Characterization of fibroblasts from rejecting tissue: the hyaluronan production is increased.
BACKGROUND
Interstitial edema of rejecting tissue can be partly attributed to the local accumulation of hyaluronan, which has strong water-binding capacity. The aim of the present study was to isolate fibroblasts from rejecting tissue and compare them, in terms of hyaluronan production and proliferation rate, with fibroblasts obtained from nontransplanted tissue. Furthermore, the fibroblast response to various cytokines involved in the rejection process was studied.


METHODS
Fibroblasts were isolated from normal rat heart tissue and from cardiac allografts undergoing rejection. The various preparations were characterized with regard to hyaluronan production (radiometric assay) and cell proliferation ( H-thymidine incorporation). In addition, the effects of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-2 on these parameters were studied.


RESULTS
Fibroblasts isolated from rejecting hearts displayed strongly up-regulated hyaluronan production and proliferation rate as compared with fibroblasts obtained from normal tissue. In the presence of TNF-alpha, the proliferation of nonconfluent cells was augmented, whereas in confluent cultures of fibroblasts from rejecting tissue, the proliferation was inhibited. IFN-gamma stimulated both hyaluronan secretion and proliferation in confluent fibroblasts from rejecting hearts but had no effect on fibroblasts from normal tissue. IL-2, finally, reduced the hyaluronan production of nonconfluent cells.


CONCLUSIONS
The activation of fibroblasts is increased in rejecting tissue. As a result, the hyaluronan concentration is elevated which, in vivo, contributes to the formation of an interstitial edema and a subsequently increased tissue pressure. Several cytokines present at rejection are involved also in the regulation of fibroblast activity.
Hellkvist
Josefin
J
Department of Transplantation Surgery, University Hospital, Uppsala, Sweden.
Tufveson
Gunnar
G
Gerdin
Bengt
B
Johnsson
Cecilia
C
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006084:Graft Rejection / Q000378:metabolism* / Q000473:pathology*; D016027:Heart Transplantation / Q000473:pathology*; D006820:Hyaluronic Acid / Q000096:biosynthesis*; D007371:Interferon-gamma / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000970:Antineoplastic Agents; D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D006820:Hyaluronic Acid