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The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis
Bintou A. Ahidjo, … , Sanjay Jain, William R. Bishai
Bintou A. Ahidjo, … , Sanjay Jain, William R. Bishai
Published September 8, 2016
Citation Information: JCI Insight. 2016;1(14):e86017. https://doi.org/10.1172/jci.insight.86017.
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Research Article Infectious disease Therapeutics

The antifibrotic drug pirfenidone promotes pulmonary cavitation and drug resistance in a mouse model of chronic tuberculosis

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Abstract

Pirfenidone is a recently approved antifibrotic drug for the treatment of idiopathic pulmonary fibrosis (IPF). Because tuberculosis (TB) is characterized by granulomatous inflammation in conjunction with parenchymal destruction and replacement fibrosis, we sought to determine whether the addition of pirfenidone as an adjunctive, host-directed therapy provides a beneficial effect during antimicrobial treatment of TB. We hypothesized that pirfenidone’s antiinflammatory and antifibrotic properties would reduce inflammatory lung damage and increase antimicrobial drug penetration in granulomas to accelerate treatment response. The effectiveness of adjunctive pirfenidone during TB drug therapy was evaluated using a murine model of chronic TB. Mice treated with standard therapy 2HRZ/4HR (H, isoniazid; R, rifampin; and Z, pyrazinamide) were compared with 2 alternative regimens containing pirfenidone (Pf) (2HRZPf/4HRPf and 2HRZPf/4HR). Contrary to our hypothesis, adjunctive pirfenidone use leads to reduced bacterial clearance and increased relapse rates. This treatment failure is closely associated with the emergence of isoniazid monoresistant bacilli, increased cavitation, and significant lung pathology. While antifibrotic agents may eventually be used as part of adjunctive host-directed therapy of TB, this study clearly demonstrates that caution must be exercised. Moreover, as pirfenidone becomes more widely used in clinical practice, increased patient monitoring would be required in endemic TB settings.

Authors

Bintou A. Ahidjo, Mariama C. Maiga, Elizabeth A. Ihms, Mamoudou Maiga, Alvaro A. Ordonez, Laurene S. Cheung, Sarah Beck, Bruno B. Andrade, Sanjay Jain, William R. Bishai

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Figure 1

Effect of pirfenidone on Mtb-infected C3HeB/FeJ mice as assessed by MMP levels, cytokine levels, and colony forming units.

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Effect of pirfenidone on Mtb-infected C3HeB/FeJ mice as assessed by MMP ...
(A) MMPSense 680, a fluorescent in vivo imaging agent activated by MMPs, was used to assess MMP activity in n ≥ 2 mice per group. As per the manufacturer’s experimental protocol, the higher the intensity the greater the MMP activity. (B) Lung cytokines assessed by ELISA represent mean (± SD) from n ≥ 3 mice per group. For comparison between treatment groups, cytokines were analyzed by 2-way ANOVA with post-hoc Tukey honest significant difference (HSD) tests. For comparison within treatment groups, cytokines were analyzed by 1-way ANOVA with post-hoc Sidak tests. All measures of variations are expressed as ± SD. (C) Lung colony forming units (CFU); data represent the mean ± SD from n ≥ 5 mice. Lung CFU counts (x) were log-transformed as log10 (x + 1) prior to analysis and 1-way ANOVA tests used to determine statistical significance between the groups. Pf, pirfenidone; ND, not determined. *P < 0.05.

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