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PubMed1999

Relationship of cellular transmigration and airway response after allergen challenge.

We examined the relationship between eosinophil migration into the bronchoalveolar space and change in FEV(1) after endobronchial allergen challenge (EBAC) in atopic asthmatic (AA) and atopic nonasthmatic (ANA) subjects. The purpose of this study was to obtain continuous, intrasubject controlled assessment of the relationship between cell migration in control and allergen-challenged segments in the same individuals over 96 h. In AA subjects, the eosinophil (Eos) count in the bronchoalveolar lavage fluid (BALF) increased from a baseline of 7,896 +/- 3,865 to 416,476 +/- 231,012 Eos/ml by 72 h (p = 0.001) in the challenged segment post-EBAC. For ANA subjects, the postsegmental challenge count was 29,874 +/- 474 Eos/ml (p = 0.03 versus baseline and p < 0.05 AA peak versus ANA peak). In both groups, there was a comparable decrease in peripheral blood eosinophil count beginning 5 h after challenge, which resolved at 24 h. In AA subjects, 416,476 +/- 231,012 Eos/ml was obtained from the allergen-challenged segment and 23,522 +/- 8,298 Eos/ml was obtained from the sham-challenged segment (p < 0.001) at 72 h. In contrast, there was no difference in the Eos count obtained from the BALF between the antigen- and sham-challenged segments of ANA subjects. We also found that increased airway neutrophils were present in equal numbers in allergen-challenged and sham-challenged segments in both AA and ANA subjects. We conclude that augmented eosinophil migration after EBAC is a characteristic of atopic asthma and is not present in atopic subjects who do not have asthma. We find that BAL eosinophilia in ANA patients as well as neutrophilia in both ANA and AA subjects are nonspecific consequences of bronchoscopy. Finally, we find no relationship between specific airway eosinophil migration into the BALF and FEV(1) < 72 h after challenge; however, at 96 h, there is a substantial decrease in FEV(1) that accompanies BALF eosinophilia.

Allergens↗
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↗
PubMed1993

A new antiinflammatory compound, leumedin, inhibits modification of low density lipoprotein and the resulting monocyte transmigration into the subendothelial space of cocultures of human aortic wall cells.

Addition of leumedin, N-[9H-(2,7-dimethylfluorenyl-9-methoxy) carbon]-L-leucine at 30-60 microM together with LDL almost completely prevented the induction of monocyte chemotactic protein mRNA, reduced monocyte chemotactic protein 1 levels by 84%, and inhibited monocyte migration into the subendothelial space of cocultures of human aortic wall cells by < or = 98%. LDL incubated with leumedin formed a stable complex that remained intact even after refloating in an ultracentrifuge. Leumedin at 50 microM did not change conjugated diene formation during coculture modification of LDL or Cu++ catalyzed oxidation of LDL. Unlike LDL from control rabbits, LDL isolated from rabbits that were injected with 20 mg/kg leumedin was remarkably resistant to modification by the coculture and did not induce monocyte migration to a significant degree. Moreover, HDL isolated from rabbits injected with leumedin was far more effective in protecting against LDL modification by the artery wall cocultures than HDL from control rabbits. We conclude that leumedins can associate with lipoproteins in vivo, rendering LDL resistant to biological modification and markedly amplifying the protective capacity of HDL against in vitro LDL oxidation by artery wall cells.

Animals↗
PubMed1997

Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL.

Heme catabolic processes produce the antioxidants biliverdin and bilirubin, as well as the potent prooxidant free iron. Since these products have opposing effects on oxidative stress, it is not clear whether heme catabolism promotes or inhibits inflammatory processes, including atherosclerotic lesion formation. Heme oxygenase (HO) catalyzes the rate-limiting step of heme catabolism. We used cocultures of human aortic endothelial cells and smooth muscle cells to examine the possible role of HO in early atherosclerosis. Heme oxygenase-1 (HO-1), the inducible isoform of HO, was highly induced by mildly oxidized LDL, and augmented induction was observed with hemin pretreatment. This augmented HO-1 induction resulted in the reduction of monocyte chemotaxis in response to LDL oxidation. Conversely, inhibition of HO by a specific inhibitor, Sn-protoporphyrin IX, enhanced chemotaxis. Furthermore, pretreatment with biliverdin or bilirubin, the products of HO, reduced chemotaxis. Oxidized phospholipids in the mildly oxidized LDL appear to be responsible for HO-1 induction, since oxidized but not native arachidonic acid-containing phospholipids also induced HO-1. These results suggest that HO-1 induced by mildly oxidized LDL may protect against the induction of inflammatory responses in artery wall cells through the production of the antioxidants biliverdin and bilirubin.

Bilirubin↗
PubMed2004

Endotoxin induces leukocyte transmigration and changes in permeability of the airway epithelium via protein-kinase C and extracellular regulated kinase activation.

Lipopolysaccharide (LPS) endotoxin of Gram-negative bacteria compromises the integrity of the airway epithelial barrier and initiates migration of leukocytes across the epithelium. The goal of the present study was to identify the role of extracellular regulated kinase (ERK1/2) transduction pathways in these processes. The first aim was to determine whether LPS induces ERK1/2 activation and changes in epithelial permeability in epithelial cells alone or only in the presence of immune cells. The second aim was to determine whether the changes in the epithelial permeability were diminished by ERK1/2 blockade. The third aim was to investigate the role of protein kinase C (PKC) activation as an upstream event in activation of ERK1/2. In vitro 20 microg/ml LPS challenge reduced epithelial barrier function, and induced ERK1/2 phosphorylation in primary cultures of bovine tracheal epithelium and in the transformed human airway epithelial cell line, Calu-3. LPS initiated migration of neutrophil-like and monocyte-like transformed HL-60 cell across sheets of Calu-3 cells. The migration rate and the associated changes in the electrical resistance, permeability to albumin, and ERK1/2 phosphorylation were all blocked by calphostin C, the specific blocker of PKC and by PD98059 (2'-amino-3'-methoxyflavone), a selective cell-permeable inhibitor of MAP kinase kinase. In rats, in vivo perfusion of the lumen of an isolated segment of trachea with LPS (0.1 mg/ml) initiated migration of neutrophils and increased the permeability to albumin. Again, these effects were markedly inhibited by PD98059 and calphostin C (by > 50%). We conclude that epithelial ERK1/2 is activated by endotoxin via PKC and is an important pathway in regulation of epithelial permeability.

Animals↗
PubMed2006

Shear flow-dependent integration of apical and subendothelial chemokines in T-cell transmigration: implications for locomotion and the multistep paradigm.

Lymphocyte extravasation requires that emigrating cells process chemoattractant signals, typically mediated by chemokines, encountered on endothelial surface (apical) and subendothelial (basal) compartments. These signals are delivered under conditions of hemodynamic shear, a fundamental feature of all physiologic leukocyte-endothelial interactions. To analyze lymphocyte responsiveness to spatially distributed chemokines and their effects on transendothelial migration (TEM) under hydrodynamic shear, we constructed a transwell-based flow assay. We observed that the inflammatory chemokine CCL5 (RANTES) induces negligible human T-cell migration across inflamed human umbilical vascular endothelial cells (HUVECs) when displayed alone in the subendothelial compartment under static or hemodynamic shear conditions or when combined with apical CXCL12 (SDF-1alpha) under static conditions. However, under shear stress, T cells encountering apically presented CXCL12 were primed to undergo robust LFA-1-dependent TEM toward subendothelial CCL5. Notably, locomotive T cells arriving at endothelial junctions were retained and extended pseudopodia into and through the junctions, thereby increasing sensitivity to subendothelial CCL5. These findings provide the first evidence that lymphocytes integrate, conditional to shear forces, permissive apical chemokine deposits, and integrin engagement signals, resulting in morphologic changes and amplified chemotaxis to an otherwise weak subendothelial chemokine signal.

Cells, Cultured↗
PubMed2005

CD14 deficiency leads to increased MIP-2 production, CXCR2 expression, neutrophil transmigration, and early death in pneumococcal infection.

CD14 is a myeloid receptor for bacterial cell membrane/wall components, for which we previously showed a strong induction in cerebrospinal fluid (CSF) during meningitis. Here, we studied CD14 function in murine Streptococcus pneumoniae meningitis by using wild-type (WT), CD14(-/-) mice, and WT mice pretreated with neutralizing anti-CD14 antibodies. Early polymorphonuclear leukocytes (PMN) immigration was more pronounced in CSF of CD14(-/-) than of WT mice. This was not a result of altered adherence molecule expression in blood and CSF PMN or brain endothelial cells. Macrophage inflammatory protein-2 (MIP-2) and keratinocyte-derived chemokine levels were similar in CSF in both strains, but MIP-2 was higher in infected brain and in brain-derived endothelial cells infected in vitro in CD14(-/-) than in WT mice. CD14(-/-) PMN demonstrated increased expression of CXC chemokine receptor 2 (CXCR2) after infection and stronger in vitro chemotaxis than WT PMN toward CSF from WT or CD14(-/-) mice and toward MIP-2. Excess PMN migration in CD14(-/-) mice did not result in improved bacterial clearing but in increased tumor necrosis factor in CSF, higher disease severity, and earlier death. Pretreatment with anti-CXCR2 reduced PMN infiltration into CSF and brain MIP-2 production and abolished earlier mortality in CD14(-/-) mice. In conclusion, CD14 plays a protective role in pneumococcal meningitis by slowing PMN migration via MIP-2 and CXCR2 modulation.

Animals↗
PubMed2005

Annexin 1-deficient neutrophils exhibit enhanced transmigration in vivo and increased responsiveness in vitro.

The role of the endogenous anti-inflammatory mediator annexin 1 (AnxA1) in controlling polymorphonuclear leukocyte (PMN) trafficking and activation was addressed using the recently generated AnxA1 null mouse. In the zymosan peritonitis model, AnxA1 null mice displayed a higher degree (50-70%) of PMN recruitment compared with wild-type littermate mice, and this was associated with reduced numbers of F4/80+ cells. Intravital microscopy analysis of the cremaster microcirculation inflamed by zymosan (6 h time-point) indicated a greater extent of leukocyte emigration, but not rolling or adhesion, in AnxA1 null mice. Real-time analysis of the cremaster microcirculation did not show spontaneous activation in the absence of AnxA1; however, superfusion with a direct-acting PMN activator (1 nM platelet-activating factor) revealed a subtle yet significant increase in leukocyte emigration, but not rolling or adhesion, in this genotype. Changes in the microcirculation were not secondary to alterations in hemodynamic parameters. The phenotype of the AnxA1 null PMN was investigated in two in vitro assays of cell activation (CD11b membrane expression and chemotaxis): the data obtained indicated a higher degree of cellular responses irrespective of the stimulus used. In conclusion, we have used a combination of inflammatory protocols and in vitro assays to address the specific counter-regulatory role of endogenous AnxA1, demonstrating its inhibitory control on PMN activation and the consequent impact on the inflamed microcirculation.

Animals↗
PubMed2004

Transmigrated neutrophils down-regulate the expression of VCAM-1 on endothelial cells and inhibit the adhesion of flowing lymphocytes.

As the first leukocytes recruited during inflammation, neutrophils are ideally situated to regulate the subsequent recruitment of mononuclear leukocytes. Here, we found that human neutrophils recruited by endothelial cells (EC), which had been stimulated with tumor necrosis factor alpha for 4 h, inhibited the adhesion of flowing, mixed mononuclear cells or purified lymphocytes over the subsequent 20 h but did not affect the adhesion of a secondary bolus of neutrophils. The degree of inhibition of lymphocyte adhesion increased with the duration of neutrophil-EC contact and with the number of recruited neutrophils. Antibody-blocking studies showed that lymphocyte adhesion was mediated predominantly by vascular cell adhesion molecule-1 (VCAM-1). Recruited neutrophils reduced the EC expression of VCAM-1 but not intercellular adhesion molecule-1 (ICAM-1) or E-selectin in a manner that mirrored the time- and number-dependent reduction in lymphocyte adhesion. VCAM-1 was not shed into the culture supernatant, and a panel of protease inhibitors was unable to reverse its down-regulation, indicating that it was not proteolytically degraded by neutrophils. In EC that had been in contact with neutrophils, the mRNA message for VCAM-1 but not ICAM-1 was down-regulated, indicating that alterations in transcriptional activity were responsible for the reduction in VCAM-1. Thus, under some inflammatory milieu, neutrophils may delay the recruitment of mononuclear leukocytes by regulating the expression of EC adhesion receptors.

Cell Adhesion↗
PubMedDate not supplied

Sperm transmigration as a cause of ectopic pregnancy.

This case represents the phenomenon of contralateral sperm transperitoneal migration: sperm gaining access to the left oviduct after entering the peritoneal cavity via the right oviduct. The ovum from the left ovary after being successfully fertilized could not be transported into the uterine cavity due to the previous segmental resection, ultimately resulting in an ectopic pregnancy.

Adult↗
PubMed2000

Human mast cells transmigrate through human umbilical vein endothelial monolayers and selectively produce IL-8 in response to stromal cell-derived factor-1 alpha.

Mature mast cells are generally considered to be less mobile cells residing within tissue sites. However, mast cell numbers are known to increase in the context of inflammation, and mast cells are recognized to be important in regulating local neutrophil infiltration. CXC chemokines may play a critical role in this process. In this study two human mast cell-like lines, HMC-1 and KU812, and human cord blood-derived primary cultured mast cells were employed to examine role of stromal cell-derived factor-1 (SDF-1) in regulating mast cell migration and mediator production. It was demonstrated that human mast cells constitutively express mRNA and protein for CXCR4. Stimulation of human mast cells with SDF-1, the only known ligand for CXCR4, induced a significant increase in intracellular calcium levels. In vitro, SDF-1 alpha mediated dose-dependent migration of human cord blood-derived mast cells and HMC-1 cells across HUVEC monolayers. Although SDF-1 alpha did not induce mast cell degranulation, it selectively stimulated production of the neutrophil chemoattractant IL-8 without affecting TNF-alpha, IL-1beta, IL-6, GM-CSF, IFN-gamma, or RANTES production, providing further evidence of the selective modulation of mast cell function by this chemokine. These findings provide a novel, SDF-1-dependent mechanism for mast cell transendothelial migration and functional regulation, which may have important implications for the local regulation of mast cells in disease.

Animals↗