Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages.

A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease.

Action of the chemical agent fipronil (active ingredient of acaricide Frontline®) on the liver of mice: an ultrastructural analysis.

Fipronil, active ingredient of the acaricide Frontiline®, is a phenyl-pyrazolic derivative, and its efficacy in the elimination of several plagues, even in low concentrations, has already been demonstrated; however, its effect on nontarget organisms has not been thoroughly explained. In this sense, the objective of this study was to evaluate the effects of different dosages of fipronil on the liver of mice in artificial conditions. Results showed that the animals exposed to fipronil present significant ultrastrucutural changes in hepatic cells with evident cellular and cytoplasm disorganization in hepatocytes characterized by an increase in the number of organelles, mainly mitochondria and rough endoplasmic reticulum, organelles that, in the case of the exposed animals, were probably responsible for the enzymes' synthesis that have the function of inactivating the toxic metabolites. A fat accumulation in the hepatocytes' cytoplasm (steatosis) was observed, in addition to extended vacuolated areas, mainly in regions next to the cell nucleus. Alterations observed in the nuclei of the hepatocytes pointed out cell death processes. Moreover, Kupffer cells increased in number (hyperplasia) suggesting an increase in the phagocytic activity of the liver in the exposed animals.

Prostanoid production in endothelial and Kupffer liver cells from monocrotaline intoxicated rats.

UNLABELLED: A single dose of monocrotaline, a pyrrolizidine alkaloid, was injected into rats in order to produce 25 (Group I) and 45 (Group II) days later a progressive and so called delayed liver injury. The present study investigated the prostanoid production of Kupffer cells and endothelial cells separated from Monocrotaline and saline (Group III) injected rat livers. Kupffer cells: formation of 6 keto Prostaglandin F1 alpha, the major prostacycline metabolite, gradually decreased in Groups I vs II (P < 0.01) and in both Groups I and II vs Controls (P < 0.01). In addition Prostaglandin F2 alpha showed a significant increase in Groups I and II when compared to Group III, (P < 0.001), and Thromboxane B2 was present in both Groups of Monocrotaline treated animals, while it was not detectable in the control Group III. Endothelial cells: 6 keto Prostaglandin F1 alpha decreased in Groups 1 vs II. This differences was significant when compared, and compared to controls (Group III, P < 0.001). Prostaglandin E2 was detected only in Groups I and II. Prostaglandin F2 alpha and Thromboxane B2 could not be detected in any Group. Ultramicroscopy showed morphological cell damage in nonparenchymal cells in Monocrotaline intoxication in Group II, rats sacrificed 45 days after the injection, while it shows normal features in those treated animals sacrificed 25 days after the injection, as well as in control group. CONCLUSION: A single Monocrotaline injection produces, 25 and 45 days later, severe and progressive alterations in the prostanoid production in Kupffer and Endothelial cells, while ultramicroscopic alterations was only observed 45 days after the injection of Monocrotaline. A decreased production of vasodilators and the presence of vasoconstrictor prostanoids that can participate in the production of the circulatory derangements enhancing liver injury and portal hypertension were also observed.

Cyclophosphamide affects the dynamics of granuloma formation in experimental visceral leishmaniasis.

We observed histopathological and ultrastructural hepatic changes following the intracardiac inoculation of Leishmania donovani amastigotes into inbred LHC hamsters (group I). Since granuloma formation is known to be T-cell-dependent, we also examined infected hamsters under cyclophosphamide immunosuppressive treatment (group ICy) and evaluated the production of interleukin-2 (IL-2) by their cells. Group I showed more intense hepatocyte and endothelial cell clasmatosis as well as hepatocyte degeneration and necrosis, deposits of connective tissue fibers, granulomas with multinucleated giant cells (MGCs) of foreign-body and Langhans' types and reduced production of IL-2 by spleen cells. In contrast, group ICy hamsters exhibited larger eosinophil and lymphocyte populations within sinusoids and peri-sinusoidal areas but showed no MGCs in granulomas. A striking decline in IL-2 production was noted. These results suggest that cyclophosphamide induces a delay in the natural evolution of L. donovani-induced granulomatous hepatic inflammation.

Efecto inhibidor del extracto del hepatocarcinoma transplantado ss1k y del plasma de los portadores sobre la actividad mitótica de los epatocitos y células litorales del hígado del ratón joven / Inhibition by hepatocarcinoma ss1k and plasma from tumor bearing mice on mitotic activity of hepatocytes and litoral cells in young mice

Un extracto del hepatocarcinoma probablemente diferenciado de crecimiento rápido ss1k y el plasma de animales portadores de tumor se inyectaron por vía intraperitoneal a las 16.00/oo (hora del día/horas postinyección) en ratones machos dela cepa C3HS de 21-28 días. Los animales control fueron inyectados con solución fisiológica. Cuatro horas antes del sacrificio se les inyectó Colcemid. Se les sacrificó a las 08:00, 12:00 y 16:00 durante cuatro días consecutivos. La actividad mitótica se expresó como metafases colchicínicas por 1000 núcleos. Se observó inhibición de la actividad mitótica de hepatocitos y células litorales durante los tres primeros días, más intensa en el 2 día, y una onda compensadora de la actividad mitótica de ambas poblaciones celulares al cuarto día. Este efecto se ejerce probablemente sobre el pasaje G1-S del ciclo celular.

Hepatic ultrastructure in secondary syphilis

We describe the ultastructural findings in liver biopsy specimens from 19 patients with secondary syphilis. These patients were unselected, had negative tests for hepatitis B surface antigen, and were not jaundiced. Most hepatocytes appeared normal; a few showed minor nonspecific changes, including some prominence of lipofuscin. Kupffer cell and endothelial cell hyperplasia were noteworthy in some specimens, occasionally forming clusters with monomuclear cells. However, these findings, have no specificity. Although triponemes were seen in Warthin-stained sections by light microscopy in three instances, no organisms were detected in the blocks selected for electron microscopy.(AU)

Schistosomal pigment in human and murine infections with Schistosoma mansoni.

Schistosomal pigment was studied by optical and electron microscopy in liver biopsies of patients with different clinical forms of schistosomiasis and in livers of mice experimentally infected with Schistosoma mansoni. Phagosomal and residual forms of the pigment are described. The quantity of pigment is low in subclinical and in hepatointestinal forms of schistosomiasis; it is high in young patients with the hepatosplenic form, and low in the old ones. The participation of the pigment in the pathogenesis of schistosomal lesions is discussed.