TEMPORAL AND SPATIAL IMMUNOLOCALIZATION OF CYTOKINES IN MURINE CHRONIC GRANULOMATOUS TISSUE - IMPLICATIONS FOR THEIR ROLE IN TISSUE-DEVELOPMENT AND REPAIR PROCESSES

BACKGROUND: Cytokines have profound effects on various aspects of gran ulomatous tissue formation. However, there is little information regar ding their distribution during tissue development. This study investig ated the temporal and spatial distribution of transforming growth fact or-beta (TGF-beta), platelet-derived growth factor (PDGF), epidermal g rowth factor (EGF), basic fibroblast growth factor (bFGF), tumor necro sis factor-alpha (TNF-alpha), interleukin-1alpha (IL-1) and IL-1beta i n developing granulomatous tissue. EXPERIMENTAL DESIGN: Murine chronic granulomatous air pouches were induced and full thickness biopsies ta ken at intervals up to 28 days. Samples were prepared for immunohistoc hemistry and labeled using antibodies against TGF-beta, bFGF, PDGF, EG F, TNF-alpha, IL-1alpha and IL-1beta. RESULTS: Immunoreactivity to TGF -beta, PDGF, TNF-alpha, IL-1alpha and IL-1beta was localized to a prop ortion of macrophages within the granulomatous tissue. Immunopositive macrophage numbers increased with time, and with the exception of PDGF were associated with areas of fibrogenesis between days 14 to 28. Het erogeneous labeling of capillaries for EGF was observed within the gra nulomatous tissue juxtaposed to dermal musculature. Diffuse labeling o f bFGF, associated with extracellular matrix, was always observed. Aft er day 14, bFGF immunoreactivity was discretely localized to endotheli al cells and the basement membrane of vessels within the granulomatous tissue. TGF-beta immunoreactivity was also associated with extracellu lar matrix components, being most intense in the area of fibrogenesis between 14 and 28 days. Occasional fibroblasts were also labeled with TGF-beta in this region. CONCLUSIONS: The spatial and temporal confine ment of the individual cytokines suggests that a sequential coordinate d process of repair and fibrosis is occurring. It is hoped that these observations will provide a more effective therapeutic approach for th e sequential application of cytokines in abnormalities of wound healin g.