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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.
AuthorsSelvakumar Subbian, Liana Tsenova, Paul O'Brien, Guibin Yang, Mi-Sun Koo, Blas Peixoto, Dorothy Fallows, Jerome B Zeldis, George Muller, Gilla Kaplan
JournalThe American journal of pathology (Am J Pathol) Vol. 179 Issue 1 Pg. 289-301 (Jul 2011) ISSN: 1525-2191 [Electronic] United States
PMID21703411 (Publication Type: Journal Article)
CopyrightCopyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Chemical References
  • Antitubercular Agents
  • CC 3052
  • Cytokines
  • Phosphodiesterase 4 Inhibitors
  • RNA, Messenger
  • Thalidomide
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Matrix Metalloproteinases
  • Isoniazid
Topics
  • Animals
  • Antitubercular Agents (therapeutic use)
  • Blotting, Western
  • Colony-Forming Units Assay
  • Cyclic Nucleotide Phosphodiesterases, Type 4 (chemistry, metabolism)
  • Cytokines (metabolism)
  • Drug Synergism
  • Drug Therapy, Combination
  • Female
  • Isoniazid (therapeutic use)
  • Lung (drug effects, pathology)
  • Macrophage Activation (drug effects)
  • Male
  • Matrix Metalloproteinases (metabolism)
  • Mycobacterium tuberculosis (pathogenicity)
  • Phosphodiesterase 4 Inhibitors (therapeutic use)
  • Pulmonary Fibrosis (enzymology, pathology, prevention & control)
  • RNA, Messenger (genetics)
  • Rabbits
  • Reverse Transcriptase Polymerase Chain Reaction
  • Thalidomide (analogs & derivatives, therapeutic use)
  • Tuberculosis, Pulmonary (enzymology, pathology, prevention & control)

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