Implanted
biomaterials trigger acute and chronic inflammatory responses. The mechanisms involved in such acute inflammatory responses can be arbitrarily divided into phagocyte transmigration, chemotaxis, and adhesion to implant surfaces. We earlier observed that two
chemokines-
macrophage inflammatory protein 1alpha/
monocyte chemoattractant protein 1-and the phagocyte
integrin Mac-1 (CD11b/CD18)/surface
fibrinogen interaction are, respectively, required for phagocyte chemotaxis and adherence to
biomaterial surfaces. However, it is still not clear how the initial transmigration of phagocytes through the endothelial barrier into the area of the implant is triggered. Because implanted
biomaterials elicit histaminic responses in the surrounding tissue, and histamine release is known to promote rapid diapedesis of inflammatory cells, we evaluated the possible role of
histamine and mast cells in the recruitment of phagocytes to
biomaterial implants. Using i.p. and s. c. implantation of
polyethylene terephthalate disks in mice we find: (i) Extensive degranulation of mast cells, accompanied by histamine release, occurs adjacent to short-term i.p. implants. (ii) Simultaneous administration of H1 and H2
histamine receptor antagonists (
pyrilamine and
famotidine, respectively) greatly diminishes recruitment and adhesion of both neutrophils (<20% of control) and monocytes/macrophages (<30% of control) to implants. (iii) Congenitally mast cell-deficient mice also exhibit markedly reduced accumulation of phagocytes on both i.p. and s.c implants. (iv) Finally, mast cell reconstitution of mast cell-deficient mice restores "normal" inflammatory responses to
biomaterial implants. We conclude that mast cells and their granular products, especially
histamine, are important in recruitment of inflammatory cells to
biomaterial implants. Improved knowledge of such responses may permit purposeful modulation of both acute and chronic
inflammation affecting implanted
biomaterials.