title: Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology.
abstract: Tuberculosis (TB) is responsible for significant morbidity and mortality worldwide. Even after successful microbiological cure of TB, many patients are left with residual pulmonary damage that can lead to chronic respiratory impairment and greater risk of additional TB episodes due to reinfection with Mycobacterium tuberculosis. Elevated levels of the proinflammatory cytokine tumor necrosis factor-α and several other markers of inflammation, together with expression of matrix metalloproteinases, have been associated with increased risk of pulmonary fibrosis, tissue damage, and poor treatment outcomes in TB patients. In this study, we used a rabbit model of pulmonary TB to evaluate the impact of adjunctive immune modulation, using a phosphodiesterase-4 inhibitor that dampens the innate immune response, on the outcome of treatment with the antibiotic isoniazid. Our data show that cotreatment of M. tuberculosis infected rabbits with the phosphodiesterase-4 inhibitor CC-3052 plus isoniazid significantly reduced the extent of immune pathogenesis, compared with antibiotic alone, as determined by histologic analysis of infected tissues and the expression of genes involved in inflammation, fibrosis, and wound healing in the lungs. Combined treatment with an antibiotic and CC-3052 not only lessened disease but also improved bacterial clearance from the lungs. These findings support the potential for adjunctive immune modulation to improve the treatment of pulmonary TB and reduce the risk of chronic respiratory impairment.
authors.affiliation: Laboratory of Mycobacterial Immunity and Pathogenesis, The Public Health Research Institute at the University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Subbian
authors.forename: Liana
authors.initials: L
authors.lastname: Tsenova
authors.forename: Paul
authors.initials: P
authors.lastname: O'Brien
authors.forename: Guibin
authors.initials: G
authors.lastname: Yang
authors.forename: Mi-Sun
authors.initials: MS
authors.lastname: Koo
authors.forename: Blas
authors.initials: B
authors.lastname: Peixoto
authors.forename: Dorothy
authors.initials: D
authors.lastname: Fallows
authors.forename: Jerome B
authors.initials: JB
authors.lastname: Zeldis
authors.forename: George
authors.initials: G
authors.lastname: Muller
authors.forename: Gilla
authors.initials: G
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D015153:Blotting, Western; D003114:Colony-Forming Units Assay; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry* / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D007538:Isoniazid / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000473:pathology*; D008262:Macrophage Activation / Q000187:drug effects*; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000472:pathogenicity; D058988:Phosphodiesterase 4 Inhibitors / Q000627:therapeutic use; D011658:Pulmonary Fibrosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000235:genetics; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013792:Thalidomide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D014397:Tuberculosis, Pulmonary / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000995:Antitubercular Agents; C115112:CC 3052; D016207:Cytokines; D058988:Phosphodiesterase 4 Inhibitors; D012333:RNA, Messenger; D013792:Thalidomide; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020782:Matrix Metalloproteinases; D007538:Isoniazid