Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates
By Barry Iii Cho, D. Mcmurray, J. Flynn, Clifton E Gae Lee, S. Park, J. Raleigh, S. Nae, E. Klein, U. Manjunatha, Jacqueline Gonzales and 8 more. Infection and Immunity, 2008
637 citations recorded by the source corpus.
ABSTRACT Understanding the physical characteristics of the local microenvironment in which Mycobacterium tuberculosis resides is an important goal that may allow the targeting of metabolic processes to shorten drug regimens. Pimonidazole hydrochloride (Hypoxyprobe) is an imaging agent that is bioreductively activated only under hypoxic conditions in mammalian tissue. We employed this probe to evaluate the oxygen tension in tuberculous granulomas in four animal models of disease: mouse, guinea pig, rabbit, and nonhuman primate. Following infusion of pimonidazole into animals with established infections, lung tissues from the guinea pig, rabbit, and nonhuman primate showed discrete areas of pimonidazole adduct formation surrounding necrotic and caseous regions of pulmonary granulomas by immunohistochemical staining. This labeling could be substantially reduced by housing the animal under an atmosphere of 95% O2. Direct measurement of tissue oxygen partial pressure by surgical insertion of a fiber optic oxygen probe into granulomas in the lungs of living infected rabbits demonstrated that even small (3-mm) pulmonary lesions were severely hypoxic (1.6 ± 0.7 mm Hg). Finally, metronidazole, which has potent bactericidal activity in vitro only under low-oxygen culture conditions, was highly effective at reducing total-lung bacterial burdens in infected rabbits. Thus, three independent lines of evidence support the hypothesis that hypoxic microenvironments are an important feature of some lesions in these animal models of tuberculosis.
Subfields: Epidemiology, Infectious Diseases, Surgery
View Paper: https://www.semanticscholar.org/paper/4dcf8a0a52917a721e9b7025ae592bde965826c6
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In Epidemiology
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In Infectious Diseases
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In Surgery
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Citations in the corpus
- Mycobacterium tuberculosis: Success through dormancy (2012, background): “The role of hypoxia in vivo was impressively analyzed by Via et al. (2008), who introduced the hypoxia-activated compound pimonidazole to different experimental animal species and directly measured oxygen tension in granulomas of guinea pigs, rabbits, and nonhuman primates.”
- The immune response in tuberculosis. (2013, background): “Thus, an interesting line of inquiry is to determine the blood transcriptome in this cavitary model of TB and whether type I IFN–inducible genes are induced, as would be anticipated from studies with HN878 in the mouse model from the same group (24, 99) and from our own studies of the type I and typ”