| Phosphodiesterase-4 inhibition combined with isoniazid treatment of rabbits with pulmonary tuberculosis reduces macrophage activation and lung pathology. | |
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MedLine Citation:
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PMID: 21703411 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Selvakumar Subbian; Liana Tsenova; Paul O'Brien; Guibin Yang; Mi-Sun Koo; Blas Peixoto; Dorothy Fallows; Jerome B Zeldis; George Muller; Gilla Kaplan |
Publication Detail:
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Type: Journal Article Date: 2011-05-07 |
Journal Detail:
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Title: The American journal of pathology Volume: 179 ISSN: 1525-2191 ISO Abbreviation: Am. J. Pathol. Publication Date: 2011 Jul |
Date Detail:
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Created Date: 2011-06-27 Completed Date: 2011-10-28 Revised Date: 2012-02-15 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: United States |
Other Details:
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Languages: eng Pagination: 289-301 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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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. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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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* |
| Grant Support | |
ID/Acronym/Agency:
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R01 AI054338-11/AI/NIAID NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antitubercular Agents; 0/CC 3052; 0/Cytokines; 0/Phosphodiesterase 4 Inhibitors; 0/RNA, Messenger; 50-35-1/Thalidomide; 54-85-3/Isoniazid; EC 3.1.4.17/Cyclic Nucleotide Phosphodiesterases, Type 4; EC 3.4.24.-/Matrix Metalloproteinases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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