Abstract
BackgroundPreviously, we have demonstrated that mucociliary clearance (MCC) is diminished within the first months after surgery in lung transplant patients and the explanation for the reduction in MCC is unknown. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation.MethodsFifteen C57BL/6 mice underwent vagotomy on the right side to simulate denervation associated with lung transplantation in humans. For 6 days, seven mice (controls) were intraperitoneally injected with three 100 µL doses of phosphate buffered saline and eight mice (immunosuppressed) were injected with three 100 µL injections of tacrolimus (1 mg/kg), mycophenolate mofetil (30 mg/kg), and prednisone (2 mg/kg) once daily. Then, mice inhaled the radioisotope 99mtechnetium and underwent gamma camera imaging of their lungs for 6.5 hrs. Counts in the right lung at 1–1.5 hrs and at 6–6.5 hrs were first background-corrected and then decay-corrected to time 0 counts. Decay-corrected counts were then divided by time 0 counts. Retention at each time point was subtracted from 1.00 and multiplied by 100% to obtain percent removed by mucociliary clearance.ResultsAlthough there was a slowing of MCC at 1–1.5 hrs for the immunosuppressed mice, there was no statistical difference in MCC measured at 1–1.5 hrs for the two groups of mice. At 6–6.5 hrs, MCC was significantly slower in the immunosuppressed mice, compared to controls, with 7.78±5.9% cleared versus 23.01±11.7% cleared, respectively (p = 0.006).ConclusionsThese preliminary results suggest that chronic treatment with immunosuppressive medications significantly slows MCC in vagotomized C57BL/6 mice. These findings could shed light on why MCC is reduced in lung transplant patients whose lungs are denervated during surgery and who are chronically treated with immunosuppressive drugs post surgery.
Highlights
Mucociliary clearance (MCC) is a vital pulmonary defense mechanism providing protection in the lower and upper airways against inhaled pathogens and irritants
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
We found in a previous study in mice that denervation did not affect basal mucociliary clearance (MCC), suggesting that denervation alone does not account for the observed reduction in MCC in lung transplant patients [6]
Summary
Mucociliary clearance (MCC) is a vital pulmonary defense mechanism providing protection in the lower and upper airways against inhaled pathogens and irritants. Insoluble agents that deposit in the airway mucus are removed within hours by the MCC apparatus Impairment to this defense mechanism leads to prolonged exposure to irritants, bacteria and viruses, the development of infections and subsequent re-injury to the MCC apparatus [1]. The depressant effects of these volatile anesthetic agents on cilia [5] and on tracheal flow appear to be reversible [4] This reversibility suggests that mucus clearance would be restored post-operatively in the absence of additional factors. We hypothesized that chronic treatment with a commonly prescribed regimen of immunosuppressive drugs significantly impairs MCC. We tested this hypothesis in a murine model of lung transplantation
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