The Treated Pulmonary Lesion and Its Tubercle Bacillus I. Pathology and Pathogenesis

We, Loring; Hm, Vandiviere

doi:10.1097/00000441-195607000-00005

Cited by 8 publications

(4 citation statements)

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“…Tuberculosis can be triggered from subclinical latent infection by treatments for inflammatory disorders that block TNF-α (3,4) or failing CD4 + T cell immunity associated with HIV infection (5). During disease, multiple granuloma phenotypes, including solid nonnecrotizing and caseous necrotic granulomas are present in the lung (6,7). Events governing granuloma development during tuberculosis remain ill defined.…”

Section: Introductionmentioning

confidence: 99%

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Reece¹,

Loddenkemper²,

Askew³

et al. 2010

J. Clin. Invest.

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The hallmark of human Mycobacterium tuberculosis infection is the presence of lung granulomas. Lung granulomas can have different phenotypes, with caseous necrosis and hypoxia present within these structures during active tuberculosis. Production of NO by the inducible host enzyme NOS2 is a key antimycobacterial defense mechanism that requires oxygen as a substrate; it is therefore likely to perform inefficiently in hypoxic regions of granulomas in which M. tuberculosis persists. Here we have used Nos2 -/-mice to investigate host-protective mechanisms within hypoxic granulomas and identified a role for host serine proteases in hypoxic granulomas in determining outcome of disease. Nos2 -/-mice reproduced human-like granulomas in the lung when infected with M. tuberculosis in the ear dermis. The granulomas were hypoxic and contained large amounts of the serine protease cathepsin G and clade B serine protease inhibitors (serpins). Extrinsic inhibition of serine protease activity in vivo resulted in distorted granuloma structure, extensive hypoxia, and increased bacterial growth in this model. These data suggest that serine protease activity acts as a protective mechanism within hypoxic regions of lung granulomas and present a potential new strategy for the treatment of tuberculosis.

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Section: Introductionmentioning

confidence: 99%

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Reece¹,

Loddenkemper²,

Askew³

et al. 2010

J. Clin. Invest.

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“…Active human pulmonary tuberculosis (TB) is a chronic, complex disease in which patients present a diverse spectrum of lesions ranging from diffuse areas of inflammation and swelling of alveoli to caseous, highly organized granulomas and open cavities in intimate contact with the airways (9,25). Computed tomography (CT) has been used to study defined types of lesions and the rate of response of such lesions to chemotherapy.…”

mentioning

confidence: 99%

“…Studies on surgically removed tissues have revealed that most TB lesions contain surprisingly few bacilli, except for the surfaces of open cavities (19,25,41). Cavities are the best-oxygenated TB lesions, and most have the same oxygen tension as the communicating bronchi at apparently normal atmospheric oxygen tension (15).…”

mentioning

confidence: 99%

Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

et al. 2008

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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.Active human pulmonary tuberculosis (TB) is a chronic, complex disease in which patients present a diverse spectrum of lesions ranging from diffuse areas of inflammation and swelling of alveoli to caseous, highly organized granulomas and open cavities in intimate contact with the airways (9, 25). Computed tomography (CT) has been used to study defined types of lesions and the rate of response of such lesions to chemotherapy. Open cavities, caseous lesions, centrilobular densities (i.e., nodules or branching linear structures of 2 to 4 mm in length that are well separated from the pleural surface or the septum between pulmonary lobes), ground-glass opacities, and tissue consolidations are all apparent in active tuberculosis patients by use of this technique (17,24,30). The most comprehensive study of CT findings during TB chemotherapy was that of Im and colleagues (17), who studied CT scans of patients undergoing TB chemotherapy for up to 20 months and then compared their findings with postmortem autopsy results to assist in interpretation. In this study there were significant differences in the rates at which different lesion types responded to chemotherapy.Surgical lung resection has been employed periodically as salvage therapy for patients who have failed chemotherapeutic treatment, and the resected tissues have proven useful for studying the heterogeneity of lesions that can occur within a single infected person (19,40,41). Studies on surgically removed tissues have revealed that most TB lesi...

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“…Imaging of pulmonary tuberculosis using computed tomography and examination of surgically resected pulmonary lesions have revealed the histological heterogeneity of lesions that can occur within a single infected individual [10][11][12][13]. Most of these tuberculous lesions, including caseous lesions, cavities and centrilobular opacities, have been thought to harbor the pathogen [14]. However, the finding that M. tuberculosis DNA is present not only in macrophages within tuberculous lesions, but also in other non-professional phagocytic cells in normal lung tissue contradicts the dominant view that latent organisms exist only in old, classical tuberculous lesions [15].…”

Section: Introductionmentioning

confidence: 99%

Adaptation of Mycobacteria on Solid, Egg-Based Media to Anaerobic Conditions and Characterization of Their Diagnostic Phenotypes

Udou

2013

J UOEH

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: Recent evidence indicates that human pulmonary tuberculous granulomas are hypoxic, and a related dormancy model has been established for Mycobacterium tuberculosis using liquid media in tightly sealed tubes. In the present study, we examined the growth capacity of various mycobacterial species on solid, egg-based media under oxygen-limited conditions. During primary anaerobic cultivation on an Ogawa egg-based medium, all of the inoculated mycobacterial strains persisted for 10 weeks without detectable colony formation on the surface of the medium. Because these anaerobic cultures were restored and possessed the capacity to grow within 3 weeks following transfer to microaerobic conditions (5% or 10% oxygen tension), it was evident that the organisms persisted in a non-replicative dormant state as seen with anaerobic cultures in liquid media. The colonies grown under microaerobic conditions were also capable of growth under anaerobic conditions. Anaerobic growth could be observed only when the microaerobically grown colonies were subcultured under anaerobic conditions, suggesting that preliminary adaptation to the environment under reduced oxygen tensions is an essential process to enable growth under anaerobic conditions. A similar mode of anaerobic growth on slants of an egg-based medium was also observed with clinical isolates of M. tuberculosis. All of the clones that were adapted to grow in the anaerobic environments retained their species-specific colonial morphologic features, while, among the biochemical characteristics tested, heat-stable catalase activity and niacin accumulation in the medium disappeared during adaptation to anaerobic growth. Based on these results, we conclude that egg-based media actively support the anaerobiosis of mycobacteria exhibiting either a non-replicative dormant state or anaerobic growth, both of which are associated with latency and reactivation of tuberculosis. It was also evident that the use of egg-based media would be of great advantage in the diagnostic characterization of the reactivated clones of mycobacteria.

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The Treated Pulmonary Lesion and Its Tubercle Bacillus I. Pathology and Pathogenesis

Cited by 8 publications

References 0 publications

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Serine protease activity contributes to control of Mycobacterium tuberculosis in hypoxic lung granulomas in mice

Tuberculous Granulomas Are Hypoxic in Guinea Pigs, Rabbits, and Nonhuman Primates

Adaptation of Mycobacteria on Solid, Egg-Based Media to Anaerobic Conditions and Characterization of Their Diagnostic Phenotypes

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