1: Biomaterials. 2007 Jan;28(3):371-82. Epub 2006 Sep 15.


The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function.

Schmidt DR, Kao WJ.

School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave., Madison, WI 53705, USA.

Macrophages play a critical role in mediating the host response to biomaterials, perhaps most notably by guiding the host inflammatory response through the release of inflammatory molecules such as the cytokine interleukin-1 (IL-1). The extent of the macrophage response following interaction with the biomaterial surface contributes greatly to device efficacy, yet the molecular mechanisms of this interaction are still unclear. The extracellular matrix (ECM) protein fibronectin (FN) is recognized by macrophages and frequently used in biomaterial modification to elicit greater cellular adhesion and tissue integration. Macrophage interaction with FN and other ECM molecules on the biomaterial surface has been shown to induce a variety of inflammatory responses, thus both FN and IL-1 can be utilized as model molecules to better understand the mechanisms of material-mediated macrophage responses. This literature review presents a comprehensive survey of past and current research on the interrelated role of IL-1, FN, and FN-derivatives in determining biomaterial-modulated macrophage function.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 16978691 [PubMed - indexed for MEDLINE]

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2: Matrix Biol. 1996 Nov;15(5):313-20; discussion 321.


Structure and function of fibronectin modules.

Potts JR, Campbell ID.

Department of Biochemistry, University of Oxford, UK.

Fibronectin is an important component of the extracellular matrix and is involved in a diverse range of physiological processes. It is a mosaic protein composed almost entirely of three types of module, F1, F2 and F3. Although the structures of single F1, F2 and F3 modules have been available for a number of years, in many cases the key to understanding the structure-function relationships in fibronectin and other proteins containing these modules lies in studies of module pairs and larger domains. This review focuses on recent advances in the understanding of the structure and function of fibronectin modules.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8981327 [PubMed - indexed for MEDLINE]

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3: Ciba Found Symp. 1995;189:177-91; discussion 191-9.


Mechanisms of VCAM-1 and fibronectin binding to integrin alpha 4 beta 1: implications for integrin function and rational drug design.

Humphries MJ, Sheridan J, Mould AP, Newham P.

School of Biological Sciences, University of Manchester, UK.

Integrin alpha 4 beta 1 can mediate both cell-cell and cell-extracellular matrix adhesion by binding to either fibronectin or vascular cell adhesion molecule 1 (VCAM-1). Both interactions are important for extravasation of leukocytes from the blood implying that rationally designed inhibitors of alpha 4 beta 1 function may be useful for treating a various inflammatory conditions. The mechanisms of ligand binding by alpha 4 beta 1 are complicated by the fact that alternative splicing can generate different isoforms of the receptor-binding domains in both fibronectin and VCAM-1. Therefore, in addition to developing alpha 4 beta 1 antagonists, we have also been interested in identifying isoform-specific functions. Recombinant ligand variants have been tested in adhesion and direct receptor-binding assays and each molecule was found to have a different inherent affinity for alpha 4 beta 1 that endows them with different adhesive activities. This suggests that alternative splicing may regulate alpha 4 beta 1-dependent motility in vivo. The initial strategy that we have adopted to develop alpha 4 beta 1 inhibitors has been to identify key amino acid residues and peptide sequences participating in the receptor-ligand binding event and to use this information to generate synthetic mimetics. Three active sites have been identified in fibronectin by testing truncated proteins, expressing recombinant fragments and screening synthetic peptides. Two of these sites employ versions of a novel integrin-binding motif, LDVP/IDAP. A key active site in VCAM-1 has been identified by similar approaches as the related sequence IDSP. Since IDSP-like sequences are probably used by other integrin-binding immunoglobulins, derivatives of these peptides may turn out to be the forerunners of a new generation of therapeutic agents with multiple applications.

Publication Types:
Review

PMID: 7587632 [PubMed - indexed for MEDLINE]

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4: Cold Spring Harb Symp Quant Biol. 1992;57:203-12.


Mechanisms of fibronectin and integrin function during cell adhesion and migration.

Yamada KM, Aota S, Akiyama SK, LaFlamme SE.

Laboratory of Developmental Biology, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.

Publication Types:
Review

PMID: 1339659 [PubMed - indexed for MEDLINE]

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5: Australas J Dermatol. 1990;31(1):47-56.


Fibronectin: structure, function and significance in wound healing.

Brotchie H, Wakefield D.

Department of Immunopathology, Prince Henry Hospital, Little Bay, NSW.

Several recent reports suggest a therapeutic role for topical application of autologous fibronectin in promoting healing of chronic skin and corneal ulcers. Fibronectin assists in wound healing by contributing to haemostasis, assisting in control of infection and debridement of wounds, and promoting re-epithelialisation, granulation tissue and ultimately a connective tissue of adequate tensile strength to repair the skin defect. The potential for fibronectin to be a therapeutic adjunct demands a close understanding of its structural and functional properties, and such knowledge, particularly emerging from research reported in the last five years, is reviewed.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 2073208 [PubMed - indexed for MEDLINE]

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6: Rev Infect Dis. 1987 Jul-Aug;9 Suppl 4:S412-9.


Fibronectin: an enhancer of phagocyte function.

Proctor RA.

Department of Medicine, University of Wisconsin, Madison 53706.

Although fibronectin does not act as a direct opsonin as originally described, it does mediate important interactions with phagocytes throughout the inflammatory process. Fragments of fibronectin released by neutrophil proteases are chemoattractants for monocytes. Moreover, subendothelial matrix fibronectin and "inflammatory" fibronectin released from phagocytes enhance phagocyte adherence to host tissues at an inflammatory site. Fibronectin also increases chemokinesis. Once the phagocyte enters tissues, fibronectin promotes C3- and Fc-receptor activation, allowing complement-coated bacteria to be ingested. Finally, fibronectin enhances the bactericidal activity of monocytes. Thus, fibronectin plays an important, but indirect role, in the activities of phagocytes.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 3326137 [PubMed - indexed for MEDLINE]

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7: Rev Infect Dis. 1987 Jul-Aug;9 Suppl 4:S317-21.


Fibronectin: a brief overview of its structure, function, and physiology.

Proctor RA.

Department of Medicine, University of Wisconsin, Madison.

Fibronectin is a large glycoprotein that is composed of blocks of three types of repeating, homologous peptide sequences. Several of the homologous blocks form functional domains that are organized in a linear array on two nearly identical subunit arms. Specific domains allow fibronectin to promote cell-to-cell adhesion, cell-to-basement-membrane attachment, clot stabilization, embryogenesis, nerve regeneration, fibroblast migration, macrophage function, and pathogen (virus, fungus, bacteria, and protozoa) binding to mammalian cells and extracellular matrix. Thus, this complex and multifunctional protein is involved in the pathogenesis of infections from the initiation of the infection through the final stages of wound healing.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 3326130 [PubMed - indexed for MEDLINE]

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8: J Cell Sci Suppl. 1987;8:199-209.


Activation of keratinocyte fibronectin receptor function during cutaneous wound healing.

Grinnell F, Toda K, Takashima A.

Department of Cell Biology and Anatomy, University of Texas Health Science Center, Dallas 75235.

Keratinocytes freshly isolated from unwounded skin could not attach and spread on fibronectin (FN)-coated culture dishes and could not bind and phagocytose FN-coated beads. These adhesive functions were activated, however, in keratinocytes that were isolated from healing wounds. Moreover, adhesiveness of basal keratinocytes to FN substrata was activated during epidermal cell or explant culture. Activation was specific for attachment to FN compared to other adhesion ligands, and occurred even when epidermal cells were cultured on collagen, basement membrane matrix, or lectin-coated substrata. Biochemical studies showed that keratinocytes have a 140 x 10(3) Mr FN receptor analogous to the fibroblast receptor for FN, and that this receptor is expressed in activated keratinocytes but not in keratinocytes freshly isolated from unwounded skin. The absence of FN receptors from keratinocytes in unwounded skin is not surprising since the basal keratinocytes of the epidermis are attached to a basement membrane containing laminin and type IV collagen. During wound repair, however, these cells migrate over or through a FN-coated matrix. Consequently, expression of FN receptors may be an essential feature of healing. Believing that FN is the required substratum for keratinocyte migration during wound healing, we have initiated clinical studies to determine if topical application of FN is useful as a therapy for non-healing cutaneous ulcers.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 2460476 [PubMed - indexed for MEDLINE]

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9: Prog Clin Biol Res. 1984;154:155-75.


The role of fibronectin in monocyte/macrophage function.

Mosesson MW.

"Fibronectin" is a term describing a class of immuno-chemically related glycoproteins that are found in blood, in connective tissues, and in most basement membranes. All types of fibronectins have distinct binding domains that serve to mediate an adhesive function between collagen, cells (e.g., fibroblasts, macrophages), fibrin(ogen), and/or certain glycosaminoglycans (e.g., heparin). Monocytes and macrophages are phagocytic cells which collectively comprise the "mononuclear phagocytic" system. Plasma fibronectin (CIg) mediates: a) the attachment of monocytes to gelatin-coated surfaces; and b) the attachment of gelatin-coated RBCs or latex particles to surface-bound monocytes. This process was mediated only by surface-bound forms of fibronectin. Particle attachment to cells, per se, was not associated with augmented particle ingestion, although particle binding did result in increased expression of the monocyte C3 and Fc receptors. These data indicate that monocytes have surface receptors for fibronectin. It appears that the relatively strong affinity between fibrin and fibronectin may provide a mechanism for recognition and subsequent clearance of fibrin-fibrinogen complexes from the blood by attachment to fibronectin receptors on mononuclear phagocytes. One can also speculate that fibronectin binds to exposed or denatured collagen at sites of injury, leading to macrophage attachment and differentiation. Such events probably play an important role in wound organization and healing.

Publication Types:
Review

PMID: 6089231 [PubMed - indexed for MEDLINE]

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10: Prog Liver Dis. 1982;7:109-31.


Plasma fibronectin and hepatic Kupffer cell function.

Saba TM.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7051141 [PubMed - indexed for MEDLINE]