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1.  Kinetics of Chemokine-Glycosaminoglycan Interactions Control Neutrophil Migration into the Airspaces of the Lungs 
Chemokine-glycosaminoglycan (GAG) interactions are thought to result in the formation of tissue-bound chemokine gradients. We hypothesized that the binding of chemokines to GAGs would increase neutrophil migration towards CXC-chemokines instilled into lungs of mice. To test this hypothesis we compared neutrophil migration towards rhCXCL8 and two mutant forms of CXCL8, which do not bind to heparin immobilized on a sensor chip. Unexpectedly, when instilled into the lungs of mice the CXCL8 mutants recruited more neutrophils than rhCXCL8. The CXCL8 mutants appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro. A comparison of the murine CXC-chemokines KC and MIP-2 revealed that KC was more effective in recruiting neutrophils into the lungs than MIP-2. KC appeared in plasma at significantly higher concentrations and diffused more rapidly across an extracellular matrix in vitro than MIP-2. In kinetic binding studies, KC, MIP-2, and rhCXCL8 bound heparin differently, with KC associating and dissociating more rapidly from immobilized heparin than the other chemokines. These data suggest that the kinetics of chemokine-GAG interactions contributes to chemokine function in tissues. In the lungs, it appears that chemokines such as CXCL8 or MIP-2, which associate and disassociate slowly from GAGs, form gradients relatively slowly compared to chemokines that either bind GAGs poorly or interact with rapid kinetics. Thus, different types of chemokine gradients may form during an inflammatory response. This suggests a new model whereby GAGs control the spatiotemporal formation of chemokine gradients and neutrophil migration in tissue.
PMCID: PMC4113427  PMID: 20124102
chemokine; glycosaminoglycan; kinetics; neutrophil; lungs; inflammation; rodent
2.  Chemokine-induced eosinophil recruitment. Evidence of a role for endogenous eotaxin in an in vivo allergy model in mouse skin. 
Journal of Clinical Investigation  1997;100(7):1657-1666.
Selective eosinophil recruitment into tissues is a characteristic feature of allergic diseases. Chemokines are effective leukocyte chemoattractants and may play an important role in mediating eosinophil recruitment in various allergic conditions in man. Here, we describe a novel mouse model of eosinophil recruitment in which we have compared the in vivo chemoattractant activity of different C-C chemokines. Furthermore, we describe the use of antibodies to chemokines and receptor blockade to address the endogenous mechanisms involved in eosinophil recruitment in a late-phase allergic reaction in mouse skin. Intradermal injection of mEotaxin and mMIP-1alpha, but not mMCP-1, mRANTES, mMCP-5, or mMIP-1beta, induced significant 111In-eosinophil recruitment in mouse skin. Significant 111In-eosinophil recruitment was also observed in an active cutaneous anaphylactic reaction. Pretreatment of skin sites with antieotaxin antiserum, but not an antiMIP-1alpha antibody, suppressed 111In-eosinophil recruitment in this delayed-onset allergic reaction. Similarly, desensitization of the eosinophil eotaxin receptor CCR3 with mEotaxin, or blockade of the receptor with metRANTES, significantly inhibited 111In-eosinophil recruitment in the allergic reaction. These results demonstrate an important role for endogenous eotaxin in mediating the 111In-eosinophil recruitment in allergic inflammation, and suggest that blockade of the CCR3 receptor is a valid strategy to inhibit eosinophil migration in vivo.
PMCID: PMC508348  PMID: 9312163
3.  Role of epithelial interleukin-8 (IL-8) and neutrophil IL-8 receptor A in Escherichia coli-induced transuroepithelial neutrophil migration. 
Infection and Immunity  1997;65(8):3451-3456.
Escherichia coli stimulates neutrophil migration across human uroepithelial cell layers. This study investigated the role of the neutrophil chemokine interleukin-8 (IL-8) in this process. E. coli and IL-1alpha stimulated urinary tract epithelial layers to secrete IL-8 and induced transepithelial neutrophil migration. Anti-IL-8 antibody reduced neutrophil migration across epithelial cell layers, indicating a central role for this chemokine in the migration process. Furthermore, addition of recombinant IL-8 to unstimulated cell layers was sufficient to induce migration. The IL-8 dependence of neutrophil migration was maintained after removal of soluble IL-8 by washing of the cell layers. Flow cytometry analysis with fluorescein isothiocyanate-labelled IL-8 confirmed IL-8's ability to bind to the epithelial cell surface. Indirect immunofluorescence with confocal laser scanning microscopy showed that IL-8 associated with the epithelial cell layers. Prior incubation of neutrophils with antibodies to IL-8 receptor A (IL-8RA) reduced neutrophil migration. Anti-IL-8 RB antibody had no effect on neutrophil migration. These results demonstrate that IL-8 plays a key role in E. coli- or IL-1alpha-induced transuroepithelial migration and suggest that epithelial cell-produced IL-8 interacts with IL-8RA on the neutrophil surface.
PMCID: PMC175488  PMID: 9234811
4.  Prevalence of antibody to hepatitits B surface antigen among staff in an Edinburgh hospital. 
The Journal of Hygiene  1977;78(1):57-68.
Antibody to hepatitis B surface antigen was detected by radioimmunoprecipitation in 74 (5-5%) of 1336 staff members in a large general hospital in Edinburgh, in 14 (2-9%) of 480 volunteer blood donors in the area, and in 12 (6-1%) of 197 pregnant women attending for the first time at the ante-natal clinic in the hospital. Rates of antibody prevalence rose with age in the sample of hospital staff and in that of the blood donors, particularly among males. On the other hand, in the ante-natal patients antibody prevalence declined with age. The rates in hospital staff were higher than those in blood donors of comparable age and sex, and high titres of antibody were more common in the staff group. However, no association was found between antibody prevalence and a history of clinical hepatitis, blood transfusion, or recognized contact with cases of hepatitis. Staff who had previously worked in an infectious disease hospital did not show increased antibody prevalence, indicating that simple isolation measures have been adequate to minimize exposure to hepatitis B. No particular prevalence of infection was seen in physicians and surgeons, in the nursing staff, or in workers in clinical diagnostic laboratories, hospital administration or other areas. One group clearly showing increased antibody prevalence was staff currently working, or who had worked, in the Haemodialysis Unit; this correlated with the outbreak of dialysis-associated hepatitis in 1969--70. However, no evidence suggested that significant dissemination of infection had occurred to other defined groups of hospital staff. Elevated rates were also observed in a small sample of kitchen and portering staff, and in obstetric medical and nursing staff; the latter observation indicate a need for further investigation to identify unsuspected exposure to hepatitis B virus.
PMCID: PMC2129744  PMID: 264499

Results 1-4 (4)