Abstract
The development of granulomatous inflammation with caseous necrosis is an important but poorly understood manifestation of tuberculosis in humans and some animal models. In this study we measured the byproducts of oxidative stress in granulomatous lesions as well as the systemic antioxidant capacity of BCG vaccinated and non-vaccinated guinea pigs experimentally infected with Mycobacterium tuberculosis. In non-vaccinated guinea pigs, oxidative stress was evident within 2 weeks of infection as measured by a decrease in the serum total antioxidant capacity and blood glutathione levels accompanied by an increase in malondialdehyde, a byproduct of lipid peroxidation, within lesions. Despite a decrease in total and reduced blood glutathione concentrations, there was an increase in lesion glutathione by immunohistochemistry in response to localized oxidative stress. In addition there was an increase in the expression of the host transcription factor nuclear erythroid 2 p45-related factor 2 (Nrf2), which regulates several protein and non-proteins antioxidants, including glutathione. Despite the increase in cytoplasmic expression of Nrf2, immunohistochemical staining revealed a defect in Nrf2 nuclear translocation within granulomatous lesions as well as a decrease in the expression of the Nrf2-regulated antioxidant protein NQO1. Treating M. tuberculosis–infected guinea pigs with the antioxidant drug N-acetyl cysteine (NAC) partially restored blood glutathione concentrations and the serum total antioxidant capacity. Treatment with NAC also decreased spleen bacterial counts, as well as decreased the lung and spleen lesion burden and the severity of lesion necrosis. These data suggest that the progressive oxidative stress during experimental tuberculosis in guinea pigs is due in part to a defect in host antioxidant defenses, which, we show here, can be partially restored with antioxidant treatment. These data suggest that the therapeutic strategies that reduce oxidant-mediated tissue damage may be beneficial as an adjunct therapy in the treatment and prevention of tuberculosis in humans.
Highlights
Infections with Mycobacterium tuberculosis, the causative agent of human tuberculosis, is the most common cause of morbidity and mortality in patients with HIV/AIDS and is among the leading causes of death from an infectious agent [1]
There was a statistically significant (p,0.05) increase in MDA expression in M. tuberculosis-infected guinea pig lungs beginning on day 20 of infection that progressed between days 30 and 60 (Figure 1A)
Similar cell phenotypes are seen in the early stages of experimental M. tuberculosis infection in guinea pigs
Summary
Infections with Mycobacterium tuberculosis, the causative agent of human tuberculosis, is the most common cause of morbidity and mortality in patients with HIV/AIDS and is among the leading causes of death from an infectious agent [1]. The continuing spread of tuberculosis is evident from the 2009 figures that estimate the number of newly diagnosed cases of active tuberculosis worldwide to be 9.4 million [2]. Controlling the spread of tuberculosis, in developing countries, has become more challenging by the emergence of multidrug (MDR) and extensively drug-resistant (XDR) strains of bacilli that are refractory to first and second line anti-tuberculosis drugs respectively [3]. The effective treatment of patients for 6 to 9 months with existing drugs is limited in some patients by the complications associated with toxic side effects of combination drug therapy. Development of new anti-tuberculosis drugs or treatment strategies that potentiate the therapeutic value of currently available drugs is urgently needed for global tuberculosis control
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