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.
Highlights
Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide [1]
In early stages of active infection, Th1 cellular immune responses are protective, as interferon gamma (IFNγ) and interleukin 12 (IL-12) induce macrophage activation, allowing bacterial growth control; during late active disease, extensive inflammation leads to a shift toward a Th2 immune response in which IL-4, IL-10, and transforming growth factor-β (TGF-β) induce a local anti-inflammatory and immunosuppressive milieu resulting in poor containment of infection and progression of tissue damage, necrosis, and fibrosis, driving host to death [6]
In our TB murine model, there are two phases, an early phase of approximately 21 days in which the Th1-type response in the lung increases progressively and is predominant at the end of this stage, and the progressive phase that starts at day 28 post-infection in which the Th1 cytokine pattern decreases and the Th2-type response emerges in co-existence with extensive inflammatory infiltrate and progressive pneumonia, as well as an increase in the bacillary loads, which leads the animal to death [6]
Summary
Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide [1]. In early stages of active infection, Th1 cellular immune responses are protective, as interferon gamma (IFNγ) and interleukin 12 (IL-12) induce macrophage activation, allowing bacterial growth control; during late active disease, extensive inflammation leads to a shift toward a Th2 immune response in which IL-4, IL-10, and transforming growth factor-β (TGF-β) induce a local anti-inflammatory and immunosuppressive milieu resulting in poor containment of infection and progression of tissue damage, necrosis, and fibrosis, driving host to death [6] Besides these immunologic features, an intense neuroendocrine response during pulmonary mycobacterial infection creates a complex network of cytokines, hormones, and neurotransmitters that contribute to the outcome of TB pathogenesis [7, 8]
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