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. 2019 Jun 6:10:351.
doi: 10.3389/fendo.2019.00351. eCollection 2019.

Involvement of Vasopressin in the Pathogenesis of Pulmonary Tuberculosis: A New Therapeutic Target?

Mario Zetter  1 , Jorge Barrios-Payán  1 , Dulce Mata-Espinosa  1 , Brenda Marquina-Castillo  1 , Andrés Quintanar-Stephano  2 , Rogelio Hernández-Pando  1
Affiliations

Involvement of Vasopressin in the Pathogenesis of Pulmonary Tuberculosis: A New Therapeutic Target?

Mario Zetter et al. Front Endocrinol (Lausanne). .

Abstract

Tuberculosis (TB) is a highly complex infectious disease caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb). It is characterized by chronic granulomatous inflammation of the lung and systemic immune-neuroendocrine responses that have been associated with pathophysiology and disease outcome. Vasopressin (VP), a neurohypophysial hormone with immunomodulatory effects, is abnormally high in plasma of some patients with pulmonary TB, and is apparently produced ectopically. In this study, a BALB/c mouse model of progressive pulmonary TB was used to determine whether VP may play a role in TB pathophysiology. Our results show that VP gene is expressed in the lung since early infection, increasing as the infection progressed, and localized mainly in macrophages, which are key cells in mycobacterial elimination. Pharmacologic manipulation using agonist and antagonist compounds showed that high and sustained stimulation of VPR resulted in increased bacillary burdens and fibrosis at lungs, while blockade of VP receptors reduced bacterial loads. Accordingly, treatment of infected alveolar macrophages with VP in cell cultures resulted in high numbers of intracellular Mtb and impaired cytokine production. Thus, we show that VP is ectopically produced in the tuberculous lungs, with macrophages being its most possible target cell. Further, it seems that chronic vasopressinergic stimulation during active late disease causes anti-inflammatory and tissue reparative effects, which could be deleterious while its pharmacologic suppression reactivates protective immunity and contributes to shorten conventional chemotherapy, which could be a new possible form of immune-endocrine therapy.

Keywords: fibrosis; immunopathology; lung; therapy; tuberculosis; vasopressin.

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Figures

Figure 1
Figure 1
Local kinetics of VP expression and VPR during pulmonary tuberculosis (A) Absolute expression of VP mRNA in lung homogenates during the course of infection. (B) Representative micrographs of immunohistochemistry with anti-VP antibody of the infected lung on day 14 showing immunopositive macrophages forming a granuloma (400×). As well as in foamy macrophages of pneumonic areas on day 60 post-infection (C). (D,E) Absolute quantification of V1a and V2 mRNA, respectively, in lungs of healthy (control) and infected mice. Data are expressed as means ± SD of three different animals at each point. Asterisks represent statistical significance (***P < 0.0001, one-tailed ANOVA).
Figure 2
Figure 2
Effect of vasopressin agonism during early and late infection in bacilli loads and histopathology (A) Bacillary loads of lung homogenates of mice infected with M. tuberculosis strain H37Rv and treated with DdAVP twice a day during early infection. (B) Bacillary loads at lungs of mice treated during late infection, starting from day 60 onwards. (C) Representative Masson's trichrome stain micrographs of lung of control-infected (left) and DdAVP-treated infected mice (right) on day 120 post-infection. (D) Collagen amount in lungs of infected mice treated during the late infection quantified by hydroxyproline assay. (E) Representative micrographs of lung immunohistochemistry anti-TGF-β1 of control-infected (left) and DdAVP-infected (right) mice after 60 days of treatment. (F) Relative expression of TGF-β mRNA in lungs of infected mice treated with DdAVP during the late infection. Days 75, 90, and 120 of infection correspond to 15, 30, and 60 days of treatment, respectively. Data are expressed as means ± SD of three different animals at each point. Asterisk represent statistical significance (*P < 0.05, two-way ANOVA).
Figure 3
Figure 3
Blockade of VP receptors decreased bacillary loads at lung. (A) Comparison of bacillary loads at lung homogenates of control mice treated with vehicle (black-filled bars) and treated with CVP (lined bars) from day 60. (B) Effect on bacillary loads of vehicle treated (black-filled bars), CVP (lined bars), the three antibiotics (AB, Rifampicin, Isoniazide, and Ethambutol, gray filled bars) and antibiotics plus CVP (AB + CVP, white bars), during late infection, from day 60. (C) Pneumonic areas of the infected lungs of mice treated with the different experimental conditions. (D–G) Representative micrographs of automatized reconstruction of infected lungs from vehicle, CVP, AB, and CVP plus AB, respectively. Days 75, 90, and 120 of infection correspond to 15, 30, and 60 days of treatment, respectively. Data are expressed as means ± SD of three different animals at each point. Asterisk represent statistical significance (*P < 0.05, two-way ANOVA).
Figure 4
Figure 4
Effects of VP and antagonist CVP on infected alveolar macrophages. (A) Number of cultivable intracellular bacilli expressed as CFU per milliliter at 1 and 24 h post-infection in RPMI controls (black bars), incubated with three different doses of DdAVP (1 × 10−8 M, white bars; 1 × 10−7 M gray bars, and 1 × 10−6 M dark gray bars) or CVP (1 × 10−6 M, lined bars). (B) Effect of VP or CVP on mycobacterial killing by MHS cells at 24 and 72 h post-infection. (C) Quantification of IL-6 and TNFα (D) in pools of supernatants of infected MHS cells detected by ELISA. Data are expressed as means ± SEM of three different wells at each point. Asterisk represent statistical significance (*P < 0.05, two-way ANOVA).
Figure 5
Figure 5
Effects of VP on mycobacterial metabolism. (A) Reduction of MTS tetrazolium salts into colored compound formazan by Mtb H37Rv incubated in liquid 7H10 (black bars), medium plus DdAVP (clear gray bars), or medium plus VP (dark gray bars) for 7 days. (B) Number of cultivable bacilli in wells of the three experimental conditions. Data are expressed as means ± SD of three wells in two independent experiments. Asterisk represent statistical significance (***P < 0.001, ****P < 0.0001 two-way ANOVA.
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