title: Adjunctive Phosphodiesterase-4 Inhibitor Therapy Improves Antibiotic Response to Pulmonary Tuberculosis in a Rabbit Model.
abstract: OBJECTIVE
  Adjunctive host-directed therapy is emerging as a new potential approach to improve the outcome of conventional antimicrobial treatment for tuberculosis (TB). We tested the ability of a phosphodiesterase-4 inhibitor (PDE4i) CC-11050, co-administered with the first-line anti-TB drug isoniazid (INH), to accelerate bacillary killing and reduce chronic inflammation in the lungs of rabbits with experimental Mycobacterium tuberculosis (Mtb) infection.
  
  
  METHODS
  A rabbit model of pulmonary TB that recapitulates the pathologic manifestations seen in humans was used. Rabbits were infected with virulent Mtb by aerosol exposure and treated for eight weeks with INH with or without CC-11050, starting at four weeks post infection. The effect of CC-11050 treatment on disease severity, pathology, bacillary load, T cell proliferation and global lung transcriptome profiles were analyzed.
  
  
  RESULTS
  Significant improvement in bacillary clearance and reduced lung pathology and fibrosis were noted in the rabbits treated for eight weeks with INH + CC-11050, compared to those treated with INH or CC-11050 only. In addition, expression of host genes associated with tissue remodeling, tumor necrosis factor alpha (TNF-α) regulation, macrophage activation and lung inflammation networks was dampened in CC-11050-treated, compared to the untreated rabbits.
  
  
  CONCLUSIONS
  Adjunctive CC-11050 therapy significantly improves the response of rabbits with experimental pulmonary TB to INH treatment. We propose that CC-11050 may be a promising candidate for host directed therapy of patients with pulmonary TB, reducing the duration and improving clinical outcome of antibiotic treatment.
authors.affiliation: Public Health Research Institute (PHRI) of Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ, USA.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Subbian
authors.affiliation: Public Health Research Institute (PHRI) of Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ, USA; Department of Biological Sciences, NYC College of Technology, Brooklyn, NY, USA.
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.affiliation: Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Holloway
authors.affiliation: Public Health Research Institute (PHRI) of Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ, USA.
authors.forename: Blas
authors.initials: B
authors.lastname: Peixoto
authors.affiliation: Public Health Research Institute (PHRI) of Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.affiliation: Public Health Research Institute (PHRI) of Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ, USA.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dartois
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Vikram
authors.initials: V
authors.lastname: Khetani
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Zeldis
authors.affiliation: Public Health Research Institute (PHRI) of Rutgers Biomedical and Health Sciences (RBHS), Newark, NJ, USA.
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D004338:Drug Combinations; D004357:Drug Synergism; D005260:Female; D007538:Isoniazid / Q000008:administration & dosage / Q000627:therapeutic use*; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D011817:Rabbits; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D004338:Drug Combinations; D058988:Phosphodiesterase 4 Inhibitors; D007538:Isoniazid
keywords: Immune modulation; Inflammation; Lung fibrosis; Phosphodiesterase inhibitor; Pulmonary tuberculosis