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PubMed2001

Cessation of rapid late endosomal tubulovesicular trafficking in Niemann-Pick type C1 disease.

Niemann-Pick type C1 (NPC1) disease results from a defect in the NPC1 protein and is characterized by a pathological accumulation of cholesterol and glycolipids in endocytic organelles. We followed the biosynthesis and trafficking of NPC1 with the use of a functional green fluorescent protein-fused NPC1. Newly synthesized NPC1 is exported from the endoplasmic reticulum and requires transit through the Golgi before it is targeted to late endosomes. NPC1-containing late endosomes then move by a dynamic process involving tubulation and fission, followed by rapid retrograde and anterograde migration along microtubules. Cell fusion studies with normal and mutant NPC1 cells show that exchange of contents between late endosomes and lysosomes depends upon ongoing tubulovesicular late endocytic trafficking. In turn, rapid endosomal tubular movement requires an intact NPC1 sterol-sensing domain and is retarded by an elevated endosomal cholesterol content. We conclude that the neuropathology and cellular lysosomal lipid accumulation in NPC1 disease results, at least in part, from striking defects in late endosomal tubulovesicular trafficking.

Animals↗
PubMed2003

A high endothelial venule-expressing promiscuous chemokine receptor DARC can bind inflammatory, but not lymphoid, chemokines and is dispensable for lymphocyte homing under physiological conditions.

Chemokines displayed on the luminal surface of blood vessels play pivotal roles in inflammatory and homeostatic leukocyte trafficking in vivo. However, the mechanisms underlying the functional regulation of chemokines on the endothelial cell surface remain ill-defined. A promiscuous chemokine receptor, the Duffy antigen receptor for chemokines (DARC), has been implicated in the regulation of chemokine functions. Here we show that DARC is selectively expressed at the mRNA and protein levels in the high endothelial venules (HEV) of unstimulated lymph nodes (LN). To examine the biological significance of DARC expression in HEV, we performed competitive binding experiments with 20 different chemokines. The results showed that DARC selectively bound distinct members of the pro-inflammatory chemokines such as CXCL1, CXCL5, CCL2, CCL5 and CCL7, but not lymphoid chemokines such as CCL21, CCL19, CXCL12 and CXCL13 that are normally expressed in HEV. CCL2 bound to DARC failed to induce a significant cytosolic [Ca(2+)] elevation in CCR2B-expressing cells, whereas the free form of CCL2 induced a distinct [Ca(2+)] elevation, suggesting that DARC down-regulates activities of pro-inflammatory chemokines upon binding. Targeted disruption of the gene encoding DARC did not induce any obvious changes in the cell number or leukocyte subsets in the peripheral and mesenteric LN. Neither did DARC deficiency significantly affect lymphocyte migration into LN. These results suggest that DARC may be a scavenger for pro-inflammatory chemokines, but not a presenting molecule for lymphoid chemokines at HEV and that it is probably functionally dispensable for lymphocyte trafficking to HEV-bearing lymphoid tissues under physiological conditions.

Animals↗
PubMed2001

Signaling through CD31 protects endothelial cells from apoptosis.

Endothelial damage has been implicated in the pathogenesis of chronic rejection. Conversely, expression of protective genes [including A20, A1, bcl-xl, and hemoxygenase-1 (HO-1)] in the endothelium has been associated with long-term graft survival. Overexpression of protective genes in cultured endothelial cells confers protection from apoptosis and prevents expression of inflammatory molecules through inactivation of NF-kappaB. CD31 (PECAM-1) expressed at endothelial cell junctions is ligated by leukocytes during transendothelial migration. Our laboratory has recently shown that cross-linking CD31 using a monoclonal antibody (LCI-4) triggers signaling events in endothelial cells. In this study, we demonstrate that treatment with LCI-4 protected serum-starved endothelial cells from apoptosis. CD31 cross-linking also led to elevation of A20 and A1 mRNA levels and activation of the transcription factor Sp-1. In summary, signaling through CD31 on endothelial cells leads to protection from apoptosis in association with up-regulation of two protective molecules, A20 and A1.

Animals↗
PubMed2005

Chlamydial GroEL autoregulates its own expression through direct interactions with the HrcA repressor protein.

In the pathogenic bacterium Chlamydia trachomatis, a transcriptional repressor, HrcA, regulates the major heat shock operons, dnaK and groE. Cellular stress causes a transient increase in transcription of these heat shock operons through relief of HrcA-mediated repression, but the pathway leading to derepression is unclear. Elevated temperature alone is not sufficient, and it is hypothesized that additional chlamydial factors play a role. We used DNA affinity chromatography to purify proteins that interact with HrcA in vivo and identified a higher-order complex consisting of HrcA, GroEL, and GroES. This endogenous HrcA complex migrated differently than recombinant HrcA, but the complex could be disrupted, releasing native HrcA that resembled recombinant HrcA. In in vitro assays, GroEL increased the ability of HrcA to bind to the CIRCE operator and to repress transcription. Other chlamydial heat shock proteins, including the two additional GroEL paralogs present in all chlamydial species, did not modulate HrcA activity.

Bacterial Proteins↗
PubMed2004

Thromboxane A2 receptor signaling inhibits vascular endothelial growth factor-induced endothelial cell differentiation and migration.

Vascular endothelial growth factor (VEGF) is an important patho-physiological mediator of angiogenesis. VEGF-induced endothelial cell (EC) migration and angiogenesis often occur in complicated environments containing multiple agents capable of modifying the response. Thromboxane (TX) A2 is released from multiple cell types and is a prime mediator of pathogenesis of many vascular diseases. Human EC express both TXA2 receptor (TP) isoforms; however, the effects of individual TP isoforms on VEGF-induced EC migration and angogenesis are unknown. We report here that the TXA2 mimetic [1S-(1alpha, 2beta(5Z), 3alpha(1E, 3R), 4alpha]-7-[3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxab icyclo-[2.2.1]heptan-2yl]-5'-heptenoic acid (IBOP) (100 nmol/L) is a potent antagonist (IC50 30 nmol/L) of VEGF-induced EC migration and differentiation. TPbeta, but not TPalpha, expression is required for the inhibition of VEGF-induced migration and angiogenesis. IBOP costimulation suppressed nitric oxide (NO) release from VEGF-treated EC through decreased activation of Akt, eNOS, and PDK1. TPbeta costimulation also ablated the increase in focal adhesion formation in response to VEGF. This mechanism was characterized by decreased recruitment of focal adhesion kinase (FAK) and vinculin to the alpha(v)beta3 integrin and reduced FAK and Src activation in response to VEGF. Addition of NO donors together with transfection of a constitutively active Src construct could circumvent the blockade of VEGF-induced migration by TP; however, neither intervention alone was sufficient. Thus, TP stimulation appears to limit angiogenesis, at least in part, by inhibiting the pro-angiogenic cytokine VEGF. These data further support a role for antagonism of TP activation in enhancing the angiogenic response in tissues exposed to elevated TXA2 levels in which revascularization is important.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Influx of extracellular Ca2+ is necessary for electrotaxis in Dictyostelium.

Intracellular free Ca2+ ([Ca2+](i)) is a pivotal signalling element in cell migration and is thought to be required for chemotaxis of Dictyostelium. Ca2+ signalling may also be important for electrotaxis. However this suggestion has been controversial. We show that electric fields direct Dictyostelium cells to migrate cathodally and increase [Ca2+](i) in Dictyostelium cells, as determined by Fluo-3 AM imaging and (45)Ca2+ uptake. Omission of extracellular Ca2+([Ca2+](e)) and incubation with EGTA abolished the electric-field-stimulated [Ca2+](i) rise and directional cell migration. This suggests a requirement for [Ca2+](e) in the electrotactic response. Deletion of iplA, a gene responsible for chemoattractant-induced [Ca2+](i) increase, had only a minor effect on the electric-field-induced [Ca2+](i) rise. Moreover, iplA-null Dictyostelium cells showed the same electrotactic response as wild-type cells. Therefore, iplA-independent Ca2+ influx is necessary for electrotactic cell migration. These results suggest that the [Ca2+](i) regulatory mechanisms induced by electric fields are different from those induced by cAMP and folic acid in Dictyostelium cells. Different roles of the iplA gene in chemoattractant-induced and electrically induced Ca2+ signalling, and different effects of [Ca2+](i) elevation on chemotaxis and electrotaxis indicate that the chemoattractant and electric cues activate distinctive initial signalling elements.

Animals↗
PubMed1999

Neutral lipid from proteinuric rat urine is a novel inhibitor of the red blood cell calcium pump.

Proteinuria may be associated with hypertension and progression of renal insufficiency, which in turn may accompany abnormalities in cell calcium homeostasis. Therefore, urine from rats made proteinuric by puromycin aminoglycoside administration was analyzed, in a search for factors affecting cellular calcium transport. Proteinuric urine was fractionated by thin-layer chromatography and HPLC, and the effects of the fractions on the plasma membrane calcium pump in human red blood cells were assessed. Proteinuric urine contained a powerful specific inhibitor of the calcium pump that had little or no effect on the Na+/K+- or Mg2+-ATPases. The inhibitor was characterized as a neutral lipid, migrating as a single band, that inhibited 45Ca2+ efflux. To confirm the presence of an inhibitor in other proteinuric states, the urine from two patients with proteinuria was examined and subjected to chromatography as in the rat studies. These thin-layer chromatographic fractions contained a very strong inhibitor of the red blood cell calcium pump, suggesting that this substance may have relevance for the pathogenesis of proteinuric renal disease in human patients. Rat proximal tubule cells in tissue culture, when challenged with lipid-replete albumin, secreted an inhibitor of the calcium pump that migrated in the same chromatographic band as the urine factor. Therefore, the processing of fatty acids borne by albumin into endocytosing proximal tubular epithelium results in the synthesis and release of a previously unknown lipid modulator of the calcium pump, an effect that may predispose kidney tissue toward elevations in cytosolic calcium levels in target cells.

Adenosine Triphosphatases↗
PubMed1994

Vascular prostheses.

The quest for an ideal vascular graft began in the early 1950s and continues at a steady pace. The perfect graft has yet to be designed. As a result, patients with vascular prostheses may suffer complications that range from minor to catastrophic. The emergency physician may be faced with the initial presentation of patients with these vascular graft complications. If he or she is not familiar with these possibilities, then the resulting morbidity and mortality could be devastating. Probably the most unnerving complication involving the failure of vascular prostheses is that of the aortoenteric fistula. Instantaneous decisions and interventions must be made when a patient presents in this state of pre-exsanguination. Massive GI bleeding is at one end of the spectrum with other less-severe GI complications involving aortoenteric erosions and small bowel obstructions due to graft migration at the other end of the spectrum. Infection of a vascular prosthesis is a complication much feared by vascular surgeons. A spectrum of presentation also exists here whereby a patient may present with an obvious draining wound or with subtle complaints of fever, weakness, and a minimally elevated white blood cell count. The function of the emergency physician is critical here but only if he or she is able to suggest the possibility of graft infection to the admitting physician. Fortunately, thrombosis of a vascular graft is an infrequent complication that may occur at any time postoperatively, although the frequency decreases with time. There are many different causes of graft occlusion of which the emergency physician should be aware. If the cause of the thrombosis is known, then the secondary vascular reconstruction can be optimized. The dialysis population has grown rapidly over the past two decades and as a result so have complications of renal dialysis grafts. Because the dialysis population now includes large numbers of older subjects as well as those with systemic diseases such as diabetes and HIV, recognition and prompt aggressive management of clinical complications is of paramount importance.

Adult↗
PubMed2001

Elevated serum IP-10 levels observed in type 1 diabetes.

OBJECTIVE: Although most patients with type 1 diabetes are considered to have T-cell-mediated autoimmune disease, a method of measuring of pancreatic beta-cell-specific T-cell function in cases of type 1 diabetes has yet to be established. Here, we focused on interferon-inducible protein-10 (IP-10), a chemokine that promotes the migration of activated T-helper 1 (Th1) cells and measured serum IP-10 levels in patients with human type 1 diabetes, which is regarded as a Th1-mediated disease. RESEARCH DESIGN AND METHODS: Serum samples were obtained from diabetic patients, and the levels of autoantibodies (GAD and insulinoma-associated protein-2 [IA-2]) and IP-10 were measured. Diabetic patients positive for either or both of the autoantibodies were classified as Ab+ type 1, and those negative for both were classified as Ab type 1. To evaluate islet antigen-specific responses, peripheral blood from patients stimulated with or without GAD was used, and intracellular cytokine staining for flowcytometry was performed. RESULTS: The Ab+ and Ab- type 1 groups both showed a significantly higher serum IP-10 level than the healthy subjects (P < 0.001 and P < 0.05, respectively), and the IP-10 level in the recent-onset Ab+ subgroup was significantly higher than that in the established (longstanding) Ab+ subgroup (P < 0.002). Furthermore, there was a significant positive correlation between the serum IP-10 level and the number of GAD-reactive gamma-interferon-producing CD4+ cells in the Ab+ type 1 group (P < 0.007). CONCLUSIONS: Our findings demonstrate that measurement of serum IP-10 concentrations is useful in patients with type 1 diabetes.

Adult↗
PubMed2000

Macrophage migration inhibitory factor release by macrophages after ingestion of Plasmodium chabaudi-infected erythrocytes: possible role in the pathogenesis of malarial anemia.

Human falciparum malaria, caused by Plasmodium falciparum infection, results in 1 to 2 million deaths per year, mostly children under the age of 5 years. The two main causes of death are severe anemia and cerebral malaria. Malarial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in the presence of a robust host erythropoietin response. The production of a host-derived erythropoiesis inhibitor in response to parasite products has been implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1beta, tumor necrosis factor alpha, and gamma interferon while injection of interleukin-12 protects susceptible mice against lethal P. chabaudi infection. In this study, we report that ingestion of P. chabaudi-infected erythrocytes or malarial pigment (hemozoin) induces the release of macrophage migration inhibitory factor (MIF) from macrophages. MIF, a proinflammatory mediator and counter-regulator of glucocorticoid action, inhibits erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correlated with disease severity. Liver MIF immunoreactivity increased concomitant with extensive pigment and parasitized RBC deposition. Finally, MIF was elevated three- to fourfold in the spleen and bone marrow of P. chabaudi-infected mice with active disease, as compared to early disease, or of uninfected controls. In summary, the present results suggest that MIF may be a host-derived factor involved in the pathophysiology of malaria anemia.

Anemia↗
PubMed2000

Effects of proximal duodenal transection and anastomosis on interdigestive sphincter of Oddi cyclic motility in conscious dogs.

Gallstones formed after gastrectomy are bilirubinate stones probably associated with biliary stasis and infection. Effects of proximal duodenal transection performed during gastrectomy on interdigestive sphincter of Oddi cyclic motility possibly relevant to this phenomenon were investigated in four conscious dogs. Although the cyclic change in sphincter motility was still in concert with the duodenal migrating motor complex after duodenal transection, the mean period was shortened (p < 0.02), and the frequency (p < 0.005) and amplitude (p < 0.001) of sphincter phasic waves during phase III were decreased. The cyclic variation of basal pressure disappeared, and the mean basal pressure throughout the cycle was significantly reduced (p < 0.003). Transient inhibition of sphincter and duodenal contractions normally seen during phase III disappeared. Duodenal transection reversed the response of the sphincter to cholecystokinin-octapeptide from inhibition to stimulation and from reduction of the basal pressure to elevation. These data suggest that duodenal transection produces significant changes in interdigestive sphincter of Oddi motility, possibly contributing to augmented duodenobiliary reflux and then lithogenesis. Myoneural continuity between the stomach and sphincter of Oddi at the proximal duodenum may play an important role in maintaining normal biliary dynamics.

Anastomosis, Surgical↗
PubMed1993

Protein phosphatases limit tumor motility.

Elevators of cAMP, such as prostaglandin E2 (PGE2), activate protein kinase A (PKA) and induce PKA-stimulated motility and metastasis by metastatic Lewis lung carcinoma cells (LLC-LN7). Non-metastatic LLC (LLC-C8) are unresponsive to cAMP elevation even though they are not deficient in the PKA enzymes. To determine whether this PKA unresponsiveness might be due to increased dephosphorylation by serine/threonine protein phosphatases (PP-1/2A) within non-metastatic LLC-C8, the effects of the PP-1/2A inhibitor okadaic acid on the migration and invasion by non-metastatic LLC-C8 cells was measured. Okadaic acid stimulated motility of non-metastatic LLC-C8 cells to a level that was comparable to that of metastatic LLC-LN7 cells. PGE2 further increased the motility of the non-metastatic LLC-C8 cells when okadaic acid was present, although not in the absence of okadaic acid. The stimulation of motility by okadaic acid was diminished when PKA activity was inhibited. Dose-response studies with concentrations of okadaic acid that selectively inhibited PP-2A or both PP-2A and PP-1 showed a progressive increase in migration of non-metastatic LLC-C8 cells, suggesting that both PP-1 and PP-2A limit their motility. By contrast, metastatic LLC-LN7 cells were more motile than were non-metastatic LLC-C8 cells, but this motility was only marginally affected by okadaic acid. Comparisons of the levels of PP-1/2A enzyme activities in the LLC variants showed more activity in non-metastatic LLC-C8 than in metastatic LLC-LN7 cells. The identity of the PP whose activity was increased in the non-metastatic LLC-C8 was assessed by using okadaic acid, which selectively inhibits PP-2A activity at low concentrations and PP-1 and PP-2A at high concentrations, and calyculin A, which inhibits PP-2A at a similar concentration to that affected by okadaic acid but is more potent at inhibiting PP-1. The inhibition of PP activities by okadaic acid and by calyculin A showed a pattern which suggested the presence both of PP-1 and of PP-2A in non-metastatic LLC-C8 cells, but the presence of PP-1 and a reduction in PP-2A in metastatic LLC-LN7 cells. The sum of these data suggests that PKA-stimulated motility is restricted both by PP-1 and by PP-2A in non-metastatic LLC, and that a deficiency in this restriction results in increased migration and invasion.

Cell Movement↗
PubMed2000

Baseline corticosterone peaks in shorebirds with maximal energy stores for migration: a general preparatory mechanism for rapid behavioral and metabolic transitions?

In captive red knots (Calidris canutus, Scolopacidae) showing a regulated body mass increase of 50% related to their migration from temperate staging sites to tundra breeding grounds, plasma corticosterone concentrations increased from less than 10 ng. ml(-1) to levels as high as 30 ng. ml(-1) when the energy storage for migration was complete. These birds did not fly, but concentrations dropped to very low levels (<5 ng. ml(-1)) as soon as the birds started their voluntary fasts to the low body masses preceding the early wing and body molts normally occurring after an unsuccessful breeding season. As the elevated levels of corticosterone are associated with stable body mass rather than with the preceding increase or subsequent decrease, it is suggested that a major role of corticosterone during the final stages just before departure may be to prepare birds for long-distance flights. Birds heading into the Arctic to breed face potentially arduous flights into unpredictable environmental and social conditions. Activation of the hypothalamic-pituitary-adrenal axis, as measured by elevated levels of corticosterone, may induce the suite of behavioral and metabolic changes necessary to negotiate these challenges successfully.

Animals↗
PubMed1995

Neutrophilic dermal infiltrates in granulocytopenic patients with acute leukemia.

Acute febrile neutrophilic dermatosis (AFND, Sweet's syndrome) is clinically characterized by fever, neutrophilic leukocytosis, and tender dermal plaques. Histological examination typically reveals infiltration of the dermis by neutrophils. In three patients (2 female, 1 male, 54-59 years) with acute leukemia (2 myelogenous, 1 lymphoblastic) dermal plaques developed during febrile episodes in chemotherapy-induced pancytopenia. The clinical appearance was compatible with AFND. The diagnosis was substantiated by skin biopsies which showed dense neutrophilic dermal infiltrates without leukemic cells. Leukocytoclastic vasculitis was considered as differential diagnosis. Plasma levels of soluble adhesion molecules ICAM-1, VCAM-1, and E-selectin regulating leukocyte transendothelial migration were in the normal range. Systemic glucocorticoids were avoided because of the high risk of infection during prolonged bone marrow aplasia. The lesions were treated with topical steroids and resolved without scarring within 1-5 weeks. AFND has been reported in association with acute leukemia at normal or elevated white blood cell counts. Although implausible from a pathophysiological point of view, similar neutrophilic dermal infiltrates were found in three patients during chemotherapy-induced pancytopenia with white blood cell counts distinctly below 1 x 10(9)/l.

Agranulocytosis↗
PubMed2004

Inflammation and atherosclerosis.

It is now generally recognized that atherosclerosis is a chronic inflammatory disease, characterized by overrecruitment of leukocytes (monocytes and T-cells) to the site of inflammation. Vascular injury in response to cardiovascular risk factors promotes endothelial dysfunction, resulting in enhanced adhesion molecule expression and secretion of pro-inflammatory cytokines and chemokines. This, in turn, leads to adherence, migration and accumulation of leukocytes within atherosclerotic lesions. The recent findings on inflammatory processes involved in atherosclerosis development provide important links between risk factors and the mechanisms of atherogenesis. Thus, research interest has increasingly focused on inflammatory biomarkers as means of predicting the risk of future clinical events. Indeed, elevated plasma levels of molecules such as soluble intercellular adhesion molecule-1, interleukin-6 or C-reactive protein (CRP) have been shown to represent inflammatory markers of future cardiovascular risk. Among these, CRP has emerged as the most powerful and accessible for clinical use. A major challenge for future research is to implement these new insights in order to improve strategies for prediction, prevention and treatment of cardiovascular events.

Animals↗
PubMed1998

Effect of aging on neointima formation and hyaluronan, hyaluronidase and hyaluronectin production in injured rat aorta.

Few studies have examined the effect of aging on arterial wall response to injury, and the results are discordant. Moreover, the effect of aging on hyaluronan synthesis in injured vessels is unknown. The aim of this present study was to determine the effect of aging on neointima formation and hyaluronan (HA), hyaluronidase and hyaluronectin production in injured rat aorta. Aorta was analysed in sham-operated rats (group D0) and 14 (D14) and 28 (D28) days after injury using biochemical and immunohistochemical techniques. Uninjured aorta of old rats was more thickened than that of young rats; it showed a decreased number of arterial smooth muscle cells (ASMC) and was characterized by HA accumulation in the intima and increased hyaluronidase activity. Intima-media wet weight was significantly increased in young rats at D14 and D28 but remained unchanged in old rats. DNA content was significantly enhanced at D14 in both young and old rats. DNA decreased slightly in young rats at D28 but significantly in old rats to return to control level. HA content and hyaluronidase activity in the intima-media were markedly increased in young rats at D14 (+148% and +116% respectively) but slightly in old rats (+23% and +15% respectively). Both HA and hyaluronidase activity continued to increase at D28, but remained more produced in young rats. The immunohistochemical analysis showed the formation of a thickened neointima in young rats, which was associated with strong expression of HA and HN. Neointima of old rats was reduced; it also showed strong expression of HA and HN but their distributions were different from those observed in neointima of young rats. In conclusion, aorta of old rats showed an increased amount of HA in the intima and elevated activity of hyaluronidase. Injury induced formation of a significant neointima in young rats but not in old rats. This was correlated with more HA and hyaluronidase production in injured aorta of young rats. As HA is considered to increase extracellular matrix space and to promote ASMC proliferation and migration, our findings suggest that HA may be implicated in intima thickening with age and after injury.

Aging↗
PubMed2002

Plasminogen activation by blood monocytes and alveolar macrophages in primary pulmonary hypertension.

The pathophysiology of primary pulmonary hypertension (PPH) remains poorly understood. Vascular wall remodeling and endothelial dysfunction reflected by modifications in plasma fibrinolytic proteins and von Willebrand factor have been well documented in PPH. We hypothesize that endothelial mediators, produced in excess in PPH patients, may stimulate migrating mononuclear cells and thereby modulate alveolar macrophage function; in particular, the plasminogen activation system. Components of the fibrinolytic system were therefore studied in plasma, blood monocytes and alveolar macrophages obtained from bronchoalveolar lavage in 10 patients with PPH and in four controls. Compared with controls, PPH patients had elevated plasma levels of tissue-type plasminogen activator (15.6 +/- 9.9 versus 5.5 +/- 3 ng/ml) and plasminogen activator inhibitor-1 (27.8 +/- 23 versus 16.4 +/- 12 ng/ml). In contrast, binding and activation of plasminogen by single-chain urokinase-type plasminogen activator (scu-PA) at the surface of blood monocytes and alveolar macrophages were not different from those of control values. Dissociation constants (K(d)) for binding of scu-PA and plasminogen to alveolar macrophages were similar in both PPH (4.7 +/- 1.5 and 0.88 +/- 0.3 micromol/l, respectively) and control (6.7 +/- 0.1 and 1.02 +/- 0.12 micromol/l, respectively) groups. These results indicate that in PPH patients the fibrinolytic activity of alveolar macrophages is normal, whereas endothelial fibrinolytic proteins are abnormally elevated in plasma.

Adult↗
PubMed2004

Exacerbation of intestinal permeability in rats after a two-hit injury: burn and Enterococcus faecalis infection.

OBJECTIVE: To determine alterations in intestinal epithelial permeability to solutes in burn injured rats with and without Enterococcus faecalis infection and the role of neutrophils in the intestinal permeability changes. DESIGN: Prospective sham-controlled animal study. SETTING: University research laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: Rats were subjected to 30% total body surface burn (B group), E. faecalis infection (EF group) induced via intra-abdominal implantation of bacterial pellet, or combination of burn injury and E. faecalis infection (B+EF group). MEASUREMENTS AND MAIN RESULTS: In vivo measurements of intestinal permeability were carried out after intraluminal injection of H lactulose and C mannitol in the ileum of sham, B, EF, and B+EF groups of rats, 1 and 2 days after injury. Lactulose permeability was increased in the injured rat groups (B, EF, B+EF) on day 1 postinjury compared with sham. The combined injury group (B+EF) had the highest level of lactulose permeability. Although a significant change in lactulose permeability from day 1 to day 2 postinjury could not be demonstrated in the B and EF groups, lactulose permeability in the B+EF group on day 2 postinjury markedly decreased from day 1 but was still significantly higher than that in the sham group. Mannitol permeability was increased in all injured rat groups on day 1 postinjury; on day 2 it remained elevated post-B, decreased post-EF, and further increased after B+EF. Ex vivo measurements of lactulose movements across intestinal epithelial monolayers (IEC-18) were carried out in the presence of blood neutrophils from sham, B, EF, or B+EF rats. We also measured ex vivo transepithelial migration of neutrophils from sham, B, EF, or B+EF rat groups. Neither the transepithelial lactulose movement in the presence of neutrophils from, nor neutrophil migration in, the B or EF rats was significantly different from sham. However, a significant increase in transepithelial lactulose movement and neutrophil migration occurred in the B+EF group. Immunoblot analyses and in situ histochemical localizations of intestinal tight junction proteins, occludin and claudin-3, showed decreases in the distribution of occludin but not claudin-3 in the B, EF, and B+EF groups. CONCLUSIONS: Alterations in intestinal solute permeability and disruption of tight junction integrity after a two-hit injury with burn and E. faecalis infection, but not after individual injuries of burn or E. faecalis infection, are likely associated with heightened neutrophil flux across the intestinal epithelium.

Animals↗