tacrolimus and Airway-Obstruction

Topics: Airway Obstruction; Female; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymphoproliferative Disorders; Medical Illustration; Postoperative Complications; Tacrolimus

Obliterative bronchiolitis (OB) is the major complication limiting the long-term survival of allografts after lung transplantation. In this study, we investigated the effect of tacrolimus (FK506) combined with GM6001，a matrix metalloproteinase (MMP) inhibitor， on the formation of OB using a mouse heterotopic tracheal transplantation model.. Syngeneic tracheal grafts were transplanted heterotopically from BALB/c mice to BALB/c mice. Allografts from C57BL/6 mice were transplanted to BALB/c mice. Isograft group, allograft group, allograft+FK506 group, allograft +GM6001 group and allograft+FK506 + GM6001 group was given respectively intraperitoneal injection of saline, saline, FK506, GM6001 and FK506 + GM6001 once a day. At 28 day after transplantation, OB incidence was determined by hematoxylin-eosin staining and the expressions of MMPs and cytokines were assessed using enzyme linked immunosorbent assay, immunohistochemical assays and western blot assay.. The tracheal occlusion rates of isograft group, allograft group, allograft+FK506 group, allograft+GM6001 group and allograft+FK506 + GM6001 group were 0, 74.1 ± 9.79%, 34.4 ± 6.04%, 40.3 ± 8.77% and 26.5 ± 5.73% respectively. There were significant differences between the latter two groups (P < .001). The serum MMP-8 and MMP-9 levels of allograft group were significantly higher than those of isograft group (P < .05) and had no significant decrease when treated by FK506. The serum MMP-8 and MMP-9 levels of allograft+FK506 + GM6001 group were significantly lower than those of allograft+FK506 group (P < .05). MMP-8 and MMP-9 protein expression in the grafts of allograft+FK506 + GM6001 group were lower than those of allograft+FK506 group verified by immunohistochemical staining and western blotting.. FK506 combined with GM6001 could alleviate tracheal obliteration in mouse heterotopic tracheal transplantation model, due to its inhibitory effect on MMPs.

Topics: Airway Obstruction; Animals; Bronchiolitis Obliterans; Dipeptides; Disease Models, Animal; Drug Therapy, Combination; Graft Survival; Humans; Lung Transplantation; Male; Matrix Metalloproteinase 8; Matrix Metalloproteinase 9; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Postoperative Complications; Tacrolimus; Trachea; Transplantation, Heterotopic; Transplantation, Homologous

The use of self-expanding metallic airway stents has been extended in recent years in inoperable patients with malignant and benign airway diseases. The risk of granulation tissue formation in the stent is a major concern. The objective of the present study was to determine whether immunosuppression modulates granulation tissue formation in airway stents, as seen in coronary stents.. The study included 19 patients with benign airway obstructions and 11 recipients of lung transplants with anastomotic obstructions who were receiving immunosuppression therapy.. The degree of in-stent granulation tissue formation was evaluated (score range, 0-3) every 3 months for 2 years.. Granulation tissue formation was significantly lower in the transplant recipients than in the nontransplant patients at 3 months (score 0.7 vs. 1.6, P = .031), 15 months (score 0 vs. 1.1, P = .026), and 18 months (score 0 vs. 1.8, P = .020). During the 2 years of follow-up, the transplant recipients underwent significantly fewer laser resections and brachytherapy treatments for in-stent granulation.. The immunosuppression given to lung transplant recipients may have an inhibitory effect on granulation tissue formation in metallic airway stents. Further studies are needed to evaluate the effect of systemic therapy or coated stents with drugs such as sirolimus.

Topics: Adult; Aged; Airway Obstruction; Bronchoscopy; Dyspnea; Female; Granulation Tissue; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Male; Methylprednisolone; Middle Aged; Stents; Surgical Wound Dehiscence; Tacrolimus; Tracheal Stenosis

This study aimed to investigate the pharmacokinetics after tacrolimus aerosol inhalation and to assess its efficacy to suppress acute and chronic airway allograft rejection. Orthotopic tracheal transplantations were performed and tacrolimus (4 mg/kg) was administered orally (PO) or via aerosol (AER). Tracheal tissue level AUCs(0-12) were similar in both treatment groups, but blood AUCs(0-12) were approximately 5.5-fold lower with AER (p < 0.001). Interestingly, only PO animals showed elevated BUN, cholesterol and triglycerides on POD 60 (p < 0.05). Histology of grafts harvested after 6 and 60 days revealed that both treatment groups were similarly effective in suppressing graft mononuclear infiltration (p < 0.001). Cellular immune activation (assessed by IFN-gamma- and IL-4-ELISPOTS), however, was far more effectively suppressed by tacrolimus PO (p < 0.001). In both treatment groups, the vigorous alloreactive IgM-antibody surge was effectively inhibited (p < 0.001). Due to the insufficient systemic cellular immunosuppression, discontinuation of tacrolimus AER resulted in a far stronger (3.5-fold) graft infiltration on POD 8 compared to PO (p < 0.001). Tacrolimus aerosol reduces systemic side effects and effectively protects the airway graft from early cellular rejection and chronic obliterative airway disease.

Topics: Administration, Inhalation; Airway Obstruction; Animals; Antibody Formation; Cytokines; Graft Rejection; Immunity, Cellular; Immunosuppressive Agents; Male; Postoperative Complications; Rats; Rats, Inbred BN; Rats, Inbred Lew; Tacrolimus; Trachea; Transplantation, Homologous