endothelin-1 and Acid-Base-Imbalance

To evaluate the role of intestinal endotoxemia in the genesis of hepatopulmonary syndrome.. A rat model of cirrhosis was prepared with the method of compound factors. At the end of the eighth week, rats with cirrhosis were treated with 300 microg LPS/100 g body weight, and 1 g/rat of glycine about four h prior to LPS. After three h of LPS treatment, blood and tissues were collected for various measurements. Kupffer cells were isolated from male Wistar rats and cultured, and divided into five groups. Supernatant was harvested at 3 h after treatment with LPS for measurement of tumor necrosis factor-alpha (TNF-alpha).. Our results showed that in rats with cirrhosis, slowed and deepened breath with occasional pause was. PaO2, PaCO2 and standard bicarbonate (SB) in arterial blood were decreased. Arterial O2 and actual bicarbonate (AB) were markedly decreased. There was a close correlation between decreased O2 and endotoxin. Metabolic acidosis accompanying respiratory alkalosis was the primary type of acid-base imbalance. The alveolar-arterial oxygen gradient was sharply widened. Massive accumulation of giant macrophages in the alveolar spaces and its wall and widened alveolar wall architecture were observed. The number of bacterial translocations in mesenteric lymph nodes increased. The ratio of TC99M-MAA brain-over-lung radioactivity rose. Endotoxin, and TNF-alpha, endothelin-1 (ET-1), nitric oxide (NO) in plasma and ET-1, carbon monoxide (CO) in lung homogenates increased. After administration of a given dosage of LPS in rats with cirrhosis, various pathological parameters worsened. Plasma level of endotoxin was related to TNF-alpha, ET-1, NO in plasma and ET-1, NO, CO in lung homogenates. TNF-alpha level was related to ET-1 and NO in plasma and lung homogenates and CO in lung homogenate as well. The level of TNF-alpha increased after infusion of LPS into culture supernatant of Kupffer cells in vitro. However, TNF-alpha significantly decreased after pretreatment with glycine, PD98059 and SB212850. Glycine could antagonize the effect of LPS in vivo and in vitro.. Intestinal endotoxemia accompanying by cirrhosis may be an important mechanism in the development of hepatopulmonary syndrome in rats. Overproduction of TNF-alpha due to endotoxin stimulation of Kupffer cells via mitogen-activated protein kinase (MAPK) signal transduction pathway may be a major mechanism mediating the pathologic alterations of hepatopulmonary syndrome.

Topics: Acid-Base Imbalance; Acidosis; Animals; Bacterial Translocation; Brain; Carbon Monoxide; Endothelin-1; Endotoxemia; Hepatopulmonary Syndrome; Kupffer Cells; Lipopolysaccharides; Liver Cirrhosis; Lung; Male; MAP Kinase Signaling System; Nitric Oxide; Rats; Rats, Wistar; Respiratory Mechanics; Sulfhydryl Compounds; Technetium Tc 99m Aggregated Albumin; Tumor Necrosis Factor-alpha

In the process of developing a model of Escherichia coli endotoxin-induced acute lung injury and shock in specific pathogen-free pigs, the effects of pretreatment with metyrapone (a cortisol-synthesis inhibitor) were examined. Metyrapone was administered 1.5 h before start of endotoxin infusion at t = 0 h (MET-ETOX group, n = 6). At the end of the experiments (t = 4 h) a bronchoalveolar lavage (BAL) was performed. Control animals received only endotoxin (CON-ETOX group, n = 6) or metyrapone (MET-CON group, n = 4). The following results are presented as means +/- SEM. It was found that metyrapone successfully blocked endogenous cortisol synthesis (plasma cortisol levels were 41.0 +/- 5.9 nM in MET-ETOX vs. 339.0 +/- 37.7 nM in CON-ETOX at t = 4 h, P <0.01). At t = 4 h the MET-ETOX animals had substantially increased systemic hypotension compared to the CON-ETOX group (mean arterial pressure 26.7 +/- 4.3 vs. 77.7 +/- 12.2 mmHg, P <0.01), decreased dynamic lung compliance (10.9 +/- 0.7 vs. 13.7 +/- 0.6 ml/cmH2O, P <0.01), increased percentage of BAL neutrophils (28.4 +/- 6.5 vs. 6.6 +/-1.8, P <0.01), pulmonary edema (BAL total protein 0.82 +/- 0.21 vs. 0.42 +/- 0.09 mg/mL, P <0.05), elevated levels of interleukin-8 (1924 +/- 275 vs. 324 +/- 131 pg/mL, P <0.01) and acidosis (pH 7.11 +/- 0.03 vs. 7.23 +/- 0.06, P <0.05). The MET-ETOX group also showed an increased pulmonary hypertension between 2 and 3 h after start of endotoxin infusion and a trend toward significantly increased levels of plasma interleukin-8 (P = 0.052). Arterial pCO2, pO2/FiO2, plasma endothelin-1, plasma TNFalpha, and blood leukocytes were not markedly influenced by the plasma cortisol levels. Nitric oxide production did not seem to be altered by endotoxin infusion in this model, in contrast to other animal studies; this discrepancy could be thought to be due to endotoxin-dosage differences or species differences. It is concluded that if endogenous cortisol production is blocked by metyrapone, the reactions occurring as a result of the endotoxin-induced acute lung injury and shock are greatly enhanced and that therefore pretreatment with metyrapone might be an important addition to this model with specific pathogen-free pigs.

Topics: Acid-Base Imbalance; Animals; Blood Gas Analysis; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Endothelin-1; Endotoxins; Female; Hydrocortisone; Hypotension; Interleukin-8; Leukocytes; Male; Metyrapone; Neutrophils; Nitric Oxide; Nitrites; Peroxidase; Proteins; Pulmonary Edema; Respiratory Distress Syndrome; Respiratory Function Tests; Shock; Specific Pathogen-Free Organisms; Swine; Tumor Necrosis Factor-alpha

In a porcine endotoxin shock model, the mixed nonpeptide endothelin receptor antagonist bosentan was administered 2 h after onset of endotoxemia (n = 8). Cardiopulmonary vascular changes, oxygen-related variables, and plasma levels of endothelin-1-like immunoreactivity were compared with a control group that received only endotoxin (n = 8). Bosentan abolished the progressive increase in mean pulmonary artery pressure and pulmonary vascular resistance seen in controls. Possible mechanisms include blockade of vasoconstrictive endothelin receptors, and a lesser degree of edema and inflammation indicated by less alveolar protein and a lower inflammatory cell count observed in bronchoalveolar lavage. Further, bosentan restored cardiac index to the pre-endotoxin level by an increase in stroke volume index, improved systemic oxygen delivery, and acid base balance. Because mean arterial blood pressure was unaffected, bosentan reduced systemic vascular resistance. Endotoxemia resulted in an increase in tumor necrosis factor-alpha and endothelin-1-like immunoreactivity plasma levels, the latter being further increased by bosentan. In conclusion, in porcine endotoxemia, treatment with the endothelin receptor antagonist bosentan, administered during fulminate shock, abolished pulmonary hypertension and restored cardiac index. These findings suggest that bosentan could be an effective treatment for reversing a deteriorated cardiopulmonary state during septic shock.

Topics: Acid-Base Imbalance; Animals; Bosentan; Cardiovascular Diseases; Endothelin Receptor Antagonists; Endothelin-1; Female; Hemoglobins; Hypertension, Pulmonary; Lactic Acid; Male; Oxygen Consumption; Shock, Septic; Sulfonamides; Swine; Treatment Outcome; Tumor Necrosis Factor-alpha