title: A pilot study to examine the effect of chronic treatment with immunosuppressive drugs on mucociliary clearance in a vagotomized murine model.
abstract: BACKGROUND
  Previously, 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.
  
  
  METHODS
  Fifteen 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 (99m)technetium 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.
  
  
  RESULTS
  Although 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).
  
  
  CONCLUSIONS
  These 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.
authors.affiliation: Department of Biomedical Engineering, The Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.
authors.forename: Abhiram R
authors.initials: AR
authors.lastname: Bhashyam
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mogayzel
authors.forename: Sharon
authors.initials: S
authors.lastname: McGrath-Morrow
authors.forename: Enid
authors.initials: E
authors.lastname: Neptune
authors.forename: Alla
authors.initials: A
authors.lastname: Malinina
authors.forename: James
authors.initials: J
authors.lastname: Fox
authors.forename: Beth L
authors.initials: BL
authors.lastname: Laube
mesh_terms: D000818:Animals; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D008168:Lung / Q000187:drug effects* / Q000378:metabolism*; D016040:Lung Transplantation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009079:Mucociliary Clearance / Q000187:drug effects*; D009173:Mycophenolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use; D011241:Prednisone / Q000009:adverse effects / Q000627:therapeutic use; D016559:Tacrolimus / Q000009:adverse effects / Q000627:therapeutic use; D014628:Vagotomy
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D011241:Prednisone; D016559:Tacrolimus