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P A McCuskey

Publications and source records attributed to P A McCuskey.

At least 19 recordsLinked to original sources
PubMed1995

In vivo microscopy of hepatic metastases: dynamic observation of tumor cell invasion and interaction with Kupffer cells.

In vivo microscopy was used in the study of the biological behavior of tumor cells and of the activity of Kupffer cells in hepatic tumors in situ. Three tumor models, Friend erythroleukemia inoculated into Dilute Brown Aguti (DBA)/2 mice, murine colon adenocarcinoma (CT)-26 in Bagg Albino inbred albino (BALB)/c mice, and mammary cancer 13762 NF in Fischer rats, were investigated. Tumor cells showed a strong tendency to adhere to the sinusoidal endothelium, most frequently in the sinusoids near the tumors. Mechanical trapping of tumor cells in the narrow portion of hepatic sinusoids, a phenomenon suggested by previous investigators as a predominant pattern for tumor cells to arrest in the liver, was not confirmed. Our study documented that in tumor-bearing livers, as compared with normal control livers, the population size and the phagocytic capacity of Kupffer cells are increased in nontumorous areas but are significantly decreased inside the tumors. In vivo microscopic images showed that Kupffer cells are not only attracted to tumor cells in the hepatic circulation but also have the ability to phagocytose those tumor cells. In vivo microscopy has been shown to be a useful tool for dynamic studies in tumor biology, pathology, and pharmacology.

Animals↗
PubMed1994

An electron microscopy study of Kupffer cells in livers of mice having Friend erythroleukemia hepatic metastases.

Kupffer cells, which are part of the reticuloendothelial system, play an important role in clearing pathogenic substances, including tumor cells, from the liver. The role of Kupffer cells in tumor development is very important as Kupffer cells can be manipulated to a tumoricidal state with biological response modifiers to kill tumor cells and thus to decrease tumor burden and extend survival time. To gain additional information on the role of Kupffer cells and their interaction with tumor cells in hepatic metastases, we studied an established experimental hematogenous metastatic model (Friend erythroleukemia) in mouse livers by light and electron microscopy. Highly activated Kupffer cells were observed in close contact with tumor cells in sinusoids and also in tumor forming foci within the hepatic parenchyma. The Kupffer cells were activated by the presence of the hematogenous tumor cells and were able to lyse and phagocytose them. However, some tumor cells evaded the Kupffer cells as metastases still occurred. Kupffer cells and other macrophages were found to leave the sinusoids and migrate to sites of potential tumor development where they interacted with tumor cells and intimately wrapped their processes around fat storing cells. It is possible that these macrophages which cross biological barriers could be used to deliver drug-loaded microparticles (liposomes and microcapsules) to tumors.

Animals↗
PubMed1994

Role of Kupffer cells in iodized oil embolization.

RATIONALE AND OBJECTIVES: Iodized oil is a common oily embolic agent used in chemoembolization for treating hepatic tumors. However, how the iodized oil is cleared from the liver has been an unsettled and controversial issue. In this study, the authors attempt to clarify whether Kupffer cells are involved in the clearance of iodized oil and to evaluate the effect of hepatic arterial injection of iodized oil on the functional status of Kupffer cells. METHODS: Iodized oil was injected into the proper hepatic artery in 42 Fischer 344 rats. In vivo microscopy was performed immediately after and 1, 3, 7, 15, 30, and 60 days after injection. Electron microscopy was performed after in vivo microscopy. RESULTS: Kupffer cells actively captured and phagocytosed iodized oil droplets in the hepatic circulation. The number and functional status of Kupffer cells in the liver were significantly increased after the injection of the iodized oil and returned to normal when the liver was cleared of the oil. CONCLUSIONS: Kupffer cells play an important role in clearing iodized oil from the liver. Iodized oil activates the immune defense system in the liver, which may have a synergistic effect in tumor treatment.

Animals↗
PubMed1991

Electron microscopic study of the effects of endotoxin on the cells of the hepatic sinusoid in normal and BCG sensitized mice.

Electron microscopic studies were conducted to access ultrastructural alterations in Kupffer cells and other cells lining the hepatic sinusoids at the peak of mediator release two hours after challenge with low doses of endotoxin under various conditions including reticuloendothelial system (RES) expansion and activation with BCG. BCG is known to sensitize animals to endotoxin rendering normally innocuous, low doses of endotoxin lethal. Low non-lethal doses (5 micrograms) of endotoxin activated Kupffer cells as well as caused isolated foci of cellular injury. However, animals which were treated with BCG had a highly activated and expanded RES system as evidenced by enlarged Kupffer cells with many extended cellular processes. Granulomas were prevalent and many reactive cells were present. After two hours marked cellular injury occurred to sinusoid lining and parenchymal cells when BCG treated animals were challenged with these same low doses of endotoxin. Cellular debris, fibrin, and platelets were observed in sinusoids often associated with Kupffer cells. These results suggest that the functional state of Kupffer cells is an important determinant in the host response to endotoxin. While there appears to be an effective clearance of endotoxin; the release of mediators by the highly activated Kupffer cells can be toxic causing hepatocellular injury.

Animals↗
PubMed1991

Kupffer cell activity and hepatic microvascular events after acute ethanol ingestion in mice.

After acute ethanol ingestion in C57Bl/6 mice, phagocytic activity of Kupffer cells and hepatic microcirculation were examined by in vivo and electron microscopy. A ratio of Kupffer cells that phagocytosed 0.8 micron fluorescent latex particles to sinusoids containing blood flow (number of Kupffer cells/number of sinusoids containing blood flow) was used as a measure of Kupffer cell phagocytic activity. Three hours after ingestion of 1 gm/kg ethanol, number of Kupffer cells/number of sinusoids containing blood flow increased in both periportal and centrilobular regions by 62% and 66%, respectively, and blood ethanol was no longer detectable. Ultrastructurally, activation of KC was evidenced by the presence of many pseudopodia and filopodia. Numbers of swollen endothelial cells were increased in both regions by 249% and 174%. Interruption of sinusoidal blood flow by leukocytes was aggravated in both regions by 127% and 167%. Thirty minutes and 3 hr after ingestion of 4 gm/kg ethanol, no significant increase in number of Kupffer cells/number of sinusoids containing blood flow was seen, although number of Kupffer cells were also activated as seen with electron microscopy. An increased number of swollen endothelial cells was observed in both regions by 100% and 71% by 30 min and by 200% and 384% by 3 hr. The interruption of sinusoidal blood flow by leukocytes was also increased (periportal = 161%, centrilobular = 196%) as were sticking or plugging leukocytes in sinusoids (periportal = 320%, centrilobular = 120%) by 3 hr. The diameter of centrilobular sinusoids was decreased by 3 hr. Latex particles and platelets were attached to the sinusoidal wall after both low and high dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcohol Drinking↗
PubMed1990

Fine structure and function of Kupffer cells.

Kupffer cells are macrophages that are attached to the luminal surface or inserted in the endothelial lining of hepatic sinusoids. In this site, Kupffer cells play a key role in host defense by removing foreign, toxic and infective substances from the portal blood and by releasing beneficial mediators. Under some conditions, toxic and vasoactive substances also are released from Kupffer cells which are thought to play a role in a variety of liver diseases. Many of these activities may be modulated by the levels of gut derived endotoxin normally present in the portal blood. The ultrastructural aspects of Kupffer cell structure function in situ are best studied using perfused-fixed livers. In fixed livers, transmission and scanning electron microscopy reveal Kupffer cells during health to be irregular in shape with their exposed surfaces presenting numerous microvilli, filopodia, and lamellopodia. Long filopodia penetrate endothelial fenestrae to secure Kupffer cells to the sinusoid lining. Specific membrane invaginations known as worm-like bodies or vermiform processes are seen in the cytoplasm of Kupffer cells as are numerous endocytotic vesicles and lysosomes which vary in density, shape and size. Sometimes, annulate lamellae connected to the rough endoplasmic reticulum also are found. The principal endocytic mechanisms of Kupffer cells are phagocytosis of particulates and cells, and bristle-coated micropinocytosis for fluid-phase endocytosis of smaller substances. Many of these events are mediated by specific receptors. In some species, Kupffer cells can be distinguished from other sinusoidal lining cells and monocytes by specific cytoplasmic staining or monoclonal antibodies. Kupffer cells have been shown to be of monocytic origin as well as having the capacity for self-replication.

Humans↗
PubMed1986

Hepatic microvascular regulatory mechanisms. VIII. Glucogenic responses and morphologic changes following serotonin-induced low flow.

Changes in blood glucose, hepatic glycogen content and distribution, the number of hepatic mast cells, and hepatic morphology were assessed over 30 min in non-fasted and anesthetized Sprague-Dawley rats receiving endoportal or femoral intravenous injections of selected doses of serotonin and/or phentolamine, lodoxamide, or of Ringer's solution (control). Endoportal administration of low-flow producing doses of serotonin (1.0, 10.0, 20.0 micrograms per 100 g b.w.) elevated circulating blood glucose without decreasing hepatic glycogen content when compared to control in unit dry or wet weights. Hyperglycemia was accompanied by centrilobular glycogen depletion and apparent Kupffer cell activation. However, no change in hepatocyte or endothelial cell morphology or in the number of hepatic mast cells was observed following serotonin-induced low flow. The glucotropic response to a nonhypotensive dose of serotonin (1.0 microgram per 100 g b.w.) was modified by phentolamine (100 micrograms per 100 g b.w.) but not lodoxamide (0.1 microgram per 100 g b.w.). These blockers, when given alone, stimulated centrilobular glycogen depletion without producing a net change in blood glucose or hepatic glycogen content. By contrast, injection of serotonin (10.0 micrograms per 100 g b.w.) and/or phentolamine (100 micrograms per 100 g b.w.) into the femoral vein provoked no glucogenesis or systemic hypotension. Given these results, serotonin is suggested to stimulate hyperglycemia by activating alpha-adrenergic receptors. Since centrilobular glycogen depletion proceeds with no detectable change in total hepatic glycogen content, it is postulated that hepatic glycogen catabolism and deposition occur simultaneously and at equivalent rates during conditions of serotonin-induced hyperglycemia and low flow.

Animals↗
PubMed1985

Functional units in rainbow trout (Salmo gairdneri) liver: I. Arrangement and histochemical properties of hepatocytes.

The architectural arrangement and selected histochemical properties of hepatocytes in the rainbow trout (Salmo gairdneri Richardson) were examined. Light and transmission electron microscopic (TEM) examination following fixation by portal venous perfusion revealed a tubular arrangement of hepatocytes. Lobules, as defined in the adult mammal, were absent. Biliary epithelial cells associated with bile preductules and ductules were a prominent feature of trout liver. Patterns and location of reaction products for glucose-6-phosphatase (G-6-Pase), glucose-6-phosphate dehydrogenase (G-6-PDH), and magnesium-dependent adenosine triphosphatase (ATPase), enzymes preferentially distributed in mammalian liver, were demonstrated in trout liver. A slightly heavier staining pattern for G-6-Pase was seen around presumptive portal venules but all other enzyme reaction patterns were uniform throughout the liver parenchyma. Following ATPase localization, four sizes of biliary passageways (canaliculi, bile preductules, ductules, and ducts) were visualized. Maximum glycogen retention was achieved with freeze-drying and glycolmethacrylate embedding and with this method intense, uniform glycogen staining was observed in all areas of the liver. Companion TEM examinations revealed large depots of glycogen within hepatocytes. The results are important for interpretation and description of the effects of toxic/carcinogenic alteration on trout liver.

Adenosine Triphosphatases↗
PubMed1984

Deficient Kupffer cell phagocytosis and lysosomal enzymes in the endotoxin-low-responsive C3H/HeJ mouse.

Various substances, including lysosomal enzymes, are produced by Kupffer cells and other macrophages; their release has been implicated in the toxic response to endotoxins. C3H/HeJ mice exhibit little or no response to doses of endotoxin that are lethal in syngeneic C3HeB/FeJ mice. To explore the nature of this deficient response, the Kupffer cells of these mice were studied using in vivo microscopic as well as histochemical and electron microscopical methods. In vivo, the rate of phagocytosis of single 0.8 micron latex particles was measured in individual Kupffer cells as was the number of phagocytic cells per microscopic field. Frozen sections of livers were stained for a variety of lysosomal enzymes and liver specimens also were processed for electron microscopy. In comparison to the endotoxin-sensitive C3HeB/FeJ mice, the livers of the C3H/HeJ mice contained 60% fewer Kupffer cells that phagocytosed latex. However, the rate of phagocytosis by these cells was not statistically different and ranged from 19-26 sec. The volume density of acid-phosphatase-positive Kupffer cells was 40% less in the C3H/HeJ mice. Similar differences were observed with other lysosomal enzymes including cathepsins B and H and dipeptidyl peptidases I and II. However, light and electron microscopy revealed a relatively normal number of Kupffer cells in livers stained for peroxidase, a nonlysosomal enzyme. The results suggest that the insensitivity of C3H/HeJ mice to endotoxin may be related in part to a lysosomal enzyme deficiency and a paucity of phagocytic Kupffer cells in these animals.

Animals↗
PubMed1984

Species differences in Kupffer cells and endotoxin sensitivity.

The relative species sensitivity to Escherichia coli O111:B4 endotoxin was found to be guinea pig greater than hamster greater than mouse greater than rat. The 50% lethal dose of this endotoxin correlated with both the rate at which single latex particles were phagocytosed by individual Kupffer cells and the number of Kupffer cells in hepatic lobules that phagocytosed latex. The results suggests that the intrahepatic density and the level of activation of Kupffer cells participate in determining endotoxin sensitivity.

Animals↗
PubMed1984

In vivo and electron microscopic study of the development of cerebral diabetic microangiography.

The cerebral microvasculature of rats rendered diabetic with streptozotocin (75 mg/kg) and vehicle-treated controls paired for age and sex were studied using in vivo and electron microscopic methods at intervals from two weeks to 12 months after induction of diabetes mellitus. By one month, the pial vessels of diabetics were dilated and tortuous; and, the vasoconstrictive responses of arterioles and venules to local increases of PO2 in the artificial CSF bathing these vessels was reduced as was the linear velocity of blood flow. Increased arterio-venous shunting also was observed. By five months the responsiveness to locally increased levels of PO2 was further reduced from control values of 49.9% +/- 5 (SEM) to 6.9% +/- 1.8 (SEM) in arterioles and from 11.5% +/- 2.1 (SEM) to 2.6% +/- 0.7 (SEM) in venules. No further significant change in responsiveness was measured from five to twelve months. At 5 months, the functional changes were no longer reversible; and focal changes were noted in the thickness and density of the vascular basement membrane. Astrocytic end feet were greatly swollen and contained mitochondria having longitudinal rearrangement of their cristae. Basement membranes contained nodules of electron-lucent material which impinged on degenerating smooth muscle cells, pericytes and astrocytes. In some sites these cells appeared to be replaced by an amorphous material laced with collagen fibrils. By 11 months, these focal lesions were more frequent and more pronounced. Additional cellular replacement had taken place which resulted in greatly widened basement membranes which varied in density and content. The ultrastructure of endothelial cells was not noticeably altered except for presence of numerous cytoplasmic vesicles. The tight interendothelial junctions appeared to be intact even though dramatic changes had taken place perivascularly. These architectural and functional changes in the microvasculature are suggested to result not only from metabolic defects in the vascular wall, but also as a response to a relative hypoxia of the brain during the diabetic state.

Animals↗
PubMed1983

In vivo microscopic observations of the responses of Kupffer cells and the hepatic microcirculation to Mycobacterium bovis BCG alone and in combination with endotoxin.

Kupffer cell function and hepatic microvascular hemodynamics were studied by in vivo microscopy in Mycobacterium bovis BCG-infected NMRI mice before and after treatment with minute (0.01 mu mg) tolerance-producing doses and doses causing 70% lethality (0.5 micrograms) of Escherichia coli 0111:B5 endotoxin alone and in combination. BCG-induced granulomas distorted the hepatic microvasculature and impeded blood flow in many sinusoids; flow also was altered further by leukocytes adhering to the sinusoidal walls and by enlarged Kupffer cells that bulged into the lumen. Nevertheless, in BCG-infected mice, the ratio of Kupffer cells which phagocytosed latex to sinusoids containing blood flow and capable of delivering these particulates to Kupffer cells was significantly greater than that in uninfected mice. The phagocytosis of single latex particles by individual Kupffer cells also was more rapid. This indicated an expansion of the numbers and activation of Kupffer cells. In this hyperreactive state, the tolerance-inducing dose of endotoxin produced no change in the rate of phagocytosis after 2 h. In contrast, the 70% lethal dose reduced the rate by 123%, unless tolerance was induced, in which case there was no reduction in the rate of phagocytosis. Twenty-four hours after injection of the tolerance-inducing dose, however, the rate of phagocytosis was accelerated slightly (17%). This suggested that the Kupffer cells had been activated and perhaps were more effective in clearing subsequent endotoxin from the blood but without sufficient release of toxic substances to be lethal. That some mediators were released, however, was suggested by the microvascular alterations that accompanied the above phagocytic responses. These results further support the concept of a central role for Kupffer cells in endotoxin-mediated, nonspecific host defense mechanisms.

Animals↗
PubMed1982

In vivo microscopic studies of the responses of the liver to endotoxin.

In vivo microscopic methods concomitant with electron microscopic and histochemical procedures are being used to explore the sequelae of responses of Kupffer cells and the hepatic microvasculature to endotoxins. To gain further insight into the role of the liver in host defense and nonspecific resistance, the effects of endotoxin also are being studied in animals sensitized to endotoxin (BCG infection) or tolerant to endotoxin (pretreated with detoxified endotoxin, low doses of endotoxin, or in C3H/HeJ mice). The results to date, have demonstrated that endotoxin induces significant alterations in the hepatic microcirculation due to swelling of Kupffer and endothelial cells and the adhesion of leukocytes and platelets to the sinusoid wall. Lymphocytes frequently are associated with the Kupffer cells. Phagocytosis also is affected; following a brief period of stimulation, the rate of phagocytosis by Kupffer cells is depressed. In BCG infected animals all of these responses are exaggerated but can be minimized by pretreatment with detoxified endotoxin or minute concentrations of endotoxin 24 h prior to the challenge dose of endotoxin. The responses are not seen in the endotoxin low-responder, C3H/HeJ mouse which was found to have a deficiency in lysosomal enzymes and a paucity of functional Kupffer cells. The results provide some insight into the sequelae of cellular and microvascular events that occur in the liver during endotoxemia, endotoxin-related host defense mechanisms and non-specific resistance. In addition, support is provided for the central role of Kupffer cells in these events and that lysosomal enzymes participate in the toxic response elicited by endotoxin.

Animals↗
PubMed1979

Innervation of the periarteriolar lymphatic sheath of the spleen.

During the course of a neurohistochemical and two independent electron microscopic studies of the mouse spleen, unmyelinated adrenergic nerves containing numerous dense core and lucent vesicles and devoid of neurolemma were observed adjacent to reticular cells and lymphocytes in the white pulp. Some of these nerves formed an intimate relationship with these cells. Since adrenergic substances have been reported to modulate the cell cycle of lymphocytes in vitro, these findings are suggestive of a neural influence on the cell cycle of lymphocytes in vivo.

Adrenergic Fibers↗
PubMed1979

In vivo microscopy of the hepatic microvascular system.

In vivo microscopic study of the responses of the various segments of the hepatic microvascular system to adrenergic, cholinergic, and other aminergic substances and their antagonists have revealed the relative distribution of receptor sites in these various vessels. The results also suggest a possible interaction of cholinergic substances with periportal mast cells. The release of serotonin, histamine and possibly other products from these cells results in dramatic alterations in blood flow through the hepatic sinusoids due to the adhesion of leukocytes and platelets to the endothelium.

Animals↗
PubMed1978

Intrahepatic distribution of nerves in the rat.

The intrahepatic distribution of nerves in the rat was studied using neurohistochemical and electron microscopic methods. Innervation was restricted primarily to vessels in the portal space and hilus. Both adrenergic and cholinergic fibers were observed in the adventitia of hepatic arteries, and to a lesser extent adjacent to portal veins. Some of the cholinergic fibers, however, were not contiguous with the vasculature. Near the hilus many of these fibers were associated with ganglia while peripherally some coursed into the immediately adjacent parenchyma where end bulbs abutted on hepatocytes. Ultrastructurally, scattered small nerves, devoid of neurolemma, were found contiguous with the portal lamina of hepatocytes. Nerve fibers deeper within the lobule were not seen but numerous gap junctions were observed between contiguous hepatocytes. Central and sublobular hepatic veins lacked innervation but adrenergic nerves were demonstrated in the walls of larger hepatic veins. Innervation of the biliary system was sparse. While nerves were interposed between vessels and bile ducts, such nerves tended to be associated more closely with the vasculature.

Acetylcholinesterase↗