The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol-induced inflammation, ethanol metabolites, and th...The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol-induced inflammation, ethanol metabolites, and the indirect reactions from those metabolites. Ethanol oxidation results in the production of metabolites that have been shown to bind and form protein adducts, and to increase inflammatory, fibrotic and cirrhotic responses. Lipopolysaccharide (LPS) has many deleterious effects and plays a significant role in a number of disease processes by increasing inflammatory cytokine release. In ALD, LPS is thought to be derived from a breakdown in the intestinal wall enabling LPS from resident gut bacterial cell walls to leak into the blood stream. The ability of adducts and LPS to independently stimulate the various cells of the liver provides for a two-hit mechanism by which various biological responses are induced and result in liver injury. Therefore, the purpose of this article is to evaluate the effects of a two-hit combination of ethanol metabolites and LPS on the cells of the liver to increase inflamma-tion and fi brosis, and play a role in the development and/or progression of ALD.展开更多
The development of alcoholic liver disease (ALD) can be attributed to many factors that cause damage to the liver and alter its functions. Data collected over the last 30 years strongly suggests that an immune compone...The development of alcoholic liver disease (ALD) can be attributed to many factors that cause damage to the liver and alter its functions. Data collected over the last 30 years strongly suggests that an immune component may be involved in the onset of this disease. This is best evidenced by the detection of circulating autoantibodies, infiltration of immune cells in the liver, and the detection of hepatic aldehyde modified proteins in patients with ALD. Experimentally, there are numerous immune responses that occur when proteins are modified with the metabolites of ethanol. These products are formed in response to the high oxidative state of the liver during ethanol metabolism, causing the release of many inflammatory processes and potential of necrosis or apoptosis of liver cells. Should cellular proteins become modified with these reactive alcohol metabolites and be recognized by the immune system, then immune responses may be initiated. Therefore, it was the purpose of this article to shed some insight into how the immune system is involved in the development and/or progression of ALD.展开更多
Background: Inhaled anesthetics, including halothane, iso- and sevoflurane induce proinflammatory cytokine release. Halothane is an inhaled anesthetic agent that is metabolized by the liver into a highly reactive prod...Background: Inhaled anesthetics, including halothane, iso- and sevoflurane induce proinflammatory cytokine release. Halothane is an inhaled anesthetic agent that is metabolized by the liver into a highly reactive product, trifluoroacetyl chloride, which can react endogenously to form a trifluoroacetyl-adduct (TFA-adduct). The MAA-adduct is formed by acetaldehyde and malondialdehyde reacting with endogenousproteins and is found in both patients and animals post-consumption of alcohol. These TFA and MAA-adducts have been shown to cause the release of proinflammatorycytokines by endogenous inflammatory cells. If both adducts share a similar mechanism of cell activation, receiving general anesthesia following alcohol ingestion could exacerbate the inflammatory response caused by the inhaled general anesthetic halothane and lead to solid organ (including liver and brain) injury. Methods: Control diet and alcohol-fed rats were randomized to receive halothane pretreatments by intraperitoneal injection mixed in sesame oil. Following the intraperitoneal injections, the intact heart was removed, HECs were isolated and stimulated with unmodified bovine serum albumin (Alb), MAA-modified Alb (MAA-Alb), Hexyl-MAA, or lipopolysaccharide (LPS), and supernatant concentrations of TNF-α were determined. Results: Halothane pre-treated rat HECs demonstrated significantly greater TNF-α concentration following MAA-adduct and LPS stimulation than the non-halothane pre-treated in both pair and alcohol-fed rats, but was significantly greater in the alcohol-fed groups. Conclusion: These results demonstrate that halothane and MAA-adduct pre-treatment will increase the inflammatory response (TNF-α release) in rat HECs following LPS and MAA stimulation in vitro. Also, these results suggest that halothane exposure may increase the risk of alcohol-induced solid organ injury secondary to TNF-induced inflammation. Other investigators have reported similar proinflammatory cytokine release with other (isoflurane and sevoflurane) inhaled anesthetic exposure, suggesting that inhaled anesthetics should be used with caution in alcohol consuming humans.展开更多
文摘The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol-induced inflammation, ethanol metabolites, and the indirect reactions from those metabolites. Ethanol oxidation results in the production of metabolites that have been shown to bind and form protein adducts, and to increase inflammatory, fibrotic and cirrhotic responses. Lipopolysaccharide (LPS) has many deleterious effects and plays a significant role in a number of disease processes by increasing inflammatory cytokine release. In ALD, LPS is thought to be derived from a breakdown in the intestinal wall enabling LPS from resident gut bacterial cell walls to leak into the blood stream. The ability of adducts and LPS to independently stimulate the various cells of the liver provides for a two-hit mechanism by which various biological responses are induced and result in liver injury. Therefore, the purpose of this article is to evaluate the effects of a two-hit combination of ethanol metabolites and LPS on the cells of the liver to increase inflamma-tion and fi brosis, and play a role in the development and/or progression of ALD.
文摘The development of alcoholic liver disease (ALD) can be attributed to many factors that cause damage to the liver and alter its functions. Data collected over the last 30 years strongly suggests that an immune component may be involved in the onset of this disease. This is best evidenced by the detection of circulating autoantibodies, infiltration of immune cells in the liver, and the detection of hepatic aldehyde modified proteins in patients with ALD. Experimentally, there are numerous immune responses that occur when proteins are modified with the metabolites of ethanol. These products are formed in response to the high oxidative state of the liver during ethanol metabolism, causing the release of many inflammatory processes and potential of necrosis or apoptosis of liver cells. Should cellular proteins become modified with these reactive alcohol metabolites and be recognized by the immune system, then immune responses may be initiated. Therefore, it was the purpose of this article to shed some insight into how the immune system is involved in the development and/or progression of ALD.
文摘Background: Inhaled anesthetics, including halothane, iso- and sevoflurane induce proinflammatory cytokine release. Halothane is an inhaled anesthetic agent that is metabolized by the liver into a highly reactive product, trifluoroacetyl chloride, which can react endogenously to form a trifluoroacetyl-adduct (TFA-adduct). The MAA-adduct is formed by acetaldehyde and malondialdehyde reacting with endogenousproteins and is found in both patients and animals post-consumption of alcohol. These TFA and MAA-adducts have been shown to cause the release of proinflammatorycytokines by endogenous inflammatory cells. If both adducts share a similar mechanism of cell activation, receiving general anesthesia following alcohol ingestion could exacerbate the inflammatory response caused by the inhaled general anesthetic halothane and lead to solid organ (including liver and brain) injury. Methods: Control diet and alcohol-fed rats were randomized to receive halothane pretreatments by intraperitoneal injection mixed in sesame oil. Following the intraperitoneal injections, the intact heart was removed, HECs were isolated and stimulated with unmodified bovine serum albumin (Alb), MAA-modified Alb (MAA-Alb), Hexyl-MAA, or lipopolysaccharide (LPS), and supernatant concentrations of TNF-α were determined. Results: Halothane pre-treated rat HECs demonstrated significantly greater TNF-α concentration following MAA-adduct and LPS stimulation than the non-halothane pre-treated in both pair and alcohol-fed rats, but was significantly greater in the alcohol-fed groups. Conclusion: These results demonstrate that halothane and MAA-adduct pre-treatment will increase the inflammatory response (TNF-α release) in rat HECs following LPS and MAA stimulation in vitro. Also, these results suggest that halothane exposure may increase the risk of alcohol-induced solid organ injury secondary to TNF-induced inflammation. Other investigators have reported similar proinflammatory cytokine release with other (isoflurane and sevoflurane) inhaled anesthetic exposure, suggesting that inhaled anesthetics should be used with caution in alcohol consuming humans.
