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Active transforming growth factor-β is associated with phenotypic changes in granulomas after drug treatment in pulmonary tuberculosis

Difazio, RM and Mattila, JT and Klein, EC and Cirrincione, LR and Howard, M and Wong, EA and Flynn, JAL (2016) Active transforming growth factor-β is associated with phenotypic changes in granulomas after drug treatment in pulmonary tuberculosis. DARU, Journal of Pharmaceutical Sciences, 24 (1). ISSN 1560-8115

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© 2016 DiFazio et al. Background: Tuberculosis (TB) chemotherapy clears bacterial burden in the lungs of patients and allows the tuberculous lesions to heal through a fibrotic process. The healing process leaves pulmonary scar tissue that can impair lung function. The goal of this study was to identify fibrotic mediators as a stepping-stone to begin exploring mechanisms of tissue repair in TB. Methods: Hematoxylin and eosin staining and Masson's trichrome stain were utilized to determine levels of collagenization in tuberculous granulomas from non-human primates. Immunohistochemistry was then employed to further interrogate these granulomas for markers associated with fibrogenesis, including transforming growth factor-β (TGFβ), α-smooth muscle actin (αSMA), phosphorylated SMAD-2/3, and CD163. These markers were compared across states of drug treatment using one-way ANOVA, and Pearson's test was used to determine the association of these markers with one another. Results: TGFβ and αSMA were present in granulomas from primates with active TB disease. These molecules were reduced in abundance after TB chemotherapy. Phosphorylated SMAD-2/3, a signaling intermediate of TGFβ, was observed in greater amounts after 1 month of drug treatment than in active disease, suggesting that this particular pathway is blocked in active disease. Collagen production during tissue repair is strongly associated with TGFβ in this model, but not with CD163+ macrophages. Conclusions: Tissue repair and fibrosis in TB that occurs during drug treatment is associated with active TGFβ that is produced during active disease. Further work will identify mechanisms of fibrosis and work towards mitigating lung impairment with treatments that target those mechanisms.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Difazio, RMrod28@pitt.eduROD28
Mattila, JTjmattila@pitt.eduJMATTILA
Klein, ECeklein@pitt.eduEKLEIN
Cirrincione, LR
Howard, M
Wong, EAEAW72@pitt.eduEAW72
Flynn, JAL
Date: 1 January 2016
Date Type: Publication
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Journal or Publication Title: DARU, Journal of Pharmaceutical Sciences
Volume: 24
Number: 1
DOI or Unique Handle: 10.1186/s13069-016-0043-3
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Infectious Diseases and Microbiology
School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
ISSN: 1560-8115
Date Deposited: 22 Jul 2016 17:37
Last Modified: 30 Oct 2018 14:01


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