title: Active transforming growth factor-β is associated with phenotypic changes in granulomas after drug treatment in pulmonary tuberculosis.
abstract: 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.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA.
authors.forename: Robert M
authors.initials: RM
authors.lastname: DiFazio
authors.affiliation: Department of Infectious Diseases and Microbiology, Pitt Public Health, University of Pittsburgh, Pittsburgh, PA 15261 USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mattila
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA 15261 USA.
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Klein
authors.affiliation: University of Pittsburgh School of Pharmacy, Pittsburgh, PA 15261 USA.
authors.forename: Lauren R
authors.initials: LR
authors.lastname: Cirrincione
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA.
authors.forename: Mondraya
authors.initials: M
authors.lastname: Howard
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA.
authors.forename: Eileen A
authors.initials: EA
authors.lastname: Wong
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261 USA.
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
keywords: Collagen I; Drug treatment; Transforming growth factor-β; Tuberculosis