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PubMed1988

Patterns of femoral head migration in osteoarthritis of the hip: a reappraisal with CT and pathologic correlation.

Although medial, superior, and axial patterns of migration of the femoral head in osteoarthritis of the hip have been well described, it is not clear what anatomic and biomechanical factors determine the direction of migration. The authors studied 22 patients with bilateral (11 patients) or unilateral (11 patients) osteoarthritis by means of conventional radiography and computed tomography (CT) to define any relationships between migration in the coronal plane and that in the transverse plane and to determine whether femoral anteversion, acetabular anteversion, femoral neck-shaft angle, or acetabular inclination were related to particular migration patterns. Anterior migration was evident in 14 of the 19 hips with a superior migration pattern, whereas posterior migration was present in five of the seven hips with a medial migration pattern. In the remainder of cases, no migration in the transverse plane was present. Femoral anteversion as determined with CT, femoral neck-shaft angle, angle of acetabular inclination, and acetabular anteversion angle in this relatively small sample were all found to be within normal limits and appeared to have no influence on the occurrence of a specific pattern of femoral head migration.

Aged↗
PubMed2004

Lysophosphatidic Acid Stimulates Ovarian Cancer Cell Migration via a Ras-MEK Kinase 1 Pathway.

Lysophosphatidic acid (LPA) is present at high concentrations in ascites and plasma of ovarian cancer patients. Studies conducted in experimental models demonstrate that LPA promotes ovarian cancer invasion/metastasis by up-regulating protease expression, elevating protease activity, and enhancing angiogenic factor expression. In this study, we investigated the effect of LPA on ovarian cancer migration, an essential component of cancer cell invasion. LPA stimulates both chemotaxis and chemokinesis of ovarian cancer cells and LPA-stimulated cell migration is G(I) dependent. Moreover, constitutively active H-Ras enhances ovarian cancer cell migration, whereas dominant negative H-Ras blocks LPA-stimulated cell migration, suggesting that Ras works downstream of G(i) to mediate LPA-stimulated cell migration. Interestingly, H-Ras mutants that specifically activate Raf-1, Ral-GDS, or phosphatidylinositol 3'-kinase are unable to significantly enhance ovarian cancer cell migration, suggesting that a Ras downstream effector distinct from Raf-1, Ral-GDS, and phosphatidylinositol 3'-kinase is responsible for LPA-stimulated cell migration. In this article, we demonstrate that LPA activates mitogen-activated protein kinase kinase 1 (MEKK1) in a G(i)-Ras-dependent manner and that MEKK1 activity is essential for LPA-stimulated ovarian cancer cell migration. Inhibitors that block MEKK1 downstream pathways, including MEK1/2, MKK4/7, and nuclear factor-kappa B pathways, do not significantly alter LPA-stimulated cell migration. Instead, LPA induces the redistribution of focal adhesion kinase to focal contact regions of the cytoplasm membrane, and this event is abolished by pertussis toxin, dominant negative H-Ras, or dominant negative MEKK1. Our studies thus suggest that the G(i)-Ras-MEKK1 signaling pathway mediates LPA-stimulated ovarian cancer cell migration by facilitating focal adhesion kinase redistribution to focal contacts.

Cell Movement↗
PubMed2006

Regulatory role of c-Met in insulin-like growth factor-I receptor-mediated migration and invasion of human pancreatic carcinoma cells.

Pancreatic carcinoma cells overexpress the insulin-like growth factor-I (IGF-I) receptor (IGF-IR) and the hepatocyte growth factor (HGF) receptor, c-Met, which are both known to mediate tumor cell migration and invasion. We hypothesized that IGF-IR and c-Met cooperate to induce migration and invasion of human pancreatic carcinoma cells and that IGF-I-mediated migration and invasion depend on c-Met. Migration and invasion assays were done with the human pancreatic cancer cell line L3.6pl treated with PBS, IGF-I, HGF, or IGF-I plus HGF. To determine if c-Met is necessary for IGF-IR-mediated migration and invasion, c-Met was down-regulated in L3.6pl cells via adenoviral infection with a c-Met ribozyme before IGF-I treatment. IGF-I and HGF increased cell migration and invasion. Furthermore, IGF-I plus HGF had a greater than additive effect on cell migration and invasion compared with either growth factor alone. Down-regulation of c-Met nearly completely inhibited IGF-I-mediated migration and invasion. Our findings suggest that IGF-IR and c-Met cooperate to induce migration and invasion of human pancreatic carcinoma cells. Furthermore, c-Met is required for both HGF- and IGF-I-mediated migration and invasion. Elucidation of the signaling pathways that contribute to tumor progression and metastasis should provide a foundation for the development of targeted therapies for pancreatic carcinoma.

Carcinoma↗
PubMed1998

Tumor necrosis factor alpha is necessary for granulocyte-macrophage-colony-stimulating-factor-induced eosinophil transendothelial migration.

BACKGROUND: We have previously shown that granulocyte macrophage-colony stimulating factor (GM-CSF) was capable of inducing eosinophil migration across naked filters but not endothelial monolayers. Tumor necrosis factor alpha (TNF-alpha) has been shown to be a key factor in granulocyte adhesion and transendothelial migration. METHODS: We, therefore, pretreated human umbilical vein endothelial cell (HUVEC) monolayers with TNF-alpha and studied whether TNF-alpha could support GM-CSF-induced eosinophil transendothelial migration. RESULTS: We found that TNF-alpha supported GM-CSF-induced eosinophil transendothelial migration and that this process was: (1) dependent upon GM-CSF and TNF-alpha dose; (2) time-dependent; (3) not due to TNF-alpha having a chemotactic effect itself; (4) not due to TNF-alpha-induced soluble factor production by endothelium, and (5) inhibitable by actinomycin D. We next studied the specificity of this response. Neutrophils did not migrate across TNF-alpha-pretreated endothelium in response to GM-CSF. TNF-alpha pretreatment of A549 human type-II-like epithelial lung cells (A549) did not support GM-CSF-induced transepithelial migration. Neither interleukin (IL)-1 nor GM-CSF pretreatment of the HUVEC supported GM-CSF-induced transendothelial migration. However, IL-5 induced eosinophil migration through naked filters as well as TNF-alpha-pretreated HUVEC in a manner analogous to GM-CSF. Antibodies to ICAM-1, but not VCAM-1 significantly inhibited this response. Although IL-1 did not support GM-CSF-induced eosinophil transendothelial migration, IL-1 and TNF-alpha induced equivalent expression of ICAM-1 on HUVEC. CONCLUSION: Thus, TNF-alpha-supported eosinophil transendothelial migration in response to GM-CSF (and IL-5) is dependent upon ICAM-1, and is both specific and complex.

Antibodies, Blocking↗
PubMed1997

Role of resident mast cells and macrophages in the neutrophil migration induced by LTB4, fMLP and C5a des arg.

In the present study, we have investigated the participation of resident peritoneal cells (macrophages and mast cells) in the neutrophil migration induced in rats by the intraperitoneal administration of LTB4, fMLP or C5a des arg. The intraperitoneal injection of LTB4 (10 nmol), fMLP (10 nmol) and C5a des arg (zymosan-activated plasma, 1 ml) caused an intense neutrophil migration compared to the saline control (1,000, 1,500 and 2,000%, respectively). An 83% depletion in the number of resident cells following peritoneal lavage reduced the LTB4-stimulated neutrophil migration by 73.6% without affecting that caused by fMLP and C5a des arg. Increasing the peritoneal macrophage population (236%) by pretreating the cavities with thioglycollate enhanced the neutrophil migration induced by LTB4 (129%), but did not alter that induced by fMLP and C5a des arg. Similarly, reducing the population of peritoneal mast cells containing toluidine-blue-staining granules by subchronically pretreating the cavities with compound 48/80 diminished the LTB4-induced NM by 69% but had no effect on the responses to fMLP and C5a des arg. Pretreating the animals with dexamethasone strongly inhibited (70%) the neutrophil migration induced by the intraperitoneal injection of LTB4, fMLP and C5a des arg. Indomethacin, BW A4C and NDGA had no such effect. The incubating medium from peritoneal macrophages and mast cells stimulated with LTB4 induced neutrophil migration when injected into the peritoneal cavity of rats. This migration was strongly reduced (70%) by treating the cells with dexamethasone. In contrast, stimulating the cells with fMLP or C5a des arg did not result in the release of any promigratory activity into the incubating fluid. Our results suggest that LTB4 induces neutrophil migration via a mechanism dependent on resident mast cells and macrophages while that induced by C5a des arg and fMLP seems to be independent of such cellular involvement. The neutrophil migration induced by LTB4 is apparently mediated by factor(s) whose release is blocked by dexamethasone. fMLP and C5a appear to cause in vivo migration by the formation of a concentration gradient and by a glucocorticoid-sensitive mechanism different from that stimulated by LTB4.

Animals↗
PubMed2000

Effects of cardiac natriuretic peptides on oxidized low-density lipoprotein- and lysophosphatidylcholine-induced human mesangial cell migration.

The objectives of the present study were (1) to determine whether oxidized LDL and lysophosphatidylcholine (lyso-PtdCho), a major phospholipid component of oxidized LDL, stimulate the migration of cultured human mesangial cells and (2) to investigate the possible effects on mesangial cell migration of the cardiac natriuretic peptides atrial and brain natriuretic peptide (ANP and BNP). Oxidized LDL (10 and 100 microg/mL) and lyso-PtdCho (10(-7) to 10(-5) mol/L) stimulated migration in a concentration-dependent manner. In contrast, the effects of native LDL and phosphatidylcholine were modest or nonexistent. Protein kinase C (PKC) inhibitor and downregulation of PKC activity by phorbol ester inhibited oxidized LDL- and lyso-PtdCho-induced migration. Human ANP(1-28) and human BNP-32 significantly inhibited oxidized LDL- and lyso-PtdCho-induced migration in a concentration-dependent manner. C-ANF (des-[Glu(18),Ser(19),Gly(20),Leu(21),Gly(22)]ANP(4-23)), a specific ligand for ANP clearance receptors, could not inhibit oxidized LDL- and lyso-PtdCho-induced migration. Inhibition by ANP and BNP of lyso-PtdCho-induced migration was paralleled by an increase in the cellular level of GMP. Oxidized LDL- and lyso-PtdCho-induced migrations were inhibited by 8-bromo-cGMP. The results suggest that oxidized LDL and lyso-PtdCho stimulate the migration of human mesangial cells, at least in part, through a PKC-dependent process and that ANP and BNP inhibit this stimulated migration, probably through a cGMP-dependent process.

Atrial Natriuretic Factor↗
PubMed1994

Expression and subcellular distribution of basic fibroblast growth factor are regulated during migration of endothelial cells.

Migration of endothelial cells is involved in normal and pathological angiogenesis and in re-endothelialization after vascular injury or rupture of atherosclerotic plaques. Several types of endothelial cells are known to synthesize basic fibroblast growth factor (bFGF); in some of these, migration is increased by exogenous bFGF and inhibited by anti-bFGF antibodies. Using immunocytochemical techniques and RNase protection analysis, we studied endothelial cells from bovine coronary arteries and veins as well as from adrenal microvessels. We found that bFGF mRNA and peptide were present in confluent endothelial cells and were upregulated during migration stimulated by removal of some cells from the monolayer. During migration, extracellular matrix stores of bFGF were depleted, and bFGF immunoreactivity began to accumulate in the cytoplasm of endothelial cells between 2 and 6 hours. After migration had begun, but before the initiation of DNA synthesis, bFGF immunoreactivity increased in the nuclei and nucleoli. Exogenous bFGF stimulated endothelial migration, and antibodies to bFGF markedly inhibited migration, suggesting that an intracrine function of nuclear bFGF is not sufficient for cell migration. In all three types of endothelial cells studied, bFGF was identified as an endogenous regulator, but not as the sole regulator, or migration. Moreover, bFGF expression and subcellular localization were found to be regulated during endothelial cell migration.

Animals↗
PubMed1998

Heparan sulfate proteoglycans mediate a potent inhibitory signal for migration of vascular smooth muscle cells.

Migration of vascular smooth muscle cells (SMCs) is a key step in vascular remodeling and formation of pathological lesions in diseased arteries and may be controlled by extracellular matrix (ECM) and by factors that regulate ECM composition, such as platelet-derived growth factor (PDGF). In culture, PDGF-AB and -BB enhance but PDGF-AA (although having no effect alone) suppresses SMC migration stimulated by other PDGF isoforms. To determine whether the migration-inhibitory mechanism of PDGF-AA was mediated by ECM composition, we examined baboon SMC migration in a Boyden chamber assay using filters coated with different ECM proteins. PDGF-AA suppressed the PDGF-BB-induced migration of baboon SMCs on a filter coated with basement membrane proteins (Matrigel) and fibronectin but failed to inhibit cell migration on a type I collagen (Vitrogen)-coated filter. Fibronectin and fibronectin fragments that contain heparin-binding domains permitted PDGF-AA inhibition of cell migration, but a fragment lacking heparin-binding domains did not. Treatment of SMCs with heparin lyases II and III, but not with chondroitin ABC lyase, diminished the PDGF-AA-mediated inhibition of migration. PDGF-AA stimulated accumulation of proteoglycan (PG) in the cell layer more potently than did PDGF-BB, whereas the turnover of cell layer PG was unaffected by either PDGF-AA or -BB. Northern blot analysis revealed that PDGF-AA increased syndecan-1 mRNA expression more than did PDGF-BB, whereas both PDGF isoforms decreased perlecan expression. The changes in cell migration and PG synthesis induced by PDGF-AA were accompanied by changes in the morphology of SMCs. PDGF-AA dramatically induced the spreading of SMCs, whereas the heparin lyase treatment of PDGF-AA-stimulated cultures diminished cell spreading. The data suggest that PDGF-AA selectively modifies heparan sulfate PG accumulation on SMCs and thereby influences the interactions of SMCs with heparin-binding ECM proteins. These interactions, in turn, generate signals that suppress SMC migration.

Animals↗
PubMed1995

Effects of interstate migration on the geographic distribution of stroke mortality in the United States.

BACKGROUND AND PURPOSE: This study examines the effects of lifetime net interstate migration on the geographic distribution of stroke mortality in the United States. METHODS: National Center for Health Statistics and Bureau of the Census data were used to map the geographic distribution of age-adjusted, race-, and race/sex-specific stroke mortality rates by interstate migration status for natives, outmigrants, nonmigrants, inmigrants, and residents in the United States for 1979 to 1981. RESULTS: High age-adjusted stroke mortality rates were significantly clustered in the southeastern United States for both whites and blacks; in addition, for whites, low-rate states were concentrated in some Mountain and northeastern states. Migrant status did not change this large-scale pattern, but individual states showed significant migration effects, which varied in magnitude and direction. Among whites, states that benefited from migration, with markedly lower stroke mortality rates among residents than natives, included Arizona, Colorado, District of Columbia, and Florida, whereas states that suffered from migration included California, Idaho, Montana, North Dakota, Nevada, and Oklahoma. Among blacks, only Colorado showed an apparent large benefit from migration, whereas 21 states suffered from migration. CONCLUSIONS: Although the overall large-scale spatial distribution of resident stroke mortality rates cannot be explained by migration effects, some individual states had rates that were strongly influenced by migration. Patterns of mortality among migrant groups in Sun Belt retirement destination states probably result from differential selection effects for retirement migration in older adults. Patterns of mortality for black migrants to the North are probably influenced by "carryover" effects from their origin states.

Adult↗
PubMed2002

Shear stress-induced endothelial cell migration involves integrin signaling via the fibronectin receptor subunits alpha(5) and beta(1).

Endothelial cell (EC) migration is required for angiogenesis, neovascularization, and reendothelialization. Integrins, known as alphabeta-heterodimeric cell-surface receptors, regulate cell migration and are essential for mechanotransduction of hemodynamic forces. Therefore, we investigated the effect of shear stress on EC migration and the contribution of the integrins and integrin-dependent signaling pathways in a scratched-wound assay. Laminar shear stress-induced EC migration was significantly reduced by integrin-receptor blocking with RGD peptides or with neutralizing antibodies against integrin subunits alpha(5) and beta(1), whereas antibodies against alpha(v)beta(3) or alpha(2)beta(1) had no effect. Cell-surface levels of the integrin alpha(5) and beta(1) were specifically upregulated in migrating ECs at the wound edges. Consistent with the important role of integrins for shear stress-increased cell migration, blockade of the integrin-associated adapter protein Shc by overexpression of dominant negative construct inhibited shear stress-stimulated EC migration. Moreover, pharmacological inhibition of the integrin downstream effector signaling molecules ERK1/2 or phosphatidyl-inositol-3-kinase prevented shear stress-induced EC migration. In contrast, inhibition of the NO synthase had no effect. Taken together, our results indicate that laminar shear stress enhances EC migration via the fibronectin receptor subunits alpha(5) and beta(1), which serve as central mechanotransducers in ECs. Shear stress-induced enhancement of EC migration might contribute importantly to accelerated reendothelialization of denuded arteries.

Cell Movement↗
PubMed1989

111Indium-labeled neutrophil migration into the lungs of bleomycin-treated rabbits assessed noninvasively by external scintigraphy.

Factors controlling neutrophil migration into the lung are poorly understood, but their identification is important for our understanding of the pathogenesis of inflammatory lung diseases. Pulmonary inflammation is difficult to quantify, and neutrophils in tissues and BAL may not accurately represent cell migration. In this study, intravenously delivered pulses of rabbit neutrophils labeled with Indium-111 (111In-neutrophils) were used to monitor neutrophil migration into the lungs. Radioactivity quantified in the lung "region of interest" (ROI) of external gamma camera scintigrams recorded 24 h after intravenous 111In-neutrophil injection accurately reflected the actual neutrophil-associated lung tissue radioactivity. ROI radioactivity at 24 h also correlated closely with the percent of 111In-neutrophils that had migrated into lavageable air spaces, and this parameter therefore provided an index of total lung 111In-neutrophil migration. Using 24-h ROI radioactivity and percent of injected 111In-neutrophils recovered in BAL at 24 h as indices of neutrophil migration into the lung, it was found that intratracheal saline caused only a transient neutrophil migration, whereas 10 U/kg intratracheal bleomycin induced migration that persisted for as long as 3 wk. 111In-neutrophil migration into the lung, assessed by external scintigraphy, correlated with total neutrophils quantified in histologic sections (r = 0.71, p = 0.006). The data suggest that this approach will be valuable in investigating mechanisms controlling neutrophil migration in lung inflammation, and that 111In-neutrophil scintigraphy may provide a noninvasive index of total lung neutrophil load that might be useful in staging inflammation in patchy diseases such as idiopathic pulmonary fibrosis.

Animals↗
PubMed1979

Alveolar macrophage migration. Influence of lung lining material and acute lung insult.

Migration of alveolar macrophages collected by lavage from normal rhesus monkeys was tested in an under agarose migration system. Lung lining material and serum albumin obtained from normal rhesus monkeys enhanced the random migration of alveolar macrophages. A chemotactic effect for alveolar macrophages was demonstrated in response to lung lining material. Gel filtration of lung lining material using Sephadex G-200 indicated the presence of 4 distinct fractions. Fraction IV, which had a molecular weight of less than 5,000 daltons, had the greatest ability to enhance alveolar macrophage migration. Macrophages obtained from lungs of rhesus monkeys after they breathed an oxidant gas (ozone) for 7 days demonstrated decreases in both the number of cells randomly migrating and the distance they migrated. The addition of normal lung lining material to macrophages exposed to ozone enhanced their random mobility but did not restore migration values to control values. Ozonized lung lining material or rhesus monkey serum did not significantly alter alveolar macrophage migration from that of control lung lining material or serum. These data indicate that components of the acellular lining material of the lung can produce directional migration of alveolar macrophages and may serve to direct the central flow and clearance of macrophages from alveolar regions. Intraluminal alveolar macrophage accumulation during lung insult with ozone appeared to be related more to migration inhibition of resident cells than to recruitment of additional cells by chemotaxis.

Animals↗
PubMed1987

Augmentation of rat alveolar macrophage migration by surfactant protein.

Since the alveolar macrophage (AM) resides in an environment made unique by the presence of pulmonary surfactant, we studied the effect of constituents of pulmonary surfactant on the migration of these cells in vitro. Whole pulmonary surfactant, surfactant phospholipids, and a delipidated preparation of surfactant consisting mainly of protein were tested for their effect on AM migration. Migration was measured in multiwell chemotaxis chambers with endotoxin-activated rat serum (EARS) as the stimulus. The delipidated surfactant material (DSM) markedly augmented the migration of rat AM. Enhancement was seen only when migration was stimulated with EARS. Augmentation of stimulated migration occurred over a wide range of protein concentrations in DSM (3.5 to 56 micrograms/ml) in a dose-dependent fashion. Rat AM that were preincubated with DSM and then tested in the chemotaxis assay without DSM showed increased migration towards EARS when compared with AM preincubated in buffer alone. The enhancing effect of DSM on AM migration was significantly diminished by heating the DSM and by enzymatic digestion with trypsin, suggesting that the active constituent in DSM was protein. Thus, it appears that proteins isolated from pulmonary surfactant augment the stimulated migration of AM via an interaction between the protein and the macrophage. Although the identity of these proteins remains to be elucidated, it is unlikely they include albumin since purified rat serum albumin in concentrations comparable to that of protein in DSM did not enhance the stimulated migration of AM. These results represent further confirmation that constituents of surfactant modulate the clearance function of AM in vitro. Thus, it is likely that surfactant plays a role in lung defense mediated by AM.

Animals↗
PubMed1998

Human airway epithelial monolayers promote selective transmigration of memory T cells: a transepithelial model of lymphocyte migration into the airways.

It has previously been demonstrated that T lymphocytes in the conducting airways express a pattern of adhesion molecules that are uniquely different from T lymphocytes found circulating in peripheral blood. To examine the role of airway epithelia in the determination of migratory capacity for human monocyte and lymphocyte populations in vivo, we have developed an in vitro transepithelial migration model using the human transformed bronchial epithelial cell line BEAS-2B S.6. In this study, we have demonstrated the preferential migration of human peripheral blood mononuclear cells (PBMC) across BEAS-2B S.6 cell monolayers in a physiologically appropriate direction (basal to apical epithelial cell surface). Stimulation of BEAS-2B S.6 cells with a combination of interferon-gamma and tumor necrosis factor-alpha upregulated basal-to-apical transepithelial migration by at least twofold. Monocytes migrated most efficiently, but subpopulations of CD19(+) B cells and CD2(+) cells were also recruited across epithelial cell monolayers. In the T lymphocyte subset of PBMC, CD45RO+ "memory" cells migrated preferentially. In addition, CD4(+) cells exhibited a significantly greater capacity to migrate across airway epithelium compared with CD8(+) cells. Migrated CD4(+) cells were predominantly CD29(high)/CD26(high), and within this subset uniformly expressed CD62L (L-selectin) at an intermediate level. PBMC migration across BEAS-2B S.6 cells was significantly inhibited by pertussis toxin; this result implicates a G protein signaling event as an important mediator of lymphocyte/monocyte transepithelial migration. On the basis of these data, we conclude that bronchial epithelium provides a unique microenvironment that supports the selective, G protein-dependent migration of memory T cells.

Bronchi↗
PubMed2000

The effect of transendothelial migration on eosinophil function.

In bronchial asthma, eosinophils found in the airways have an enhanced inflammatory capacity. We hypothesized that, at least in part, changes in functional phenotype are due to the effect of transendothelial migration. To model in vivo eosinophil trafficking to the lung, we cultured human pulmonary microvascular endothelial cell (HPMEC) monolayers on Transwell filters. The HPMECs were activated with interleukin (IL)-1beta to increase cell expression of intercellular adhesion molecule (ICAM)-1 and, hence, eosinophil transmigration. Peripheral blood eosinophils from allergic patients were added to HPMEC-covered Transwell filters and incubated for 3 h at 37 degrees C. The eosinophils were collected from below (migrated cells) and above (nonmigrated cells) the HPMEC monolayer to determine surface receptor expression, in vitro survival, and oxidative burst. Eosinophils never exposed to HPMECs were used as controls. Eosinophil cell surface expression of CD69, human leukocyte-associated antigen-DR (HLA-DR), and CD54 (ICAM-1) was significantly increased after transendothelial migration through IL-1beta-treated HPMECs compared with control cells (CD69: P<0.0005; HLA-DR and CD54: P<0.05) and nonmigrated eosinophils (CD69 and HLA-DR: P<0.05). Moreover, the percent in vitro survival (48 h) of migrated eosinophils was also significantly greater (P<0.0001 by trypan blue exclusion, P< 0.05 by flow cytometry) than that of control or nonmigrated eosinophils. Prolonged survival of migrated eosinophils was inhibited by addition of anti-granulocyte macrophage colony-stimulating factor (GM-CSF) antibodies (P<0.05) to the 48-h survival culture, suggesting that autocrine production of GM-CSF was, at least partially, responsible for increased eosinophil survival. Although GM-CSF protein was not measurable in survival culture supernates, GM-CSF messenger RNA (mRNA) was expressed in both nonmigrated and migrated eosinophils but not in control cells. Similarly, the eosinophils' oxidative burst induced by platelet-activating factor, formylmethionyl leucylphenylalanine, or phorbol myristate acetate was equally, and significantly, increased in both nonmigrated and migrated eosinophils (P<0.05 versus control). Therefore, whereas exposure of eosinophils to cytokine-activated HPMECs can increase surface receptor expression, in vitro survival, GM-CSF mRNA, and the respiratory burst, transendothelial migration can further potentiate receptor expression and survival in migrated cells. These results suggest that the process of transendothelial migration selectively participates in determining the eventual phenotype of airway eosinophils.

Antibodies↗
PubMed1993

Interleukin-8-induced transcellular neutrophil migration is facilitated by endothelial and pulmonary epithelial cells.

Interleukin-8 (IL-8) is an 8,000 D protein produced by many cells and has potent neutrophil chemoattractant and activating properties. Indeed, there is substantial data supporting a role for IL-8 in neutrophilic lung inflammatory responses. In vivo, neutrophils must adhere to and then migrate across endothelial and epithelial cell barriers in order to reach inflammatory foci. Therefore, we examined IL-8-induced neutrophil migration through naked filters and through human umbilical vein endothelial (HUVE) cells and human pulmonary type II-like epithelial cells (A549) cultured on these filters. IL-8 induced both dose- and time-dependent migration of neutrophils across all three barriers. At IL-8 concentrations greater than 10(-8) M, neutrophil migration across both endothelial and epithelial cell barriers was significantly greater than that observed across naked filters. In addition, time-course experiments indicated that neutrophil migration continued to occur for up to 3 h across both cellular barriers while neutrophil migration across naked filters plateaued by approximately 60 to 90 min. Migration of neutrophils through all barriers was completely inhibited by anti-IL-8 neutralizing antibody. The increased migration observed through both cellular barriers was not due to either changes in chemotactic gradients or the production of other soluble chemotactic factors by IL-8-stimulated HUVE and A549 cells versus naked filters. Furthermore, pretreatment of monolayers with actinomycin-D had no effect on the degree of transcellular migration. Thus, the facilitation of neutrophil migration through HUVE and A549 monolayers is not dependent upon new protein synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Line↗
PubMed1992

Human enterocyte (Caco-2) migration is modulated in vitro by extracellular matrix composition and epidermal growth factor.

The modulation of enterocyte sheet migration was studied using Caco-2 cells, a well-differentiated human colonic cell line. Although Caco-2 cells attached and spread equivalently over collagen types I, III, IV, and V and laminin, migration over laminin was significantly slower than migration over the collagen types. Fibronectin was a poor substrate for attachment, spreading, and migration. Epidermal growth factor (EGF) stimulated migration over laminin but did not alter Caco-2 migration over collagen or fibronectin. This effect was independent of cell proliferation, which was stimulated equivalently on both laminin and collagen I. Expression and organization of cell surface receptors for matrix (integrins) were studied using antibodies specific for beta and alpha integrin subunits. Integrin surface expression was assessed by immunoprecipitation of surface 125iodinated control and EGF-treated cells. Beta 1 surface pools did not change substantially in any condition studied. Alpha 1 subunit pools were decreased after EGF treatment on collagen I but alpha 1 pools increased after EGF treatment on laminin. Surface pools of alpha 2 subunits were increased following EGF treatment whether cells were cultured on laminin or collagen I. However, traditional immunofluorescent and laser confocal imaging demonstrated substantial differences in the character of alpha 2 subunit organization between collagen and laminin in the migrating cell front. Furthermore, a functional antibody to the alpha 2 subunit inhibited EGF stimulation of migration over laminin without substantial effects on basal migration over laminin or collagen I. Thus, EGF appears to exert a matrix-specific effect on enterocyte migration by modulation of integrin expression and organization.

Cell Movement↗
PubMed1993

VLA-4 integrin can mediate CD11/CD18-independent transendothelial migration of human monocytes.

The migration of human monocytes across unactivated and activated human umbilical vein endothelium (HUVE) in response to chemotactic factors was studied, and the adhesion molecules involved were characterized. Migration of blood monocytes or U937 cell line-derived monocytes across unactivated HUVE induced by C5a, was partially inhibited (by 75%) by mAbs (R15.7 or 60.3) to CD18 of the CD11/CD18 complex on the monocyte. However, when the HUVE was pretreated for 5 h with IL-1 alpha (0.1 ng/ml), TNF-alpha (100 U/ml), or LPS (1 ng/ml), migration induced by C5a was no longer inhibited; i.e., migration became CD18 independent. The monocyte CD18-independent migration was completely blocked by mAbs against alpha 4 or beta 1 integrin chains of VLA-4. This migration was also partially inhibited by mAbs against vascular cell adhesion molecule-1 (VCAM-1), a major counter-receptor on HUVE for VLA-4, but not by mAbs to E-selectin or intercellular adhesion molecule-1. The significant CD18-independent migration across "unactivated" HUVE was also inhibited by mAbs against alpha 4 or beta 1 chains of VLA-4, although mAbs against VCAM-1 did not inhibit under these conditions. Finally, considerable VLA-4-dependent transendothelial migration to C5a was also observed with monocytes from a patient with CD18 deficiency (leukocyte adhesion deficiency). These results suggest that (a) there is a major CD18-independent component in monocyte chemotactic factor-dependent migration across activated and unactivated endothelium; (b) that VLA-4 integrin on the monocyte has a major role in this migration; and (c) that VCAM-1 on activated endothelium functions as a counter-receptor in this process, but other ligands for VLA-4, especially on unactivated endothelium, may also be involved.

Antibodies, Monoclonal↗