Abstract
BackgroundTuberculosis (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.MethodsHematoxylin 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.ResultsTGFβ 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.ConclusionsTissue 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13069-016-0043-3) contains supplementary material, which is available to authorized users.
Highlights
Tuberculosis (TB) chemotherapy clears bacterial burden in the lungs of patients and allows the tuberculous lesions to heal through a fibrotic process
Macrophages experience spindloid transformation in tuberculous granulomas After the original uptake of mycobacterial organisms by macrophages, a chemokine and cytokine cascade leads to monocyte recruitment, differentiation of macrophages, and epithelioid transformation
We found that caseous granulomas from animals with active, untreated disease contained strongly staining fibrils of collagen I that could be visualized in the central region of the lesion while pSMAD-2/3+ and CD163+ cells were present along the periphery of the structure (Fig. 3a)
Summary
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. Granulomas, the pathologic hallmark of TB, are well-circumscribed organized collections of host immune cells that form in DiFazio et al Fibrogenesis & Tissue Repair (2016) 9:6 caseum [5]. Uncontrolled replication leads to dissemination of the bacteria and formation of new granulomas. Some granulomas can restrain bacterial dissemination or even develop locally sterilizing immunity. As a result, these granulomas are often fibrotic and can contain a calcified core (referred to as fibrocalcific lesions) [6]. The host factors that lead to control or dissemination of a single granuloma are unclear, we have demonstrated that various types of granulomas and outcomes exist within a single nonhuman primate, similar to humans [6, 8]
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