Interaction of Leptospira with the host's body in the infectious process in guinea pigs

In experiments on guinea pigs the pathogenicity of leptospires is manifested by their adhesion to liver cells, colonization of the surface of these cells, accumulation of leptospires in the renal interstice and their colonization of the nephrothelial surface of proximal convoluted tubules in the kidneys, by toxic microcirculatory disturbances, dystrophy and necrosis of nephrothelial cells. Then the primary toxic action of circulating leptospires, microcirculatory disturbances and hemorrhagic syndrome augment during the colonization of the surface of liver cells, accompanied by their dystrophy and dissociation, as well as by jaundice. The accumulation of leptospires in the renal interstice and their subsequent multiplication on the nephrothelium of the proximal convoluted tubules are responsible for the development of interstitial nephritis and necrotic nephrosis. The persistence of lesions in the liver and kidneys, occurring in some cases in spite of elimination of the infective agent from these organs due to increasing antibody production suggests the toxic action of immune complexes.     

Microvascular dysfunction induced by reperfusion injury and protective effect of ischemic preconditioning

Hepatic ischemia/reperfusion injury has immediate and deleterious effects on the outcome of patients after liver surgery. The precise mechanisms leading to the damage have not been completely elucidated. However, there is substantial evidence that the generation of oxygen free radicals and disturbances of the hepatic microcirculation are involved in this clinical syndrome. Microcirculatory dysfunction of the liver seems to be mediated by sinusoidal endothelial cell damage and by the imbalance of vasoconstrictor and vasodilator molecules, such as endothelin (ET), reactive oxygen species (ROS), and nitric oxide (NO). This may lead to no-reflow phenomenon with release of proinflammatory cytokines, sinusoidal plugging of neutrophils, oxidative stress, and as an ultimate consequence, hypoxic cell injury and parenchymal failure. An inducible potent endogenous mechanism against ischemia/reperfusion injury has been termed ischemic preconditioning. It has been suggested that preconditioning could inhibit the effects of different mediators involved in the microcirculatory dysfunction, including endothelin, tumor necrosis factor-alpha, and oxygen free radicals. In this review, we address the mechanisms of liver microcirculatory dysfunction and how ischemic preconditioning could help to provide new surgical and/or pharmacological strategies to protect the liver against reperfusion damage.     

Hemorrhagic shock primes the hepatic portal circulation for the vasoconstrictive effects of endothelin-1

To test whether hemorrhagic shock and resuscitation (HSR) alters the vascular responsiveness of the portohepatic circulation to endothelins (ETs), we studied the macro- and microcirculatory effects of the preferential ET(A) receptor agonist ET-1 and of the selective ET(B) receptor agonist sarafotoxin 6c (S6c) after 1 h of hemorrhagic hypotension and 5 h of volume resuscitation in the isolated perfused rat liver ex vivo using portal pressure-flow relationships and epifluorescence microscopy. Although HSR did not cause major disturbances of hepatic perfusion per se, the response to ET-1 (0.5 x 10(-9) M) was enhanced, leading to greater increases in portal driving pressure, total portal resistance, and zero-flow pressures and more pronounced decreases in portal flow, sinusoidal diameters, and hepatic oxygen delivery compared with time-matched sham shock controls. In sharp contrast, the constrictive response to S6c (0.25 x 10(-9) M) remained unchanged. Thus HSR primes the portohepatic circulation for the vasoconstrictive effects of ET-1 but does not alter the effects of the ET(B) receptor agonist S6c. The enhanced sinusoidal response may contribute to the subsequent development of hepatic microcirculatory failure after secondary insults that are associated with increased generation of ET-1.     

Comparative study of intravital microcirculation and hemorheological changes following burn injury of different severity in rats

It was shown in experiments on rats that burn injury is followed by microcirculatory disturbances, hemoconcentration and increasing blood viscosity that is especially pronounced in the vessels with low blood pressure. The microcirculatory changes in the mesentery correlated with the in vitro investigated dynamic viscosity and blood composition. The disturbances were more pronounced after severe burn followed by a mortal shock than after moderate burn without fatal consequences. This investigation confirms great importance of hemorheological changes and microcirculatory disturbances in the early period of burn disease.     

Vascularization of the testes of the white rat in the high altitude conditions of the Pamir and Antarctica

By means of histometric and morphometric methods vascularization of the white rat testes has been studied at adaptation to living conditions in the Alpian Pamir (at the altitude of 4,000 m) and in the Antarctic Continent (at the altitude of 3,488 m). The leading factor in development of the parenchymatous rearrangements of the testes are certain disturbances of the microcirculatory link in the intraorganic bed. Different degree in manifestation of the morphological signs of the circulatory disturbances are revealed: plethora, interstitial tissue edema, degenerative changes in the spermatogenic epithelium cells and hence decreasing activity of spermatogenesis. The disturbances noted are essentially various in different stages of adaptation to the altitude. In contrast to the Pamir series of the experiment, in the group of the animals adapting to the living conditions of "Vostok" station, dilatation of the capillary lumens and signs of moderate plethora accompanying them remain up to the end of the observations.     

ACTH inhibits the development of primary decompensation of the systemic and portal circulation in acute blood loss in rats]

Using the method of contact luminescent biomicroscopy of the liver and intestine coupled with the measurement of systemic blood pressure by micromanometer and ultrasonic registration of blood flow velocity in portal vein and hepatic artery it has been established that in rats with acute decompensatory hemorrhage fragments of ACTH (1-24) and (4-10) improve the state of portal macro- and microcirculation and increase the life span 2-3-fold. ACTH does not influence the dynamics of acute compensatory hemorrhage and the development of the posthemorrhagic microcirculatory disturbances (local microstases, microthromboses, erythrocyte aggregation).     

Role of nitric oxide in hepatic microvascular injury elicited by acetaminophen in mice

Nitric oxide (NO) is suggested to play a role in liver injury elicited by acetaminophen (APAP). Hepatic microcirculatory dysfunction also is reported to contribute to the development of the injury. As a result, the role of NO in hepatic microcirculatory alterations in response to APAP was examined in mice by in vivo microscopy. A selective inducible NO synthase (iNOS) inhibitor,l-N6-(1-iminoethyl)-lysine (L-NIL), or a nonselective NOS inhibitor, NG-nitro-l-arginine methyl ester (L-NAME), was intraperitoneally administered to animals 10 min before APAP gavage. L-NIL suppressed raised alanine aminotransferase (ALT) values 6 h after APAP, whereas L-NAME increased those 1.7-fold. Increased ALT levels were associated with hepatic expression of iNOS. L-NIL, but not L-NAME, reduced the expression. APAP caused a reduction (20%) in the numbers of perfused sinusoids. L-NIL restored the sinusoidal perfusion, but L-NAME was ineffective. APAP increased the area occupied by infiltrated erythrocytes into the extrasinusoidal space. L-NIL tended to minimize this infiltration, whereas L-NAME further enhanced it. APAP caused an increase (1.5-fold) in Kupffer cell phagocytic activity. This activity in response to APAP was blunted by L-NIL, whereas L-NAME further elevated it. L-NIL suppressed APAP-induced decreases in hepatic glutathione levels. These results suggest that NO derived from iNOS contributes to APAP-induced parenchymal cell injury and hepatic microcirculatory disturbances. L-NIL exerts preventive effects on the liver injury partly by inhibiting APAP bioactivation. In contrast, NO derived from constitutive isoforms of NOS exerts a protective role in liver microcirculation against APAP intoxication and thereby minimizes liver injury.     

Redistribution of erythrocytes in the rat mesenteric microcirculation during reperfusion following short-term ischemia

The erythrocyte redistribution in the rat mesentery microvessels and the development of postischemic microcirculatory disturbances were influenced by the thrombosis in narrow parts of arterioles and the increase in leukocyte adhesion to venule walls obstructing the blood outflow. The presence of branches and anastomoses in microvascular bed had a pronounced effect on reperfusion disturbances.     

The dose-dependent action of naloxone on systemic and portal circulation in acute blood loss in rats

Using the method of contact luminescent biomicroscopy of the liver and the intestine coupled with the ultrasonic measurement of systemic blood pressure, blood flow velocity in the portal vein and hepatic artery it has been established that in rats with acute decompensatory hemorrhage naloxone increases blood pressure and improves the state of protal macro and microcirculation only after i. v. injection of large dose (5 mg/kg). Naloxone does not influence the dynamics of acute compensatory hemorrhage and the development of the posthemorrhagic microcirculatory disturbances (local microstases, microthromboses, erythrocyte aggregation).     

Ischemic preconditioning: tolerance to hepatic ischemia-reperfusion injury

Hepatic ischemia-reperfusion (I/R) injury still remains an unresolved problem in both liver resectional surgery and liver transplantation and may be responsible for liver failure, lung injury and death. The current review summarizes the findings reported to date on the effectiveness of ischemic preconditioning against liver and lung damage associated with hepatic I/R injury and the underlying protective mechanisms. The effect of ischemic preconditioning on the mechanisms potentially involved in hepatic I/R injury, including alterations in energy metabolism, neutrophil accumulation, microcirculatory disturbances, formation of proinflammatory mediators, such as endothelin and tumor necrosis factor-alpha, and reactive oxygen species generation have been evaluated. In this review, we address the role of preconditioning in the increased vulnerability of fatty livers to hepatic I/R injury. The effectiveness of ischemic preconditioning versus pharmacological strategies that could simulate the benefits of liver preconditioning has been also discussed.     

Molecular mechanisms of hepatic ischemia-reperfusion injury and preconditioning

Ischemia-reperfusion injury is, at least in part, responsible for the morbidity associated with liver surgery under total vascular exclusion or after liver transplantation. The pathophysiology of hepatic ischemia-reperfusion includes a number of mechanisms that contribute to various degrees in the overall injury. Some of the topics discussed in this review include cellular mechanisms of injury, formation of pro- and anti-inflammatory mediators, expression of adhesion molecules, and the role of oxidant stress during the inflammatory response. Furthermore, the roles of nitric oxide in preventing microcirculatory disturbances and as a substrate for peroxynitrite formation are reviewed. In addition, emerging mechanisms of protection by ischemic preconditioning are discussed. On the basis of current knowledge, preconditioning or pharmacological interventions that mimic these effects have the greatest potential to improve clinical outcome in liver surgery involving ischemic stress and reperfusion.     

Effect of chronic alcoholism on the state of the microcirculatory bed of the myocardium

Ultrastructure of myocardial capillaries of rats was studied in cases of chronic alcohol intoxication, experimental alcoholic cardiomyopathy (ACM) and its correction with antioxidants (vitamin E, dibunol). Alterations in the microcirculatory bed were similar in all groups of animals irrespective of disturbances in cardiomyocytes. Cardiomyocyte ultrastructure was improved after treatment with antioxidants, but capillary bed was the same as in untreated animals. High dibunol doses caused the onset of perivascular sclerosis. Disturbances in the microcirculatory bed are, probably, the first step in the determination of ACM pathogenesis and therapy of ACM must be directed at the correction of both alterations of cardiomyocytes and capillary bed.     

Blood aggregation and the system of microcirculation in experimental atherosclerosis, its spontaneous regression and hemosorption

Blood aggregate state and microcirculation were studied during development and spontaneous regression of experimental atherosclerosis and following hemosorption. It has been shown that experimental atherosclerosis is not only accompanied by changes in blood lipid composition, but also by disturbances in the structure and function of microcirculatory bed. Normalization of blood lipid composition and recovery of blood aggregate state and microcirculatory bed structure and function were not observed during spontaneous regression. Repeated hemosorption enhances atherosclerosis regression, normalizes lipid composition of blood and biological membranes and promotes the recovery of microcirculation.     

Organ microcirculatory disturbances in experimental acute pancreatitis. A role of nitric oxide

Microcirculatory disturbances are important early pathophysiological events in various organs during acute pancreatitis (AP). The aim of the study was to investigate an influence of L-arginine (nitric oxide substrate) and N(G)-nitro-L-arginine (L-NNA, nitric oxide synthase inhibitor) on organ microcirculation in experimental acute pancreatitis induced by four consecutive intraperitoneal cerulein injections (15 microg/kg/h). The microcirculation of pancreas, liver, kidney, stomach, colon and skeletal muscle was measured by laser Doppler flowmeter. Serum interleukin 6 and hematocrit levels were analyzed. AP resulted in a significant drop of microperfusion in all examined organ. L-arginine administration (2 x 100 mg/kg) improved the microcirculation in the pancreas, liver, kidney, colon and skeletal muscle, and lowered hematocrit levels. L-NNA treatment (2 x 25 mg/kg) caused aggravation of edematous AP to the necrotizing situation, and increased IL-6 and hematocrit levels. A further reduction of blood perfusion was noted in the stomach only. It is concluded that L-arginine administration has a positive influence on organ microcirculatory disturbances accompanying experimental cerulein-induced AP. NO inhibition aggravates the course of pancreatitis.     

The "no reflow" phenomenon in the cerebral cortex in the early postischemic period

Experiments on white rats with clinical death due to blood loss were made to demonstrate the presence of the "no-reflow" focuses in the cerebral cortex in the first minutes of recirculation. The microcirculatory disturbances were functional in nature and were determined by the spasm of the small intracranial arteries, arterioles and precapillary sphincters.     

Structural/functional disturbances in the rat sensorimotor cortex evoked by low-intensity environmental factors

The effect of low-frequency continuous vabration, hypokinesia, and shielding from the geomagnetic field were studied on 424 albino mongrel male rats. The action of these low-intensity factors of a different nature caused changes first of all in the microcirculatory bed (MCB) of the cerebral cortex. Structural disturbances, as well as the disturbances of redox metabolism in the neurons appeared close to those observed during hypoxia of a different origin; they obviously resulted from the disturbances of the MCB functions, which caused discrepancy between the needs for energy supply and the transport system state. Specificities of the disturbances evoked by different factors can be related to desynchronization of the biorhythms (e.g., caused by deprivation of the geomagnetic field).     

Histomorphologic and histochemical investigations in mannosidosis. A light and electron microscopic study.

Morphologic and histochemical studies have been performed at light and electron microscopic level on needle-liver biopsy specimens, circulating blood lymphocytes and fibroblast cultures from patients with mannosidosis. The findings demonstrated generalized storage phenomena of varying degrees in the various tissues examined. Histochemical findings were in agreement with the biochemical nature of the stored material. Enzyme histochemical methods indicated storage in the lysosomes, at least in the hepatocytes. The ultrastructural appearance of mannosidosis in itself has but a limited diagnostic significance since the morphology and distribution of vacuoles have characteristics in common with other storage diseases. Repeated liver biopsy disclosed extensive storage in the hepatic tissue. However, the progression of the disease was not accompanied by severe mechanical destruction or microcirculatory disturbances.     

Effects of thermal factors on the state of microcirculation of the small intestine in acute ischemia

The influence of normo- (38 degrees C), hyper- (42 degrees C) and hypothermia (20 degrees C) on microcirculatory disturbances caused by acute local ischemia of the small intestine was investigated with the help of biomicroscopy as well as morphological methods. Ischemia was modeled by ligation of the intestine look eventrated through the abdominal wall incision of a rat onto the microscope stage for 1 h. It was shown that hyperthermia intensified microcirculatory disorders and stimulated destructive processes in tissues and hypothermia promoting microcirculation and decreasing metabolism and restrained the development of these processes. Important peculiarity of the microvascular response to ischemia, hyper- and hypothermia was revealed: heterogeneity of the reaction of different parts of microvascular bed. Appropriate evaluation of the microcirculation state in such conditions can be obtained taking into account not only the qualitative character of microvascular reaction but also an extent of this reaction manifestation in different parts of microvascular bed.     

Morphologic indices of the rat heart after colchicine application to the vagus nerve

By means of the light optic and electron microscopic methods atrial ganglia, myocytes, vessels of the right cardiac chambers have been studied in rats 2 days--3 weeks after application of 100 mcg of colchicine on the right nervus vagus. Certain changes of the neural fibers have been described at the area of the application. In the myocardium the microcirculatory bed, focal edema and hypoxic alterations of the myocyte ultrastructure have been revealed. In the ventrical ganglia destruction of some terminals of the preganglionar fibers, chromatolysis and vacuolization of single neurocytes, as well as intraganglionar granule-containing cells have been found. The changes described take place for 7 days and they nearly completely disappear in 10 days. A suggestion is made that some phenomena, in particular, destruction of the preganglionar fibers and changes of the cardiac microcirculatory bed are connected with certain disturbances of the quick transport of substances in the nervus vagus fibers.     

Effects of SP1-11 and its N-terminal fragment SP1-4 on several indices of the microcirculatory system in stress]

In the experiments on rats it was shown that 5-hour immobilization induced the disturbances of terminal blood flow, degranulation of mast cells, increase of venular permeability and contractile activity of lymphaticus. I/p injection SP1-11 (125 micrograms/kg) before stress aggravated the disturbances caused by immobilization. The prophylactic i/p injection SP1-4 induced tranquilizing (100%), sedative (30%) or narcosis (20%) effect. In the rats with sedative or narcosis effects the relative normalization of components of microcirculatory system was observed.