improving the resulting experimental models. If good experimental models for liver research are successfully developed, the results obtained from their study might be particularly useful in patients with liver disease. Therefore experimental liver microsurgery could be an invaluable way to translate laboratory data on liver research into new clinical diagnostic and therapeutic strategies.

Coupling inflammation with evo-devo.

Inflammation integrates diverse mechanisms that are associated not only with pathological conditions, such as cardiovascular diseases, type 2 diabetes, obesity, neurodegenerative diseases and cancer, but also with physiological processes like reproduction i.e. oogenesis and embryogenesis as well as aging. In the current review we firstly propose that the inflammatory response could recapitulate the phylogenia. In this way, highly conserved inflammatory mechanisms that play a main role in the evolutive development of different animal species, both invertebrates as well as vertebrates, are identified. Therefore, we also hypothesize that inflammation could represent a key tool used by nature to modulate organisms according to the environmental conditions in which these develop. Thus, inflammation could be the pathway by which the environmental factors could be related to the evolutionary development. If so, the diverse human chronic inflammatory diseases that nowadays the Western society suffer would represent the way for adapting to the abrupt changes in their lifestyle. Nonetheless, the distribution of the different pathological conditions varies in terms of intensity and magnitude among Western country populations depending on their genetic polymorphism. In this case, it should be considered that this set of diseases, distributed between all the individuals that constitute the Westernized society, would represent a true Social Inflammatory Syndrome whose final result is its remodeling. In this context, the use of inflammation by the Western society could represent the camouflaged expression of efficient mechanisms of evolution and development. In addition, if the different types of the inflammatory response involved in these diverse chronic pathological conditions could trace the biochemical origins of life, perhaps inflammation could represent an archaeological tool of unsuspected usefulness for understanding our own origin.

Functional interaction between the dorsal hippocampus and the striatum in visual discrimination learning.

The hippocampus and the striatum have traditionally been considered as part of different and independent memory systems. However, there is evidence that supports a functional interaction between the hippocampus and the dorsal striatum at least in particular learning tasks. Here, we evaluated the functional contribution of both brain regions in a visual discrimination learning task using cytochrome c oxidase (CO) quantitative histochemistry. Compared with other brain metabolic mapping techniques, CO activity reflects steady‐state neuronal energy demand. Rats were trained for 6 days in a water T‐maze to find a hidden escape platform associated with an intramaze visual cue. A control group of animals swam for an equivalent amount of time compared as the trained group but without any escape platform available. After finishing the behavioral task, CO activity was measured in subdivisions of the dorsal hippocampus and the dorsal striatum in both groups. Results show significantly higher CO activity in the CA1 area and the dentate gyrus of the dorsal hippocampus in the trained rats compared with the control group. In addition, a significant negative functional cross‐correlation between area CA1 of the dorsal hippocampus and the anterodorsal striatum was found. Our results support current theories on competitive interaction of different memory systems during visual discrimination learning.

The Interstitial Lymphatic Peritoneal Mesothelium Axis in Portal Hypertensive Ascites: When in Danger, Go Back to the Sea

Portal hypertension induces a splanchnic and systemic low-grade inflammatory response that could induce the expression of three phenotypes, named ischemia-reperfusion, leukocytic, and angiogenic phenotypes.During the splanchnic expression of these phenotypes, interstitial edema, increased lymph flow, and lymphangiogenesis are produced in the gastrointestinal tract. Associated liver disease increases intestinal bacterial translocation, splanchnic lymph flow, and induces ascites and hepatorenal syndrome. Extrahepatic cholestasis in the rat allows to study the worsening of the portal hypertensive syndrome when associated with chronic liver disease. The splanchnic interstitium, the mesenteric lymphatics, and the peritoneal mesothelium seem to create an inflammatory pathway that could have a key pathophysiological relevance in the production of the portal hypertension syndrome complications. The hypothetical comparison between the ascitic and the amniotic fluids allows for translational investigation. From a phylogenetic point of view, the ancestral mechanisms for amniotic fluid production were essential for animal survival out of the aquatic environment. However, their hypothetical appearance in the cirrhotic patient is considered pathological since ultimately they lead to ascites development. But, the adult human being would take advantage of the potential beneficial effects of this “amniotic-like fluid” to manage the interstitial fluids without adverse effects when chronic liver disease aggravates.

Different brain networks underlying the acquisition and expression of contextual fear conditioning: a metabolic mapping study

The specific brain regions and circuits involved in the acquisition and expression of contextual fear conditioning are still a matter of debate. To address this issue, regional changes in brain metabolic capacity were mapped during the acquisition and expression of contextual fear conditioning using cytochrome oxidase (CO) quantitative histochemistry. In comparison with a group briefly exposed to a conditioning chamber, rats that received a series of randomly presented footshocks in the same conditioning chamber (fear acquisition group) showed increased CO activity in anxiety-related brain regions like the ventral periaqueductal gray, the ventral hippocampus, the lateral habenula, the mammillary bodies, and the laterodorsal thalamic nucleus. Another group received randomly presented footshocks, and it was re-exposed to the same conditioning chamber one week later (fear expression group). The conditioned group had significantly higher CO activity as compared with the matched control group in the following brain regions: the ventral periaqueductal gray, the central and lateral nuclei of the amygdala, and the bed nucleus of the stria terminalis. In addition, analysis of functional brain networks using interregional CO activity correlations revealed different patterns of functional connectivity between fear acquisition and fear expression groups. In particular, a network comprising the ventral hippocampus and amygdala nuclei was found in the fear acquisition group, whereas a closed reciprocal dorsal hippocampal network was detected in the fear expression group. These results suggest that contextual fear acquisition and expression differ as regards to the brain networks involved, although they share common brain regions involved in fear, anxiety, and defensive behavior.