Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates.
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.
Via
Laura E
LE
Tuberculosis Research Section, Laboratory of Clinical Infectious Disease, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD 20852, USA.
Lin
P Ling
PL
Ray
Sonja M
SM
Carrillo
Jose
J
Allen
Shannon Sedberry
SS
Eum
Seok Yong
SY
Taylor
Kimberly
K
Klein
Edwin
E
Manjunatha
Ujjini
U
Gonzales
Jacqueline
J
Lee
Eun Gae
EG
Park
Seung Kyu
SK
Raleigh
James A
JA
Cho
Sang Nae
SN
McMurray
David N
DN
Flynn
JoAnne L
JL
Barry
Clifton E
CE
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
D000995:Antitubercular Agents; D009593:Nitroimidazoles; D011838:Radiation-Sensitizing Agents; D008795:Metronidazole; C033815:pimonidazole; D010100:Oxygen