title: Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates.
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% O(2). 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.
authors.affiliation: Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20852, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Via
authors.forename: P Ling
authors.initials: PL
authors.lastname: Lin
authors.forename: Sonja M
authors.initials: SM
authors.lastname: Ray
authors.forename: Jose
authors.initials: J
authors.lastname: Carrillo
authors.forename: Shannon Sedberry
authors.initials: SS
authors.lastname: Allen
authors.forename: Seok Yong
authors.initials: SY
authors.lastname: Eum
authors.forename: Kimberly
authors.initials: K
authors.lastname: Taylor
authors.forename: Edwin
authors.initials: E
authors.lastname: Klein
authors.forename: Ujjini
authors.initials: U
authors.lastname: Manjunatha
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gonzales
authors.forename: Eun Gae
authors.initials: EG
authors.lastname: Lee
authors.forename: Seung Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: James A
authors.initials: JA
authors.lastname: Raleigh
authors.forename: Sang Nae
authors.initials: SN
authors.lastname: Cho
authors.forename: David N
authors.initials: DN
authors.lastname: McMurray
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
authors.forename: Clifton E
authors.initials: CE
authors.lastname: Barry
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D006099:Granuloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006168:Guinea Pigs; D006801:Humans; D000860:Hypoxia / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008252:Macaca fascicularis; D008795:Metronidazole / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D009593:Nitroimidazoles; D010100:Oxygen / Q000032:analysis / Q000378:metabolism; D011817:Rabbits; D011838:Radiation-Sensitizing Agents; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
chemical_list: D000995:Antitubercular Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D008795:Metronidazole; C033815:pimonidazole; D010100:Oxygen