Calcineurin Inhibitor-Based Triple Immunosuppressive Therapy Induces Profibrotic Changes in the Jejunal Mucosa of Male Rats: A Digital Image Analysis of Collagen Fibers

Background/Objectives: Long-term immunosuppressive therapy administered to solid organ transplant recipients may induce adverse effects in various tissues, including the gastrointestinal tract. The aim of the present study was to evaluate the influence of prolonged treatment with calcineurin inhibitor (CNI)-based triple immunosuppressive regimens on the morphology of the jejunal mucosa in male rats. Particular attention was paid to fibrotic changes occurring within the mucosal connective tissue, including the intestinal villi and lamina propria. Methods: Animals were treated for six months with regimens containing either cyclosporine A (CyA) or tacrolimus (TAC) in combination with rapamycin and prednisone. To assess the content of collagen fibers, jejunal sections were stained using the Mallory trichrome method and subsequently subjected to quantitative digital image analysis. Results: Histological examination demonstrated increased collagen deposition in the jejunal mucosa of rats receiving immunosuppressive treatment compared with the control group. Quantitative analysis confirmed an increase in collagen fiber content, indicating enhanced extracellular matrix accumulation and changes consistent with fibrotic remodeling of the mucosal connective tissue. The highest collagen fiber content was observed in animals treated with the cyclosporine-based regimen. Conclusions: These findings suggest that long-term administration of CNI-based triple immunosuppressive therapy may be associated with changes consistent with fibrotic remodeling of the jejunal mucosa. The present study provides novel data on the effects of clinically relevant multidrug immunosuppressive protocols, whereas most previous experimental studies investigating the effects of immunosuppressive agents have focused on single-drug exposure in animal models or in vitro systems.