Effects of cyclosporine A and bronchial transection on mucociliary transport in rats.
ABSTRACT Posttransplant infection remains the leading cause of morbidity and mortality after lung transplantation. We hypothesized that bronchial transection and immunosuppression by cyclosporine both play a key role in the impairment of airway mucociliary clearance, a basic defense system.
Sixty-four rats were assigned to four groups of 16 each according to surgical procedure and drug therapy as follows: sham-operated and saline solution; bronchial transection and saline solution; sham-operated and cyclosporine; bronchial transection and cyclosporine (10 mg/kg/day). Eight animals from each group were euthanized on postoperative day 30 or 90. In vitro mucus transportability, in situ mucociliary transport, and ciliary beating frequency were measured.
There was a significant impairment (p < 0.001) on ciliary beating frequency due to either bronchial transection or cyclosporine therapy. In vitro transportability was impaired only in cyclosporine-treated groups (p < 0.001). In situ mucociliary transport was reduced in cyclosporine-treated animals as well as in those that underwent bronchial transection (p < 0.001). This impairment was significantly recovered 90 days after operation. In contrast, the effects of cyclosporine did not change over 90 days of treatment.
These results support our hypothesis that mucociliary clearance is impaired after bronchial transection and cyclosporine therapy. Further studies are necessary to relate this finding with posttransplant infection and also to test some drugs aiming to protect airway mucociliary system.
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ABSTRACT: Lung transplant recipients suffer from a high number of viral infections. It has been suggested that the defense against viral infections is impaired in lung transplants. Therefore, we investigated in rat lung transplants whether antibody responses against an intrapulmonary viral infection were impaired in 3 groups of rats with: (1) BN-to-LEW allogeneic lung transplants, (2) LEW-to-LEW syngeneic lung transplants, and (3) nontransplanted LEW lungs. All rats (including those with nontransplanted, normal lungs) were treated with cyclosporine on days 2 and 3 after operation; this treatment is adequate to induce permanent graft acceptance of the allografts. Six months after transplantation, viral infections with Sendai virus (parainfluenza type I) were induced intratracheally. At day 0, immediately before infection, and at days 4, 7, 21, and 56 after infection, 4 rats in each group were killed for histological evaluation of the lungs. The number of antibody-positive cells in the bronchus-associated lymphoid tissue (BALT) in the lungs and in the spleen, and presence of the virus in the lungs were determined by immunohistology. Serum antibody titers were followed for 56 days after infection. The allogeneically transplanted lungs failed to respond adequately against the virus: the number of antibody-positive cells in the BALT did not increase after infection, serum antibody titers were hardly detectable, and virus was present in the airways of the lungs up to day 21 after infection. In contrast, in the syngeneically and nontransplanted lungs, the number of antibody-forming cells in the BALT increased steeply until day 7, serum antibody titers rose until day 14, and virus could be detected only on day 4 after infection. This study shows that in rat lung allografts, both the local antibody production in the BALT and the systemic antibody response against a respiratory viral infection are inadequate. As a consequence, the virus is present longer in these allografted lungs and can exert its damaging effect over a longer period of time. These results may explain why lung transplants are so susceptible to viral infections.Transplantation 07/1995; 59(11):1583-9. · 3.78 Impact Factor
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ABSTRACT: Patients with lung transplantation are prone to respiratory infections. Generally this is attributable to the effects of immunosuppressive drugs but mucociliary clearance has been found to be impaired in these subjects. A study was performed to determine whether this finding is accompanied by a reduction in ciliary beat frequency (CBF). Six patients who had undergone single lung transplantation for fibrosing lung disease were investigated. CBF was measured in mucosal samples from native and transplanted bronchi by a videophotometry method. The CBF was reduced in the transplanted bronchi in all cases when both fastest and slowest beating cilia were examined. The fastest beating cilia on the native side had a mean (SD) CBF of 12.1 (1.3) Hz compared with 9.6 (2.0) Hz on the transplanted side. The slowest beating cilia also had reduced CBF on the transplanted side. In patients with fibrotic lung disease, CBF is reduced in transplanted bronchi in comparison with native bronchi.Thorax 07/1993; 48(6):629-31. · 8.38 Impact Factor
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ABSTRACT: Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-beta stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (alpha and beta), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10,000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-beta stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of well-differentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.American Journal of Transplantation 12/2005; 5(11):2660-70. · 6.19 Impact Factor