The goal of the research proposed in this grant is to better define the structure and function of a specific human neutrophil (PMN) receptor that mediates PMN adherence to laminin, a major basement membrane glycoprotein. Data presented here demonstrate that PMN adherence to laminin is mediated both by the major class of integrins found on PMNs, called the CD11/CD18 family of receptors, and by a separate receptor that is antigenically related to the VLA class of integrins, in particular, the VLA-6. This is a novel observation since VLA receptors have not been previously described on PMNs. One goal of this project is to characterize the nature of this novel PMN laminin receptor and define its relationship to defined VLA receptors. The second goal is to characterize the external stimuli and subsequent cellular responses involved in the functional expression of the receptor, particularly after stimulation of PMNs with tumor necrosis factor (TNF) and chemoattractants. This is of particular interest since data presented here shows that exposure of PMNs to TNF activates this novel laminin receptor, and because others have reported that PMNs adherent to laminin undergo a massive respiratory burst in response to TNF while PMNs in suspension do not. The third goal is to determine the ability of this receptor to mediate or modulate the adherence-dependent function of directed PMN migration. Recruitment of circulating PMNs into areas of inflammation requires that PMNs must first adhere to the endothelium, or to exposed subendothelial matrix if the endothelium is retracted, and then migrate through endothelial cell junctions and subendothelial basement membrane. Considerable evidence exists that adherence of stimulated PMNs to vessel walls contributes to several syndromes of vascular injury, including Adult Respiratory Distress Syndrome and reperfusion following ischemia. Thus, PMN adhesion processes must be reversible and exquisitely regulated to allow efficient PMN extravasation with minimal vascular injury. Understanding the mechanisms by which laminin influences PMN adherence and the adherence-dependent phenomenon of migration might suggest strategies for decreasing PMN-mediated vascular injury and enhancing PMN influx into infectious foci.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
1R29AI026733-01A2
Application #
3454772
Study Section
Pathobiochemistry Study Section (PBC)
Project Start
1990-07-01
Project End
1995-06-30
Budget Start
1990-07-01
Budget End
1991-06-30
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Bohnsack, J F; Chang, J; Zhou, X et al. (1995) Mechanisms of beta 1 integrin-dependent adherence of granulocytic HL60 to fibronectin. J Leukoc Biol 57:592-9
Bohnsack, J F; Chang, J (1994) Activation of beta 1 integrin fibronectin receptors on HL60 cells after granulocytic differentiation. Blood 83:543-52
Yang, K D; Augustine, N H; Shaio, M F et al. (1994) Effects of fibronectin on actin organization and respiratory burst activity in neutrophils, monocytes, and macrophages. J Cell Physiol 158:347-53
Williams, P A; Bohnsack, J F; Augustine, N H et al. (1993) Production of tumor necrosis factor by human cells in vitro and in vivo, induced by group B streptococci. J Pediatr 123:292-300
Bohnsack, J F; Chang, J K; Hill, H R (1993) Restricted ability of group B streptococcal C5a-ase to inactivate C5a prepared from different animal species. Infect Immun 61:1421-6
Hill, H R; Augustine, N H; Williams, P A et al. (1993) Mechanism of fibronectin enhancement of group B streptococcal phagocytosis by human neutrophils and culture-derived macrophages. Infect Immun 61:2334-9
Yang, K D; Bohnsack, J F; Hill, H R (1993) Fibronectin in host defense: implications in the diagnosis, prophylaxis and therapy of infectious diseases. Pediatr Infect Dis J 12:234-9
Bohnsack, J F; Zhou, X N; Gustin, J N et al. (1992) Bacterial evasion of the antibody response: human IgG antibodies neutralize soluble but not bacteria-associated group B streptococcal C5a-ase. J Infect Dis 165:315-21
Shyur, S D; Raff, H V; Bohnsack, J F et al. (1992) Comparison of the opsonic and complement triggering activity of human monoclonal IgG1 and IgM antibody against group B streptococci. J Immunol 148:1879-84
Bohnsack, J F (1992) CD11/CD18-independent neutrophil adherence to laminin is mediated by the integrin VLA-6. Blood 79:1545-52

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