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PubMed2003

Canine ectopia: report of two cases.

Transmigration of mandibular canine is a rare elusive phenomenon described in dental literature. The eruption of such transmigrated canines is even rarer. Two rare cases one of midline mandibular canine and the other of transmigrated mandibular canine across the midline and erupted distal to the opposite lateral incisor are presented. The transmigrated canine maintained its nerve supply from the original site. It is suggested that on routine evaluation of orthopantomograms when the dentist finds an excessive mesial inclination of the unerupted mandibular canine at 8-9 years associated with proclination of lower anteriors. increased axial inclination of the unerupted canine and an enlarged symphyseal cross section area of the chin, it is best to keep such a patient under routine evaluation.

Adolescent↗
PubMedDate not supplied

The transperitoneal migration of ova in the rabbit.

The purpose of this study was to assess the incidence and direction of the transperitoneal migration of ova in the rabbit. Sixteen New Zealand white rabbits underwent unilateral microsurgical enclosure of either the left (n = 9) or right (n = 7) ovary within a peritoneal bursa. Each animal was bred later to induce ovulation. The fallopian tubes were removed and flushed retrogadely to retrieve ova. The number of transmigrated ova retrieved from the oviduct ipsilateral to the ovary within the bursa was compared with the number of ovulated follicles present on the contralateral ovary. Three ova migrated to the left fallopian tube from a total of 49 ovulation sites on the right ovary. No ova transmigrated to the right oviduct from 33 ovulation sites on the left ovary. Chi-square analysis shows that there is no statistical difference between the tendency to right or left transmigration. This finding substantiates the numerous studies of reproductive physiology in the rabbit that have assumed previously the net transmigration of ova to be zero.

Animals↗
PubMed1997

T cell adhesion to endothelial cells and extracellular matrix is modulated upon transendothelial cell migration.

During inflammation, T cells transmigrate from the bloodstream into perivascular tissues. As T cells transmigrate, they undergo a series of attachments to and detachments from the endothelium and then extravasate into the extracellular matrix (ECM). T cell migration into the ECM involves a number of mechanisms that influence cell-ECM interactions. The modulation of integrin expression and affinity are two such mechanisms in which cells can alter their ability to interact with other cells and ECM. We show in vitro that transmigrated T cells exhibit down-regulation of very late activation antigen-4 and leukocyte function-associated antigen-1 integrin surface expression and a decrease in binding to recombinant vascular cell adhesion molecule-1 and recombinant intercellular adhesion molecule-1. Also, transmigrated T cells displayed an increase in binding to collagens I and IV and fibronectin. Further, brain sections of experimental autoimmune encephalomyelitis mice demonstrated that as T cells migrated farther into the tissue, very late activation antigen-4 expression was lost while CD4 expression remained unchanged. The significance of these findings in the modulation of the inflammatory response is discussed.

Animals↗
PubMed1997

Transcriptional activation of vascular cell adhesion molecule-1 gene in vivo and its role in the pathophysiology of neutrophil-induced liver injury in murine endotoxin shock.

Polymorphonuclear leukocytes (neutrophils) can cause hepatic parenchymal cell injury during endotoxin (ET) shock. Because adhesion molecules are critical for inflammatory cell damage, the role of vascular cell adhesion molecule-1 (VCAM-1) was studied in the pathophysiology of ET shock. ET-sensitive mice (C3Heb/FeJ) were treated with 700 mg/kg galactosamine in combination with 100 microg/kg Salmonella abortus equi ET, 15 microg/kg TNF-alpha, or 13 to 23 microg/kg IL-1. VCAM-1 mRNA formation was strongly activated in animals treated with ET, TNF-alpha, or IL-1. In contrast, only TNF-alpha and IL-1, not ET, induced VCAM-1 gene transcription in livers of ET-resistant mice (C3H/HeJ). Immunohistochemistry and isolation of liver cells during endotoxemia indicated that VCAM-1 mRNA and protein were only formed in endothelial cells and Kupffer cells, not in hepatocytes. Galactosamine/ET induced neutrophil accumulation in sinusoids (515 +/- 30 neutrophils/50 high power fields) followed by transmigration at 7 h. At that time, severe liver injury was observed (necrosis, 53 +/- 5%). An anti-VCAM-1 Ab (3 mg/kg) attenuated the area of necrosis by 60%. The Ab reduced neutrophil transmigration by 84%, but had no effect on the total number of cells in the liver vasculature. Flow cytometric analysis identified the presence of very late Ag-4 on mouse peripheral neutrophils. Our data demonstrated cytokine-dependent VCAM-1 gene transcription and protein expression in the liver during endotoxemia. Neutrophils were able to use very late Ag-4/VCAM-1 interactions to transmigrate into liver parenchyma in vivo. Preventing transmigration by blocking VCAM-1 protected hepatocytes against neutrophil-induced injury.

Animals↗
PubMed1998

The interrelationship of alpha4 integrin and matrix metalloproteinase-2 in the pathogenesis of experimental autoimmune encephalomyelitis.

Previous studies have suggested that surface expression of alpha4 integrin by autoreactive T-cell clones is necessary for the clones to induce experimental autoimmune encephalomyelitis (EAE), a mouse model for human multiple sclerosis. To provide direct evidence for this phenomenon, we have transfected alpha4 integrin into C19alpha4-LO, a myelin basic protein-reactive T-cell clone that does not express alpha4 integrin and does not induce EAE when adoptively transferred into a susceptible mouse strain. Transfection of alpha4 integrin converted this clone to an alpha4 integrin-expressing clone that induced EAE. We then examined potential mechanisms by which alpha4 integrin may facilitate the disease process. C19 T-cell clones adhered equally to a monolayer of microvascular endothelial cells, regardless of level of alpha4 integrin expression. However, in contrast to T-cell clones that do not express alpha4 integrin, T-cell clones that express alpha4 integrin (endogenously or by transfection) transmigrated through an endothelial cell layer and subendothelial matrix at an enhanced rate and adhered to recombinant vascular cell adhesion molecule-1 (rVCAM-1) and the CS1 fragment of fibronectin, and after adhesion to these ligands, a matrix-degrading metalloproteinase (MMP-2) was induced and activated. The clones were also shown to constitutively express the membrane-type matrix metalloproteinase (MT1-MMP), an enzyme that activates MMP-2. GM6001 and UK-221,316, inhibitors of metalloproteinases, reduced alpha4 integrin-mediated transmigration and EAE induction by C19 T-cell clones. In addition, we studied a second EAE-inducing T-cell clone, MM4, which constitutively expresses alpha4 integrin and MMP-2. Engagement of alpha4 integrin on the MM4 clone up-regulated the expression and activation of MMP-2, without changing the expression of MT1-MMP. MMP inhibitors also reduced transmigration of and EAE induction by the MM4 T-cell clone. These studies demonstrate directly that expression of alpha4 integrin by autoreactive T-cell clones is required for adoptive transfer of EAE in this model. We also define a role for alpha4 integrin in the disease process in mediating the induction and coordinate activation of a matrix metalloproteinase (MMP-2), which facilitates T-cell transmigration.

Animals↗
PubMed1998

Cell-cell interactions during transendothelial migration of tumor cells.

A key event in cancer metastasis is the transendothelial migration of tumor cells. This process involves multiple adhesive interactions between tumor cells and the endothelium. After adhering to the surface of endothelial cells, tumor cells must penetrate the endothelial junction, which contains high concentrations of the cell adhesion molecules VE-cadherin and PECAM-1. Studies using an in vitro model system, consisting of melanoma cells which are seeded onto a monolayer of endothelial cells cultured on Matrigel, have revealed reorganization of the cytoskeleton and dynamic changes in the cell shape of both tumor and endothelial cells. The initial stages of transmigration are characterized by numerous membrane blebs protruding from the basolateral surfaces of the melanoma cells. Contact regions also show an abundance of microfilaments arising from the underlying endothelial cells. These adhesive interactions lead to the redistribution of both VE-cadherin and PECAM-1 and, consequently, a localized dissolution of the endothelial junction. The penetration of the endothelial junction is initiated by melanoma pseudopods. Despite the disappearance of VE-cadherin from the retracting endothelial junction, heterotypic contacts between the tumor cell and its surrounding endothelial cells show a high concentration of pan-cadherin staining, suggesting that transmigration of melanoma cells might yet be facilitated by interactions with another member of the cadherin family. Upon adhesion to the Matrigel, melanoma cells begin to spread and invade the matrix material, while the endothelial cells extend processes over the melanoma cells to reform the monolayer. Interestingly, the leading margins of these endothelial processes contain a high concentration ofN-cadherin. VE-cadherin and PECAM-1 reappear only when the advancing endothelial processes meet to reform the endothelial junction. Together, these observations suggest that endothelial cells actively participate in the transmigration of tumor cells and specific cadherins are involved in different steps of this complex process.

Animals↗
PubMed1998

Transendothelial chemotaxis of human alpha/beta and gamma/delta T lymphocytes to chemokines.

Two subpopulations of human T lymphocytes expressing different antigen receptors, alpha/beta and gamma/delta, emigrate into inflamed tissues in distinctive patterns. We compared the transmigration of alpha/beta and gamma/delta T cells to C-C and C-X-C chemokines using an in vitro transendothelial chemotaxis assay. The C-C chemokines monocyte chemoattractant protein (MCP)-1, RANTES, macrophage inflammatory protein (MIP)-1alpha and MIP-1beta stimulated similar, dose-dependent chemotaxis of purified gamma/delta T cells, whereas MCP-1, RANTES, and MIP-1alpha produced greater chemotaxis of purified alpha/beta T cells than MIP-1beta. In contrast, the C-X-C chemokines interleukin (IL)-8 and interferon-gamma inducible protein-10 (IP-10) did not promote chemotaxis of either alpha/beta or gamma/delta T cells. Three gamma/delta T cell clones with differing CD4 and CD8 phenotypes also migrated exclusively to C-C chemokines. Phenotypic analysis of mononuclear cells that transmigrated from an input population of unfractionated peripheral blood mononuclear cells confirmed the results with purified gamma/delta T cells. Our data demonstrate that human peripheral blood alpha/beta and gamma/delta T cells can transmigrate to MCP-1, RANTES, MIP-1alpha, and MIP-1beta, and suggest that both T lymphocyte subpopulations share the capacity to emigrate in response to C-C chemokines during inflammation.

Chemokine CCL2↗
PubMed2001

HER2/neu over-expression induces endothelial cell retraction.

Over-expression of the HER2/neu (HER2) proto-oncogene in breast carcinoma imparts an enhanced metastatic potential. Metastasis requires escape of the tumor cell from the vasculature into subjacent tissue, a transmigration event across an endothelial cell (EC) monolayer. EC retraction has been reported to precede transmigration in several tumor metastatic models. Using intact human iliac vein EC monolayers, we tested the abilities of MCF-7 breast cancer cells and HER cells, a transfected MCF-7 line over-expressing HER2, to induce EC retraction. We further analyzed whether HER2 signaling influenced cancer cell-induced EC retraction. MCF-7 or HER cells were co-cultured onto mature EC monolayers. More HER than MCF-7 cells induced EC retraction (76 +/- 19% vs. 17 +/- 12%, p < 0.001) with resultant exposure of subendothelial matrix (6.80 +/- 2.86% vs. 0.85 +/- 0.39%, p < 0.001). Blockade of HER2 signaling using Herceptin nearly eliminated EC retraction (p < 0.01), while stimulation of HER2 using heregulin-beta1-augmented EC retraction (p < 0.05). Further, there was no difference between cell lines in either the number of cells adhered or the strength of adherence to EC under shear stress. These data suggest that HER2 signaling enhances metastasis in breast cancer cells by inducing EC retraction, a process that appears to precede endothelial transmigration.

Antibodies, Monoclonal↗
PubMed2003

Protein phosphatase-2A restricts migration of Lewis lung carcinoma cells by modulating the phosphorylation of focal adhesion proteins.

Compared to metastatic Lewis lung carcinoma (LLC) cells, nonmetastatic LLC cells have increased levels of activity of the protein phosphatase PP-2A, which functions to limit their migration through transwell chambers. Inhibition of PP-2A in nonmetastatic LLC stimulates their transmigration to levels similar to those of metastatic LLC cells. Studies to define the signaling pathways intermediate between diminished PP-2A activity and stimulated migration showed that inhibiting PP-2A activity resulted in paxillin serine hyperphosphorylation and tyrosine dephosphorylation. Paxillin was important for the stimulated migration because the increased transmigration in response to PP-2A inhibition was dampened by expression of mutant paxillin at the LIM3 S457 and S481 residues. Inhibition of PP-2A also led to the dissolution of FAK/Src/paxillin focal adhesion complexes, which was also dependent on paxillin S457 and S481 residues. In addition, inhibition of PP-2A resulted in dephosphorylation of Src inhibitory Y527 residue, suggesting increased Src activity. The stimulated transmigration of cells with diminished PP-2A was in part dependent on this Src activity. These studies show the importance of PP-2A in limiting tumor cell migration through its modulation of proteins of the focal adhesions.

Animals↗
PubMed2002

The participation of P- and E-selectins on biomaterial-mediated tissue responses.

Biomaterial-mediated inflammatory responses often compromise the functions of implantable devices. The mechanism(s) involved in the inflammatory responses, which can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces, are not totally understood. Because adhesion molecules have been shown to involved in phagocyte transmigration, this study was designed to investigate the participation of endothelial adhesion molecules in the pathogenesis of biomaterial-mediated inflammatory responses and fibrotic tissue formation. Using transgenic adhesion molecule knockout mice, we found that (1) deficiency of P-selectin reduced polymorphonuclear neutrophils (PMN) but not macrophages/monocytes (Mphi) transmigration and adhesion. (2) Furthermore, absence of both P- and E-selectin (P/E-deficient) dramatically diminished both PMN and Mphi recruitment to the peritoneal cavity and accumulation on implanted biomaterials. (3) Finally, the impairment of inflammatory responses in P/E-deficient mice significantly reduced the extent of subsequent biomaterial-mediated fibrotic responses. We conclude that P- and E-selectins are important for both biomaterial-mediated inflammatory and fibrotic reactions. Our results also indicate that the reduction of phagocyte accumulation might be responsible to the decrease of fibrotic tissue formation surrounding material implants. Better understanding of such sequence of events may help the rational design of biomaterials with desired tissue reactivity.

Animals↗
PubMed2000

A novel lysophosphatidic acid analog, LXR-1035, inhibits leukocyte-endothelium interaction via inhibition of cell adhesion molecules.

A novel synthetic phosphorothioate analog of oleoyl lysophosphatidic acid LXR-1035 was studied for its ability to modulate leukocyte-endothelial cell interactions using intravital microscopy of the rat mesentery. Superfusion of the rat mesentery with 50 microM L-NAME elicited a significant, time-dependent increase in leukocyte rolling, adherence, and transmigration compared to control rats superfused with Krebs-Henseleit solution. However, superfusion of the rat mesentery with 300 nM LXR-1035 consistently attenuated 65-87% of the L-NAME-induced leukocyte rolling, adherence, and transmigration, without altering systemic blood pressure or mesenteric venular shear rate. Similar results were also obtained in rats subjected to 90 min of hemorrhage followed by 90 min of reperfusion. Resuscitation from hemorrhage increased significantly the number of rolling, adherent, and transmigrated leukocytes in the rat mesenteric microcirculation. However, superfusion of the rat mesentery with LXR-1035 markedly attenuated the leukocyte-endothelium interaction occurring after hemorrhage and reinfusion by 75+/-12%. Immunohistochemical localization of P-selectin expression on mesenteric venular endothelium was significantly increased after exposure to L-NAME and after hemorrhage-reinfusion, which was significantly attenuated by LXR-1035 (P<0.05). In addition, treatment of isolated rat neutrophils with 300 nM LXR-1035 significantly attenuated leukotriene B4-induced up-regulation of CD18 (P<0.05). Our data clearly demonstrate that LXR-1035 can potently inhibit the recruitment of leukocytes in the mesenteric rat microvasculature by attenuating cell-surface expression of adhesion molecules.

Animals↗
PubMed2006

KL4-surfactant prevents hyperoxic and LPS-induced lung injury in mice.

KL(4)-surfactant contains the novel KL(4) peptide, sinapultide, which mimics properties of the hydrophobic pulmonary surfactant protein SP-B, in a phospholipid formulation and may be lung protective in experimental acute respiratory distress syndrome/acute lung injury. Our objective was to determine the protective role of airway delivery of KL(4)-surfactant in murine models of hyperoxic and lipopolysaccharide (LPS)-induced lung injury and further explore the mechanisms of protection. For the hyperoxic injury model, mice exposed to 80% O(2) for 6 days received an intranasal bolus of vehicle, beractant, or KL(4)-surfactant on days 3, 4, 5, and 6 of the exposure, and lungs were evaluated on day 7. Mice in the LPS-induced lung injury model received an intratracheal bolus of LPS followed by an intranasal bolus of KL(4)-surfactant or control at 1, 3, and 19 hr post-LPS challenge, and lungs were evaluated after 24 hr. To explore the mechanisms of protection, in vitro assays were performed with human and murine endothelial cell monolayers, and polymorphonuclear leukocyte (PMN) transmigration in the presence or absence of KL(4)-surfactant or lipid controls was evaluated. Based on morphology, histopathology, white blood cell count, percentage of PMNs, and protein concentration in bronchoalveolar lavage fluid, our data showed KL(4)-surfactant, unlike vehicle or beractant, blocked neutrophil influx into alveoli and suppressed lung injury. Furthermore, in vitro assays showed KL(4)-surfactant decreased neutrophil transmigration at the endothelial cell level. KL(4)-surfactant decreased inflammation and lung permeability compared with controls in both mouse models of lung injury. Evidence suggests the anti-inflammatory mechanism of the KL(4)-peptide is through inhibition of PMN transmigration through the endothelium.

Administration, Intranasal↗
PubMed2002

Effect of tumor necrosis factor alpha, interferon gamma, and interleukin-4 on bacteria-enterocyte interactions.

BACKGROUND: Little is known about the mechanisms involved in bacterial translocation from the intestinal lumen to extraintestinal sites. Because the cytokine cascade associated with sepsis, inflammation, and trauma has been shown to affect intestinal epithelial permeability, experiments were designed to clarify the effects of selected cytokines on bacterial adherence to and internalization by cultured HT-29 and Caco-2 enterocytes. METHODS: Mature, confluent enterocytes were pretreated 48 to 72 h with tumor necrosis factor alpha (TNF-alpha), interferon gamma, (IFN-gamma), or interleukin-4 (IL-4). Adherence of Listeria monocytogenes, Salmonella typhimurium, Proteus mirabilis, and Escherichia coli was measured by enzyme-linked immunosorbent assay and bacterial internalization was quantified by the gentamicin protection assay. Enterocyte permeability was measured by transepithelial electrical resistance and by flux of 40-kDa fluorescent dextran. Bacterial transmigration across confluent enterocytes was measured using enterocytes cultivated on permeable supports. RESULTS: TNF-alpha, IFN-gamma, and IL-4 had variable effects on bacterial adherence to HT-29 and Caco-2 enterocytes, although the most consistent finding was increased bacterial adherence associated with INF-gamma. However, none of these cytokines had a noticeable effect on bacterial internalization by either Caco-2 or HT-29 enterocytes. In addition, none of these cytokines had a noticeable effect on the permeability of confluent enterocytes as measured by transepithelial electrical resistance or dextran flux. Bacterial transmigration across confluent HT-29 enterocytes was not altered by TNF-alpha, IFN-gamma, or IL-4; however, IL-4 consistently decreased bacterial transmigration across confluent Caco-2 enterocytes. CONCLUSIONS: IFN-gamma may augment the epithelial adherence of selected species of enteric bacteria, and IL-4 may act as a barrier-sustaining agent to decrease bacterial migration across the intestinal epithelium.

Bacterial Adhesion↗
PubMed2000

In vitro peritonitis: basic inflammatory reactions in a two-chamber coculture model of human peritoneum.

We developed an in vitro model of the peritoneum by coculturing human umbilical vein endothelial cells (HUVEC) and human peritoneal mesothelial cells (HPMC) to gather information on peritoneal physiology and to closer reflect the in vivo situation in humans. HUVEC and HPMC were seeded on collagen-coated polytetraflourethylene-insert membranes of pore size 3 microm. HUVEC were grown on the bottom of the membrane and HMPC on the top. The confluent cells were monitored by measuring transepithelial resistance and by confocal microscopy. The transmigration of PMNs as an important mechanism during secondary peritonitis was studied in this two-chamber model. PMNs were isolated by density separation. After stimulation of HMPC with the complement factor 5 split product C5a (1 ng/ml) or tumor necrosis factor-alpha (TNF-alpha; 10 or 50 microg/ml) for 1 h, 1 x 10(6) PMN were given to the lower compartment. Controls were cocultured cells without stimulation. After 1, 2, and 6 h nonadherent PMNs in the upper compartment were harvested and counted, interleukin-8 was measured in each compartment, and cells on the membrane were paraffin-embedded for immunohistochemistry. Each experiment was performed four times. Cells grew to confluence within 2-5 days and were detected on their respective seeding side by CD34 and cytokeratin 18 counterstaining. Transmigration of PMNs after C5a or TNF-alpha stimulation showed a significant time-dependent increase between 1 h and 6 h (P<0.05). PMNs were found in significantly higher numbers after stimulation with either C5a or TNF-alpha at 1, 2, and 6 h than without stimulation. After stimulation of HPMC, interleukin-8 secretion to the apical compartment increased in a time-dependent fashion, resulting in a gradient between the two chambers. Linear regression analysis revealed significant correlation between transmigrated PMN and interleukin-8 in stimulated cocultures; no correlation was found in controls. This new in vitro peritoneum consisting of cocultured mesothelial and endothelial cells may allow more detailed assessment of peritoneal pathophysiology. Generation of an interleukin-8 gradient affecting the migration of PNMs across the cocultured membrane represents a parameter which may be addressed in further studies.

Cell Culture Techniques↗
PubMed2005

Diazoxide ameliorates microcirculatory disturbances through PKC-dependent pathway in I/R-injured rat cremaster muscles.

Diazoxide is a selective mitochondria ATP-sensitive potassium (K(ATP)) channel opener, which has been reported to preserve the microvascular integrity of ischemia-reperfusion (I/R)-injured tissues. Our study aimed to assess diazoxide's effects on I/R-injured cremaster muscles and to further elucidate its underlying mechanisms. Male Sprague Dawley (SD) rats were randomized (n = 8 per group) into four groups: sham-operated control group, I/R group (4 h of pudic epigastic artery ischemia followed by 2 h of reperfusion), diazoxide + I/R group, and chelerythrine (PKC inhibitor)+diazoxide+I/R group. Microscopically, we observed that I/R markedly increased the number of rolling, adhering, and transmigrating leukocytes. I/R also markedly decreased the number of functional capillaries. Biochemically, we found that I/R significantly increased TNF-alpha, E-selectin,L-selectin and P-selectin expressions. However, I/R did not cause significant changes in ICAM-1 and PECAM-1 expressions. On the other hand, in I/R + diazoxide group, we found that diazoxide reduced the number of rolling, adhering, and transmigrating leukocytes. Furthermore, biochemical study revealed that diazoxide caused only a decrease in L-selectin expression but had no effect on TNF-alpha, E-selectin, P-selectin, ICAM-1, and PECAM-1 expressions. Finally, in chelerythrine + diazoxide + I/R group, we observed that diazoxide's protective effects were blocked by the addition of chelerythrine. Diazoxide's ability to protect against I/R injury was confirmed by the observation that it reduced the number of rolling, adhering, and transmigrating leukocytes, and increased the number of functional capillaries. Our results indicated that diazoxide operated via a PKC-dependent pathway to achieve protection against I/R injury.

Abdominal Muscles↗
PubMed1993

Translocation of particle-laden alveolar macrophages and intra-alveolar granuloma formation in rats exposed to Ludox colloidal amorphous silica by inhalation.

Rats were exposed to Ludox colloidal amorphous silica at concentrations of 0, 10, 50 and 150 mg/m3 for 6 h/day, 5 days/week for 4 weeks. The rats were killed after 4 weeks exposure and at 10 days or 3 months post-exposure (PE). Dose-related pulmonary lesions were observed at 50 and 150 mg/m3, but not at 10 mg/m3. Inhaled particles were mostly phagocytized by alveolar macrophages (AMs) in the alveolar duct region and a few free particles were found in Type I pneumocytes in the alveoli. Particle-laden AMs directly penetrated into the bronchiolar interstitium from alveoli and accumulated in bronchus-associated lymphoid tissue (BALT), peribronchiolar, or perivascular interstitium. The particle-laden AMs in the interstitium further migrated into the peribronchial or perivascular lymphatics and accumulated in the tracheo-bronchial lymph nodes (TBLN). Some particle-laden AMs in the BALT transmigrated directly into bronchial lumen through the epithelium. The transmigrated particle laden-AMs in the TBLN were indistinguishable from those seen in the alveoli. They were characterized by slender cytoplasmic processes, phagosomes, myelin figures (alveolar surfactant), cholesterol clefts and lipid droplets. Many migrated particle-laden AMs were necrotic and released particles in the TBLN. The released particles were phagocytized by histiocytes and formed histiocytic granulomas. Silicotic granulomas were initially formed in alveoli with particle-laden AMs and proliferating epithelioid cells. Subsequently, the granulomas were incorporated into the interstitium. However, perivascular silicotic granulomas were developed with accumulation of transmigrated particle-laden AMs and minimal collagenized fibers at 3 months PE. There was no alveolar lipo-proteinosis as seen in crystalline silica exposure.

Administration, Inhalation↗
PubMed2006

The role of granulocytes following intravesical BCG prophylaxis.

OBJECTIVES: The antitumour effect of bacillus Calmette-Guérin (BCG) still remains relatively undefined. Most investigations on its mechanism of action have focused on mononuclear cells; little consideration has been given to granulocytes. We analysed urine of patients with bladder cancer during 8 wk of intravesical BCG prophylaxis. The number of polymorphonuclear neutrophils (PMNs) and urothelial cells (UCs) was evaluated. We examined the in vitro response of the T24 UC line to human PMNs after BCG treatment. METHODS: Seventeen patients were enrolled in the study. Cytologic analyses were performed on urine samples collected before each BCG instillation and after 2 h from the first voided urine after BCG instillation. Elastase activity was determined on these samples to evaluate PMN activation. PMN-induced damage was measured on the T24 cell line treated with BCG. RESULTS: After BCG treatment, a large number of PMNs transmigrated through the urothelium and PMNs adherent to detached UCs were found. One patient, who did not respond with significant PMN transmigration, experienced recurrent disease. The number of eosinophils that transmigrated was low, with the exception of three patients with recurrent disease. In vitro, PMNs adhered to BCG-primed T24 cells and damaged the monolayer. CONCLUSIONS: The results agree with recent evidence that PMNs may play an important role in the antitumour action of BCG during the BCG induction period. This role is probably nonspecific because both normal UCs in vivo and tumour cells in vitro appeared to be injured. As suggested by results obtained from a limited number of patients, a high number of eosinophils in the urine may indicate therapy failure.

Administration, Intravesical↗
PubMed2003

Ex vivo manipulation of umbilical cord blood-derived hematopoietic stem/progenitor cells with recombinant human stem cell factor can up-regulate levels of homing-essential molecules to increase their transmigratory potential.

OBJECTIVE: The cause of delayed hematopoietic reconstitution after umbilical cord blood transplantation (UCBT) remains controversial. We hypothesized that hematopoietic stem/progenitor cells (HS/PCs) from UCB have some defects of the homing-related molecules responsible for their slow engraftment. MATERIALS AND METHODS: A homing-related molecule repertoire expressed on HS/PCs from fresh and cryopreserved UCB, mobilized peripheral blood (mPB), and bone marrow (BM) were compared using sensitive, four-color fluorescence-activated cell sorting analysis. Purified CD34+ cells were subjected to ex vivo transmigration through double-coated transwell filter inserts, and an in vivo homing assay was performed in xenotransplanted NOD/SCID mice. RESULTS: UCB-derived CD34(bright) cells expressed significantly lower levels of CD49e, CD49f, and CXCR-4 than their mPB and BM counterparts. CD34+ cells from UCB (and BM) exhibited significantly lower ex vivo transmigration than those from mPB, which were largely blocked by neutralizing antibodies to CD49e or CD49f. Recombinant human tumor necrosis factor-alpha treatment enhanced ex vivo transmigration of CD34+ cells from UCB and BM by inducing expression of the matrix metalloproteinases MMP-2/MMP-9. Short-term treatment of UCB-derived CD34+ cells with rHu-stem cell factor (rHuSCF) up-regulated levels of the homing-related molecules with their increased ex vivo transmigratory and in vivo homing potential. CONCLUSION: Our results indicate that disadvantageous transmigratory behavior of HS/PCs from UCB, which might partly explain the delayed reconstitution after UCBT, can be reversed by ex vivo manipulation with rHuSCF.

Animals↗