Relevancia del hígado en la inducción de la inflamación sistémica en ratas con cirrosis compensada

Abstract

The immune system is a complex network of cells and molecules that play a relevant role in the defence against infections through its ability to recognize and develop a response against non-self antigens. Although the inflammatory response is essential for maintaining tissue homeostasis, protecting against infection and mediating immune responses, it can also contribute to tissue injury. In fact, the immune system is abnormally activated at the systemic level in patients and experimental models with cirrhosis and ascites contributing to the progression of the disease. Immunitary cells become activated after interacting at the mesenteric lymph nodes (MLN) with bacteria translocated from the gut, and thereafter reach the bloodstream by recirculation. The alteration is characterized by expansion of activated lymphocytes and monocytes in peripheral blood and an increased production of proinflammatory cytokines. Despite the pivotal role of systemic activation of the immune system in cirrhosis, it is unknown if this abnormality already exists in the compensated pre-ascitic stage of the disease. It is possible to hypothesize that the liver, the main organ of inflammation in cirrhosis, has a crucial role as a source of abnormally activated monocytes and lymphocytes. The aim of this study was to investigate whether there is in fact systemic activation of the inflammatory immune system in rats with compensated CCl4–induced cirrhosis, and if so to establish the pivotal site where immune system cells become activated. Material and methods: We studied the phenotype and activation status of lymphocyte and monocyte subpopulations in peripheral blood, liver and in mesenteric and hepatic lymph nodes (HLN) in rats with cirrhosis without ascites (n=28) and in healthy, phenobarbital-treated age- and sex-matched rats (n=20). Cirrhosis was induced by carbon tetrachloride (CCl4) feeding by gavage on a weekly basis and rats were sacrificed at 12 weeks, when cirrhosis without ascites is almost constantly present. A subgroup of rats with cirrhosis without ascites (n=14) received a 2-week course of broad-spectrum oral non-absorbable antibiotics, or placebo, to investigate the impact of enteric bacterial products on the immune system cells. Finally, we examined the phenotype and activation status of immune cell subpopulations in rats receiving the first three doses of CCl4 (n=5) or only phenobarbital in the drinking water (n=5). Results: Systemic inflammation was present in cirrhotic rats, as shown by expansion (p<0.01) of circulating total and inflammatory monocytes, and recently activated CD134+ Th-cells. The same populations of cells were increased (p<0.01) in MLN and HLN. Bacterial translocation was absent in cirrhotic or control rats, but bacterial DNA fragments were present in the MLN of 54% of cirrhotic rats. The liver and not the gut was the source of the activated immunitary cells present in blood, as shown by the direct correlation between activated Th-cells in blood and HLN, but not in MLN, and the normalization by gut decontamination with antibiotics of activated cells in MLN, but not in blood or HLN. Conclusion: In experimental cirrhosis, systemic activation of the immune system occurs before ascites development and is driven by recirculation of cells activated in the HLN. Besides, in compensated cirrhosis, bacterial DNA fragments reach the MLN, where they elicit a local inflammatory response.